Aldrichimica Acta

Volume 12, Number 1, 1979 Volume 12 Number 1 1979

Boranes for Organic Reductions. See Page 3.

Trialkylborohydrides in Organometallic Syntheses. See Page 13.
chemists helping chemists m research 6 industry

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Aldrichimica
Volume 12, Number 1, 1979
A publication of ALDRICH CHEMICAL COMPANY, INC.

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Aldrichimica Acta, Vol. 12, No. I, 1979 1

 For years I used the Fieser Molecular chamois. Hold the syringe near the bottom
Models now supplied by you.I feel they are of a small beaker, as extremely fine jets of
probably the best models for class mercury squirt in all directions. The
demonstration. However, there is one residue can be shaken out of the syringe.
feature that I have had to change to meet This device is inexpensive, very effective,
my needs: no carbonyl. and will last for years.
I make a carbonyl by breaking apart a William D. Murray
C=C at a "joint " then gluing on the red Environmental Engineer
oxygen piece. I remove the aluminum AMP Inc.
bonding tube and cut off the long, red Harrisburg, PA 17105
bonding projection. This piece is dissolved Frequently a laboratory worker wishes
to clean some mercury for purposes such as
filling manometers, McLeod gauges, etc. Any interesting shortcut or laboratory hint
Although a preliminary cleaning may be you'd like to share with A CTA readers?
achieved by allowing the mercury to trickle Send it to Aldrich (attn:Lab Notes) and if
through a pin hole in a piece of filter paper we publish it, you will receive a handsome
red and white ceramic Aldrich coffee mug
as well as a copy of Selections from the
shaped into a cone, this method is often
Bader Collection (see"About Our Cover").
time-consuming and does not remove all
impurities.
We reserve the right to retain all entriesfor
A preferable technique with respect to consideration for future publication.
both speed and cleanliness is to draw the
mercury through the pores of a piece of
wood (a 6-in. section of a broomstick
works well) using an arrangement similar
in methylene chloride to paint over some of to that shown in the diagram.

�g
the black of my new carbonyl to enhance
the red color on that end.
-Rubber tubing wired tightly to
wood to hold Hg supply
James W. Hill -wood
Professor of Chemistry
Panhandle State University
Goodwell, OK 73939

Editor's Note: Various modifications of the

Fieser molecular models to give other func­
tional groups are discussed by Prof. Fieser The mercury cleaned in this manner can
in J. Chem Educ., 42, 408 (1965). Prof. be used for all purposes except those re­
quiring the purity achieved with triple dis­
Fieser recommended cutting a double
tillation.
bond into two to produce two carbonyl
groups. Arden P. Zipp
Chairman & Professor
Chemistry Department Dr. Dieter M. Kramsch of the Boston
} paint red State University of New York University School of Medicine called me
College at Cortland recently to ask whether we could lower our
Cortland, New York 13045
price substantially for 5-methyl-2-thio­
phenecarboxylic acid in large quantities.
Mercury may be cleaned and dried by Dr. Kramsch and his associates have
forcing it through a piece of chamois. Cut found I that this acid prevents hardening of
off the end of a IO- or 20-cc plastic the arteries in rabbits. They now want to
hypodermic syringe and slightly flare the study this effect in monkeys and, of course,
A carbonyl model may also be con­ end of the barrel.Firmly tie a small piece of need larger amounts.We had been making
tructed by following Fieser's directions for chamois over the barrel, using Nichrome or small quantities only, but our preparation
a carbonium ion. The resulting planar Chrome! wire. Remove the plunger, pour could be scaled up. Naturally, we wanted to
structure resembles a Dreiding carbonyl in the mercury, replace the plunger and help, particularly in an application that
model if one arm is painted red. force the mercury slowly through the might become so important. Hence we
quoted much lower prices for kilo quan­
c - - paint red tities,received the order and filled it rapid­
ly.
It was no bother at all, just a pleasure to
be able to help.
I) C.T. Chan, H. Wells, and D.M.
Kramsch, Circulation Res., 43, 115
( 1978).
M8,442-9 5-Methyl-2-thiophenecar­
boxylic acid, 99% .......•........ IOg $25.35
Kilo: Inquire
2 Aldrichimica Acta, Vol. 12, No. 1, 1979
 Boranes For Organic Reductions­
A Forty-Vear Od�y1
Boranes For Organic Reductions - A Forty-Year Odyssey
Herbert C. Brown Herbert C. Brown
S. Krishnamurthy and S. Krishnamurthy
Richard B. Wetherill Laboratory Richard B. Wetherill Laboratory
Purdue university Purdue University
West lafayette Indiana 47907
West Lafayette, Indiana 47907

more general, improved procedure for the

reduction of aldehydes and ketones to the
corresponding carbinols.8 ~12 Similarly, the
Bouveault-Blanc method enabled the
reduction of carboxylic acid esters to the
corresponding alcohols.13
The nonhydridic reduction procedures
for the reduction of carbonyl groups often
required elevated temperatures and long
reaction times and resulted in low yields of
the desired products. However, the dis­
covery of boron hydride reducing agents
has dramatically changed the situation, not
only for the reduction of carbonyl groups,
but for reduction of a wide variety of other
organic functional groups.
II. THE DISCOVERY OF
BORON HYDRIDES AS
REDUCING AGENTS.
HISTORICAL
DEVELOPMENTS
In 1936 there was considerable discus­
sion about the structure of borane­
I. INTRODUCTION time to summarize the progress of these carbonyl, then recently synthesized by
forty years in the application of borane and Professor H.I. Schlesinger and Dr. A.B.
In 1939 there appeared a publication in borohydride reducing agents.
the March issue of the Journal of the Burg at the University ofChicago(eq. 2).14
American Chemical Society, "Hydrides of Before the discovery of hydrides as 1/2 (BH3h
reducing agents for the reduction of
+ CO � H 3B : CO (eq. 2)
Boron. XI. The Reaction of Diborane with
Organic Compounds Containing a Car­ organic functional groups, there were It was suggested that the senior author,
bonyl Group," by H.C. Brown, H.I. available a number of nonhydridic reduc­ then a new graduate student at the Univer­
Schlesinger, and AB. Burg.2 This is the tion procedures to achieve such transfor­ sity of Chicago, undertake a study of the
first report of the application of a hydride mations. Thus, the reduction of aldehydcs reaction of diborane with aldehydes and
for the reduction of organic functional to the corresponding alcohols was achieved ketones in the hope that the results would
groups. by a variety of metal-acid (zinc dust + contribute to the better understanding of
acetic acid, sodium amalgam + acetic acid, the structure of borane-carbonyl. Soon it
Forty years have elapsed since this
iron + acetic acid, etc.) procedures (eq. I). 5 was discovered that aldehydes and ketones
original report. This observation initiated
Fe, HOAc react rapidly with diborane at 0° (or even at
rapid progress in the development of new CH3(CH2)sCHO
-78° ); hydrolysis of the resulting dialkoxy­
boron hydride reducing agents and in the (eq. 1)
6hr, 100 °
borane yielded the corresponding alcohol
exploration of their scope and applications (eqs. 3 and 4).2
CH3(CH2)sCH2OH 80%

in organic synthesis. These developments The corresponding reduction of ketone to

have revolutionized the procedures for the alcohol was achieved by sodium in ethanol 2 R 2CO + % (BH3 h _.
or zinc-sodium hydroxide in ethanol. 6- 7
(eq. 3)
regio-, stereo-, and chemoselective re­
(R2CHOhBH

duction of various organic functional The dis cov ery of the Meerwein­ (R2CHOhBH + 3 H 2O -
groups.3.4 It appears appropriate at this
(eq. 4)
Ponndorf-Verley reduction introduced a 2 R2CHOH + H2 + B(OHh

Aldrichimica Acta, Vol. 12, No. 1, 1979 3

 However, interest in this new development AICl 3 + 3 NaBH4 tivities towards various organic functional
(eq. 13)
among organic chemists was minimal Al(BH 4)al + 3 NaCl groups, reagents possessing a high degree
because diborane was a chemical rarity, of selectivity. Accordingly, we undertook a
available only in milligram quantities At this point ( 1943), the Sign al Corps program of research on "Selective Reduc­
through complex preparative proce­ became interested in the new compound, tions" to explore these possibilities. The
dures. 15-11 sodium borohydride (eq. 12), for the field reducing characteristics of the parent
The situation was soon altered by generation of hydrogen. Further research hydride, sodium borohydride, could be
pressures of World War II. The National under their sponsorship led to an improved modified by various means, such as varying
Defense Agency was interested in new method for the synthesis of sodium the cation in the complex hydride, in­
volatile uranium eompounds with as low borohydride, the basis of the present U. S. troduction of substituents ( alkyl or alkoxy)
industrial process for this chemical (eq. in the complex ion that would exert mark­
molecular weights as possible. Ura­
14). 26 ed steric and electronic influences upon the
nium(IV) borohydride appeared to be a
4 NaH B(OCH3)a �
suitable candidate in meeting these require­ reactivity of the parent ion, etc. Yet
(eq. 14)
+
another approach would be the develop­
ments. Accordingly, it was decided to un­ NaBH4 + 3 NaOCH 3
dertake the preparation of uranium boro­ ment of acidic reducing agents such as
The reaction provides a mixture of two borane and its substituted derivatives
hydride from aluminum borohydride.1s-20
solids, sodium borohydride and sodium (alkylboranes , alkoxy boranes, halo­
Indeed, this was successful and the
methoxide. Acetone was among the boranes, etc.). In the following section we
chemical proved to be volatile (eq. 5). 21
solvents tested for the separation of these shall discuss the evolution of various new
UF4
(eq. 5)
+ two components. With acetone, a vigorous boron hydrides as selective reducing agents
U(8H4 )4 1 + 2 AIF2(BH4)1
2Al(8H4'3 -
reaction was observed. Hydrolysis of the and their utility in organic synthetic
reaction mixture indicated the absence of transformations.
This development led to the need for con­
any active hydrogen and the presence of
siderable quantities of uranium boro­ IV. EVOLUTION OF
four moles of isopropyl alcohol per mole of
hydride for large-scale testing. VARIOUS BORON
sodium borohydridc. In this way it was dis­
The development of practical proce­ covered that sodium borohydride was a
HYDRIDE REAGENTS
dures for the synthesis of diborane (ingre­ valuable new reagent for the hydrogena­
AND THEIR
dient in the synthesis of aluminum boro­ tion of organic molecules (eq. 15).
APPLICABILITY
NaBH4 + 4 (CH3)iC=O
hydride) was stimulated by this require­ I. Sodium borohydride
ment. Indeed, such routes to diborane2 2 Sodium borohydride is a very mild
and lithium borohydride23 were developed NaB[OCH(CH3)i ] 4 � (eq. 15) reducing agent, insoluble in ethyl ether,
from lithium hydride and boron trifluor­ NaB(OH)4 + 4 (CH 3)i CHOH only slightly soluble in tetrahydrofuran,
ide. These intermediates could be readily The alkali metal hydride route was later but readily soluble in diglyme and tri­
utilized for the synthesis of uranium boro­ successfully extended to the synthesis of glyme. 30 In hydroxylic solvents, it reduces
hydride (eqs. 6-9). 24 lithium aluminum hydride (eqs. 16- 18).27 aldehydes and ketones rapidly at 25 ° , but is
essentially inert to the other organic func­
6LIH + 8 BF 3 :OEt2 � (eq. 6) 4LiH + AICl3 � (eq. 16) tional groups. The reductions can be
(BHahf + 6 LiBF4 LiAIH4 + 3LiCI
carried out in aqueous solutions (basic),
3LiAIH4 + AICI3 ethanol, or 2-propanol (eq. 19).
(eq. 17) 4 R 2CO NaBH4 -
4 AIH3 + 3LiCI +
AICla 3 LiBH4 Na[B(OCHR 2)4] ► (eq. 19)
4 AIHa + 4LiH
+ -4 H20

Al(BH4)al + 3 LiCI (eq. 18) NaB(OH) 4 + 4 R 2CHOH

--
(eq. 8)
4 LiAIH4
UF4 + 2Al(BH4h - (eq. 9) In aqueous solvents, sodium borohy­
U(BH4)4 f + 2 AIF2 (BH4 )l III. MODIFICATION OF dride reacts with ionizable alkyl halides to
BOROHYDRIDES
Unfortunately, lithium hydride was in very The discovery of sodium borohydride23 Table I. Comparison of sodium
short supply and could not be spared for in 1942 and of lithium aluminum hyd ridc27 borohydride with lithium
the synthesis of uranium borohydride on a in 1945 brought about a revolutionary aluminum hydride
commercial scale. The supply of sodium change in procedures for the reduction of NaBH4 LiAIH4
hydride was ample. functional groups in organic molecules. 4.28 In in
Although sodium hydride could not be Indeed, numerous major applications have EtOH THF
utilized in the same way, a new sodium appeared for both the reagents and more Aldehyde + +
hydride derivative, sodium trimethoxy­ are still appearing. Lithium aluminum
Ketone + +
R +
borohydride, 2 5 solved the problem and hydride is an exceptionally powerful reduc­
Acid chloride
+
achieved the desired transformations (eqs. ing agent capable of reducing almost all
Lactone

10- 13 ). 22,23
+
organic functional groups.29 Sodium boro­
Epoxide
Ester +
NaH B(OCH3)a -
hydride is an exceptionally mild reducing
(eq. 10)
+ Acid +
NaBH(OCH3)a agent, which rea dily reduces only Acid salt +
aldehydes, ketones, and acid chlorides tert-Amide +
6 Na8H(OCH 3)a 8 BF 3 :OEt 2 -
+ (Table I). The mildness of sodium boro­ Nitrile +
(BHahl + 6 B(OCHahl + (eq. 11) hydride limits its applicability to selective Nitro +
6 NaBF4 + 8 Et 2O reductions involving relatively reactive Olefin
groups. Cons equently, it appeared
NaBH(OCH3 h + 1/i (BH3)i
(+) Rapid reaction

(eq. 12)
desirable to develop various boron hydride
Insignificant reaction

- NaBH4 + B(OCH3h
(-)
R Reaction with solvent
reagents with markedly different reac-

4 Aldrichimica Acta, Vol. 12, No. 1, 1979

give the corresponding hydrocarbons, the addition of an equivalent amount of THF, 25°
proceeding through the intermediacy of solid magnesium chloride to a diglyme KH + (i-PrO)JB
1hr (eq. 30)
carbonium ions (eq. 20)_31 solution of sodium borohydride, brings K(i-PrO)JBH
about the facile reduction of esters ( eqs. 25
and 26). 35 Fortunately, unlike the less hindered de­
NaBH4 ►
rivatives40 (such as sodium trimethoxy­
CHa(CH2) 1 sCOOEt
NaBH.-MgC l2
diglyme, 100° borohydride), triisopropoxyborohydridc
(eq. 25) solutions in THF are quite stable and do
CH3(CH2 ) 15CH 2OH 74% not undergo disproportionation.
OCH3 Potassium triisopropoxyborohydride in
tetrahydrofuran behaves as an excep­
tionally mild reducing agent similar to
(eq. 20) sodium borohydride and lithium tri-tert­
butoxyaluminohydride.42 It reduces only
aldehydes and ketones, being essentially in­
Kollonitsch and coworkers have achieved ert to almost all other organic functional
OCH3 98% rapid reduction of esters by sodium groups. In contrast to the other two mild
borohydride in the presence of magnesium, reagents, the new reagent has the ability to
Recently, sodium borohydride has been introduce major steric control into the
calcium, barium and strontium salts_ir,,37
successfully employed for the reductive reduction of cyclic ketones (eq. 3 1).
Aluminum borohydride is synthesized
deamination of primary amines through
0 0
0�6 = 6" H
their sulfonimide derivatives (eq. 2 1 ). 3 2 by the addition of one equivalent of
aluminum chloride to three equivalents of
NaBH4, HMPT sodium borohydride solution in diglyme.
1so0 , 4hr The reaction mixture remains clear; no (eq. 31)
NaBH 4
precipitation of sodium chloride is observ­
(eq. 21) 31% 69%
ed, indicating an equilibrium38 which must Li(t-BuO)aAIH 27% 73%
favor the reverse reaction (eq. 27). K(i-PrO)aBH 92% 8%
NaN(Tsh AICI3 + 3 NaBH4 � Al(BH 4h + 3 NaCl
(eq. 27) 5. Alkali Metal Trialkylborohydrides43
In recent years, a number of alkali metal
2. Lithium Borohydride Nevertheless, the resulting solutions ex­ trialkylborohydrides have emerged as
Preliminary exploratory studies on the hibit markedly enhanced reducing power highly attractive reducing agents capable
reduction characteristics of lithium and approaching that of lithium aluminum of achieving stereo- and regioselective syn­
sodium borohydrides indicated a marked hydride itself, capable of reducing lactone, thetic transformations, unequalled by any
difference. in their reactivity. 33- 34 Lithium epoxide, carboxylic acid, tert-amide, other reagent currently available. These
borohydride is a more powerful reducing nitrite, etc. The mixture is capable of reagents are soluble in a variety of organic
agent. The reagent can be synthesized con­ hydroborating olefins to the corresponding solvents ( ethyl ether, tetrahydrofuran,
veniently in situ by the addition of an organoboranes. 38 " diglyme, benzene, pentane, etc. ) and are
equivalent quantity of lithium halide to a Zinc borohydride, synthesized from zinc stable indefinitely when stored under
solution of sodium borohydride in diglymc chloride and sodium borohydride in ethyl nitrogen.
or monoglyme (reflux, eq. 22). ether, is useful for the selective reduction of i) Lithium Triethy/borohydride ( Super­
NaBH4 LIBr
a,,8-unsaturated aldehydcs and kctones to
NaBrl (eq.
+ Hydride®)
LiBH4 +
22) the corresponding allylic alcohols (eq. Lithium hydride reacts rapidly and
28). 39 quantitatively with triethylborane in
Lithium borohydride reduces a number
refluxing tetrahydrofuran to give lithium
of representative esters to the correspond­
triethylborohydride in quantitative yield.
ing carbinols quantitatively in 1-3 hr at Zn(BH4 h
The corresponding deuterium derivative is
100° in diglyme.35 Under these conditions, synthesized from lithium deuteride ( eqs. 32
sodium borohydride alone brings only and 33). 44

6
slight reduction of such esters ( eqs. 23 and
THF, 65°
24). LiH + Et 3B LiEt3BH
0_2Shr
100% (eq. 32)
CH 3(CH2 ) 11COOEt
NaBH.-Lisr
diglyme, 100°
(eq. 23) THF, 65°
96% 4% LiD + Et 3B LiEt3BD
1hr
4. Sodium and Potassium Triisopropoxy­ 100% (eq. 33)
CH=CHCOOEt CH=CHCH2OH

0_0
borohydrides Lithium triethylborohydride (Super­
Sodium and potassium triisopropoxy­ Hydride) is an extraordinarily powerful
borohydrides are synthesized from triiso­ reducing agent, far more powerful than
(eq. 24)

V V 9a% propyl borate and sodium or potassium lithium aluminum hydride and lithium
3. Borohydrides Containing Polyvalent hydride (eqs. 29 and 30). 40,41 borohydride. 45 Lithium triethylborohy­
Metal Ions dride is the most powerful nucleophile
NaH + (i-PrO)aB
THF, 67°
Ions of higher ionic potential would be available to organic chemists, considerably
1 70hr (eq. 29)
expected to be even more effective. Thus, more powerful than nucleophiles such as
Na(i-PrO)JBH
magnesium borohydride synthesized by thiophenoxide.

Aldrichimica Acta, Vol. 12, No. 1, 1979 5

 tion of cyclic ketones (eqs. 48-50). 56, 57

6
The reagent is exceptionally useful for

0
6
the facile reductive dehalogenation of alkyl
(eq. 40)
halides. The reaction involves a clean in­
LiEt3BH, THF
M[s-Bu 3 BH]. THF
version at the reaction site (SN 2, eqs. 34- 99%
25 ° , 0.25hr
M=Li , Na, or K
37).45 (eq. 48 )

6
OH

-
O 0
(eq. 34)
65 °
2hr
>99%
(eq. 41)
Br

95%
24hr (oq . 35)
d:; � d:;OH
0 H (eq. 49)
99.6%

¢
H
f 3 65 , 3h r
° Lithium triethylborohydride adds to
C H3 • f- CH 2B r substituted styrenes providing a conve­
nient entry into Markovnikov trialkyl­
(eq. 36)
CH 3
H
f 3 boranes (eq. 42). so
CH 3 •f· CH 3 -78 0 (oq. 50)
CH 3
96%
LiEt3 B H
85%
PhCH=CH 2

L- and K-Selectrides reduce a,,B-enones

(eq. 42) and a,,B-enoates in a conj ugate fashion
( I ,4-reduction). This provides a convenient
Reduction of tertiary amides with method for the generation of enolates
lithium triethylborohydride proceeds with which are trapped with a variety of elec­
(eq. 37) carbon-nitrogen fission producing the cor­ trophiles (eq, 5 1). 58 ,59
responding alcohol (eq. 43)_ 51

Q"
l,OBEt3 7
LiEt3 BH
o
RCONR' 2 K[s-Bu3 BH]
�CHNR_il
li
THF, 0 °
-78°
Lithium triethylborohydride reduces (eq. 43)
epoxides rapidly with remarkable regio­ i
and stereospecificity to give the Markov­ 1 ) Li E!JBH
RCHO
nikov alcohol. The advantage is especially 2) H 20
evident for the reduction of labile bicyclic
COOCHa

epoxides (eq. 38). 46 ii) Lithium and Potassium Tri-sec­ (eq. 51)
butylborohydrides( L- and K-Selectride�)
A number of methods have been l � COOCH3
a, b, or c developed for the quantitative synthesis of 0

(eq. 38) alkali metal trialkylborohydrides carrying

hindered alkyl substituents (eqs. 44-
4 7). 41.44,52-55

s-Bu3 B NaH
T H F , 65 °
(eq. 44)
+
iii) Lithium and Potassium Trisiamyl­
Na[s-Bu 3BH]
3h r

a=LiAIH4 15% 85%

borohydrides ( LS- and KS-Selectrides™ )
It was desirable to achieve the synthesis
b=Li, NH N H2 31% 15%
,,........
s-Bu3 B + KH of a reagent that would reduce even 3- and
THF, 25°
c=LiEt3 BH 93% <0. 1% (eq. 45)
2

K[s-Bu 3 BH] 4-alkylcyclohexanones to the correspond­

0.25hr

Super-Hydride reduces quaternary am­ ing alcohols in a stereoselectivity of 99% or

better. Recently, we have synthesized two
monium salts rapidly and cleanly to the s-Bu3 B LiAIH(OMe)a
THF, 25 °
+ _
corresponding amines in quantitative highly hindered trialkylborohydrides · -
(eq. 45 )
0 25hr
yield. The reagent is remarkable in dis­ Ll[s-Bu 3 BH] + [ Al(OMe)a] l lithium tris(trans-2-methylcyclopentyl)­
criminating between methyl and ethyl borohydride and lithium trisiamylboro­
groups (eq. 39).47 THF hydride � both of them containing secon­
-7 8 ° (eq. 47) dary alkyl groups substituted by ,B-methyl
Li[s-Bu 3 BH] (eq. 52)_6o
LiEt3 BH, THF
PhN(C2H 5) (CH 3 hi + )==
(eq. 39 )
25° , 0.75hr
LISia 3 BH
THF
Aldehydes and ketones are reduced by
100%
PhN (C2H 5 )CH 3
4%
PhN(CH 3h
96%
+ -78 °
alkali metal trialkylborohydrides rapidly
Super-Hydride provides an advanta­ and quantitatively to the corresponding y H3 (eq. 52)
geous procedure for the deoxygenation of alcohols even at -78° . One of the remark­ Sia = (CH 3) iCHCH-

acyclic, cyclic and hindered alcohols able features of hindered trialkylboro­ The reagents can also be prepared by using
through the reduction of their p-toluene­ hydrides is their unusual ability to in­ lithium trimethoxyaluminohydride as the
sulfonate esters (eqs. 40 and 41 ). 48 ,49 troduce major steric control into the reduc- hydride source.ss

6 Aldrichimica Acta, Vol. 12, No. 1, 1979

 Lithium trisiamylborohydride reduces
cyclic ketones with super stereoselectivity.
Thus, 2-, 3-, and 4-alkylcyclohexanones
are all reduced with lithium trisiamyl­
240° (eq. 58). 63

Na B H4 + HCN --
TH F
The reactions involving borane, a strong
Lewis acid, are expected to involve a
preferential electrophilic attack at the
centers of highest electron density. Hence,
borohydride at -78° C in ;,,99% stereo­ it is an electrophilic or acidic reducing
Unlike other hydride reagents, it is stable in

>>
selectivity (eqs. 53-55). agent.
acid solutions down to pH 3. It is soluble in

6- 6
tetrahydrofuran, methanol, water and in c;::H3 t;I Cl H
dipolar aprotic solvents (HMPA, DMF, CI-C- C=O
I

CH3 t
I
CH3•c;:: - c= o
(eq. 53) sulfolane). It possesses a remarkable Cl
functional-group selectivity. preferential attack by B 2 H6

99.7% Sodium cyanoborohydride efficiently Diborane is sparingly soluble in ethyl

ether and diglyme. It readily dissolves in

6- 6
and selectively reduces alkyl halides to
alkanes,64 imines to amines, 65 and tosyl­ tetrahydrofuran in which it exists as the
hydrazones derived from aldehydes and borane-tetrahydrofuran addition com­
(eq. 54) ketones to the corresponding alkanes, 66 all pound. A standard solution of borane­
in excellent yields (eqs. 59-61). THF in tetrahydrofuran can be prepared
99.6% conveniently by treating sodium borohy­
dride in diglyme with boron trifluoride
etherate and passing the gas as generated
into tetrahydrofuran (eq. 62). 67
(eq. 55) 3 Na B H4 + 4 B F 3 : OEt 2 -
2 ( BH3 hl + 3 Na B F 4 (eq. 62)
The exploration of the reducing
99.0%
characteristics of borane in THF has
The corresponding potassium derivative NaBH3CN, HMPA (eq . 59) revealed a number of interesting features of
synthesized recently by a catalytic process I70 , 1 hr this acidic reducing agent, quite different
°

is equally effective. 61 from those of the basic borohydride

anion. 6s-10
iv) Lithium B-Isopinocampheyl-9-bora­
bicyclo[3.3.J]nonyl Hydride. An Asym­ Aliphatic and aromatic carboxylic acids
metric Reducing Agent62 are reduced rapidly and quantitatively to
A trialkylborohydride containing an the corresponding alcohols by borane in
asymmetric alkyl group, lithium B-iso­ tetrahydrofuran, either at 0° or 25° (or
even at -78° ). (In view of the usual inertness
89%
pinocampheyl-9-borabicyclo[3. 3. l ]nonyl
hydride, has been synthesized (eq. 56). of carboxylic acids toward many reducing
agents, this high reactivity toward borane

d:z
p H 6-8 must be considered exceptional. ) The reac­
1 ) 9-BBN HNR 2
tion is applicable to a variety of structures
2) t-Buli
-78° such as sterically hindered acids, di- and
NR2 polycarboxylic acids, phenolic acids,
(1 R, SR) (+) (eq. 56)
A (eq. 60)
amino acids, etc. (eq. 63). 11
OCH2R
I
3 BH rTH F 0 '0
NH2 3 RCOOH I I
"' 8
�
63% (pure endo)
RCH2 0 ,.. ,O 'OCH2R
B ,.. B

100%
NaBH3CN (eq. 63)
The reagent, prepared from ( +)-a-pinene, DMF
rapidly and quantitatively reduces a wide (eq. 61)
variety of ketones to the corresponding CH 3(CH 2) 4COO(CH2)sCN
alcohols. The alcohols produced are op­ 96%
tically active (3-36% e.e.) and are con­
7. Borane
sistently enriched in the R enantiomer (eq.
Reductions involving complex boro­
57).

�<ju
hydrides and their substituted derivatives
discussed in the earlier sections (1-6)
appear to involve transfe r of the hydride
OB moiety from the complex anion to an
RCOR' [;�HR'
� Li
-78 , 1hr
° electron-deficient center of the functional
group. Consequently, these are called
H20 nucleophilic or basic reducing agents.
Rb�R'
Cl H
• Borane-T HF can tolerate a variety of func­
(eq. 57)
6. Sodium Cyanoborohydride tional groups and a number of func­
Sodium cyanoborohydride, synthesiz­
CI-C-C=O
ci f tionalized alcohols have been prepared
ed from sodium borohydride and hydrogen from the corresponding carboxylic acids in
cyanide, is a white crystalline solid, mp preferential attack by NaBH4 excellent isolated yields.

Aldrichimica Acta, Vol. 12, No. I, 1979 1

 B rCH2 (CH2)gCH 20 H
HOCH 2(CH 2)4COOC2H 5
OH
91%
88% - THF
oo
(eq. 68)
tative series of alkyl methyl ketones.
Asymmetric induction in the alcohol
products in the range of 9 to 37% was
observed. 8 1 Even more important, this new
reagent achieves the asymmetric hydro­
boration of cis-2-butene to give, after ox­
CN

-
O idation,2-butanol of optical purity as high
92% 60%
82%
as 98.4% (eq. 73). 7 7
THF
Another major application of borane­ - �-- • GJ"h"{�CH ,CH,
�
oo
(eq. 69)
THF is the facile reduction of primary,
• "hB H
IS:)
secondary, and tertiary amides to the cor­ (+)-(1R, SR)
* *
(·)·(1R, 2S, 3R, SR) (eq. 73)
responding amines. Here again the reac­
[ ]
lO
tion can tolerate many functional groups
(-)-(1R, 2S, 3R, SR) OH
(eqs. 64-66). 7 2

CH3(CH2)4CONH2 CH3CHCH 2CH 3

BH3 -THF

CH3(CH 2)4CH2NH2 (eq. 64) (-) (R) e.e. 98.4%

Cyclic hydroboration of 1,5-cyclo­

87%
octadiene yields a bicyclic dialkylborane,
9-borabicyclo[3.3. I]nonane (9-BBN). 78 It 9-Borabicy clo[3.3. l]nonane reduces
exhibits certain unique physical and a,,8-unsaturated aldehydes and ketones
(eq. 65)
CH3(CH2)4 CH2NHMe
chemical characteristics. It is a white rapidly and quantitatively to the cor­
crystalline solid (mp 154- 155° ), thermally
98%
responding allylic alcohols. The develop­

0
stable,relatively insensitive to air and solu­ ment of a unique nonaqueous work-up
ble in a variety of organic solvents (eq. 70).
CONMei
procedure renders possible the isolation of
the alcohols in excellent yields. Unlike con­
BH,-THF
1 ) BHrTHF ventional reagents,the mildness of 9-BBN
2) A permits the presence of almost any other
(eq. 70)
N 02
functional group,such as ester,amide, car­
boxylic acid, nitro, halogen, and nitrile
(eq. 74). 82

0
Until recently, the majority of borane

0
reductions were carried out in tetra­
hydrofuran as the solvent. The recently in­
0 oQ)
troduced borane-methyl sulfide complex 73 9-BBN ,-C, H .,
has several advantages over borane-THF. A systematic examination of the reduc­
ing characteristics of these dialkylboranes THF, 0 ° H2N y H2

OH
It is exceptionally stable and is soluble in a HOCH 2
(disiamylborane and 9-BBN) towards
{0
variety of aprotic solvents such as ethyl
(�)
J
representative organic functional groups
(eq. 74)
ether, tetrahydrofuran, hexane, toluene,

0
has revealed a number of possible +
\H 2
methylene chloride,diglyme,etc. Further,
applications for these reagents in selective
100%
the reactivity of borane-methyl sulfide
reductiohs. 79 One of the major applications
OH
towards organic functional groups paral­
C H �CHC H ,O H
of disiamylborane is the selective reduction
OH

(r·
lels that of borane-THF. Consequently, it
of lactone to hydroxyaldehyde (eq. 7 1). 80

6
is an advantageous reagent for the reduc­
tion of many organic functional groups. 74
8. Dialkylboranes COOEt
Hydroboration of certain hindered (eq. 71 ) 100% 95% 76%
H
Q � oHO
olefins or structurally suited dienes yields
O OH
Reduction of tertiary amides to alcohols
OBSla2
dialkylboranes preferentially. Thus, hy­
74%
droboration of 2-methyl-2-butene rapidly represents another promising area of
forms the dialkylborane, disiamylborane application for 9-BBN yet to be explored in
(Sia2BH). 75 The addition of the third mole The reaction appears to be general. A detail. It should be pointed out that we are
number of interesting applications of this now in a position to control the course of
of olefin is very sluggish. Similarly, di­
reagent for this type of transformation this reaction to get three different products
cyclohexylborane (CHex2 BH) and diiso­
pinocampheylborane (IPC2 BH) (an asym­ have been reported. 79 a by using various reagents (eq. 75).
metric dialkylborane) can be prepared by Preliminary investigations indicate that Dialkylboranes are consistent reagents
the hydroboration of the corresponding disiamylborane exhibits promise for the for introducing steric control in the reduc­
olefins.76 More recently, diisopinocam­ selective reduction of tertiary amides to the tion of cyclic ketones. Increasing the size of
pheylborane has been synthesized in very corresponding aldehydes ( eq. 72). 79 a the alkyl substituent(s) on boron enhances
Sia2BH 9BSia 2
RCONMe2
high purity (chemical as well as optical, the stereoselectivity dramatically (eq. 76). 83
RCHNMe2 9. Catecholborane and Chloroborane
(eq. 72)
eqs. 67-69). 77
�
�···� RCHO Several heterosubstituted boranes
2 Me2C=CH BH 3
,ie THF, 0°
+ fast
also exhibit valuable properties as reducing
Recently, diisopinocampheylborane of agents. Thus,catechol reacts with borane
(eq. 67)
high optical purity has been examined for to produce a new useful reducing agent,
the asymmetric reduction of a represen- catecholborane (CB) (eq. 77). 84, 85
8 Aldrichimica Acta, Vol. 12, No. 1, 1979
 - PhCD
0
-
-
II

(·)·(1R, 2S, 3R, 5R) (eq. 82)

RCONMe2 RCHO (eq. 75) OH
PhC-0
>98% e.e.
<I>-H
I

(S)-(+)
Certain "ate" complexes derived from B­
alkyl-9-BBN derivatives, such as lithium
d i-n-bu tyl -9-b orab icyclo[3 . 3 . I ]nonane

0 0 Procedures have been developed for the "ate" complex, have been discovered to be

6°- 6 = 6·• "

efficient reducing agents (eq. 83). 9 1
Li+
convenient synthesis of mono- and di­

n -Bu n-Bu
chloroboranes (eqs. 79 and 80). 88

A
BH3 2 BHa BCla
THF-THP
(eq. 79)
" - ./
74% 26%
9-BBN
+
60% (eq. 76)
oo
40%
Sla2BH 79% 21%
CHex2BH 94% 6%
IPC2BH BHa 2 BCla
THF-THP
(eq. 80)
94% 6% +

OH OH
RH
O + BH3 2!::!E... RCHCHa
OH
Aliphatic sulfoxides are rapidly deoxy­
genated to the corresponding sulfides in
(eq . 77)
B-H 2 H2 !
excellent yields by dichloroborane in tetra­

cro,
+
0/ (eq. 83)
hydrofuran at 0 ° in a matter of minutes.
The reaction can tolerate a variety of other
reactive functional groups such as ketone,
The reducing characteristics of this new
ester and amide (eq. 8 1 ). 89 V. SUMMARY
reagent have been explored in detail. 86 The
0
RSA'
reagent is quite useful for the deoxygena­ " HBCl 2 ·THF The systematic exploration of the reduc­
(eq. 81)
ing characteristics of various hydride
RSR ' HOBCl 2
tion of a,/3-unsaturated aldehydes and
ketones through the reduction of their + reagents that have evolved during the
course of forty years ( 1 939- 1 979) has led to
10. Trialkylboranes and" Ate" Complexes
tosylhydrazones ( eq. 78). s7
0 NNHTs
better understanding and appreciation of

�- 0
Recently, certain trialkylboranes have the scope and applicability of each reagent.
� � catecholborane been found to be effective reagents for the
_ _ The reactivities of hydride reagents toward
Na____...,
OA c reduction of aldehydes to the correspond- various organic functional groups at 0-25°
(eq. 78)
ing alcohols. Especially interesting is the under standard conditions are summarized
asymmetric reduction ofbenzaldehyde-a-d in Table 2. S ymbol ( +) indicates rapid
to benzyl-a-d alcohol by chiral B-isopino- reaction; symbol (-) indicates very slow or
campheyl-9-borabicyclo[3. 3. l]nonane (eq. insignificant reaction; symbol (±) indicates
66% 82). 90 a borderline case, the reactivity being sen-
Table II. Summary of behavior of various functional groups toward the hydride reagents
NaBH4 Li(O-t- NaBH4 +LiCI NaBH4 + AICl3 BH 3 S ia2BH 9-BBN AIH 3 Ll(OMe)aAIH LIAIH 4 LIEt 3BH
In Bu)aAIH in in in In In in In In In
ethanol d iglyme d iglyme THF THF THF THF THF THF THF
------------
Aldehyde + + + + + + + + + + +
Ketone + + + + + + + + + + +
Ac id chloride R + + + + + + + +
Lactone ± + + + + + + + + +
Epoxide ± + + + ± ± + + + +
Ester ± + + ± ± + + + +
Ac id + + ± + + +
Acid salt + + +
tert-Am ide + + + + + + +
N it rile + ± + + + +
N itro + + +
Olefin + + +
A "" Reacts with solvent; reduced in non hydroxylic solvent

Aldrichimica Acta, Vol. 12, No. 1, 1979 9

 s1t1ve to the structure of the functional Cragg, "Organoboranes in Organic Synthesis," 40) H.C. Brown, E.J. Mead, and C.J. Shoaf, J. Am.
group (both steric and electronic effects). A Marcel Dekker, New York, N.Y., 1973, p 3 1 9; (e) Chem. Soc., 78, 3616 ( 1956).

quick inspection of Table 2 reveals that by

H.O. House, "Modern Synthetic Reactions," 2nd 41) C.A. Brown, ibid., 95, 4 1 00 ( 1 973).
ed., Benjamin, Menlo Park, Ca., 1972, p 45; (f)
judicious choice of reducing agent it should
42) C.A. Brown, S. Krishnamurthy, and S.C. Kim,
E.R.H. Walker, Chem. Soc. Rev.. 5, 23 ( 1976); (g) Chem. Commun., 373 ( 1973).
be possible to reduce one group selectively
C.F. Lane, Chem. Rev., 76, 773 ( 1976). 43) For a review on this subject, see S. Krishnamurthy,

in the presence of a second or to carry out

5) (a) J. Bouis and H. Carlet, Justus liebigs Ann. A ldrichimica A cta, 7, 55 ( 1974).
Chem., 124, 352 ( 1 862); (b) C. Schorlemmer, ibid., 44) H.C. Brown, S. Krishnamurthy, and J.L. H ub­
the reverse operation. A word of caution is 1 77, 303 ( 1875); (c) P.A. Levene and F.A. Taylor, J. bard, J. Am. Chem. Soc., 1 00, 3343 ( 1 978).
in order. The reactivities of the various
Biol. Chem., 35, 28 1 ( 19 18); (d) A.J. Hill and E.H. 45) H.C. Brown and S. Krishnamurthy, ibid., 95, 1 669

functional groups can be greatly altered by

Nason, J. Am. Chem. Soc., 46, 2236 ( 1924); (e) ( 1973).
H.T. Clarke and E.E. Dreger, Org. Synth., Coll. 46) S. Krishnamurthy, R.M. Schubert, and H.C.
the structures containing them. Conse­ Vol. I, 304 ( 1941). Brown, ibid., 95, 8486 ( 1 973).
quently, these generalizations must be used
6) (a) H. Thoms and C. Mannich, Ber., 36, 2544 47) M . P. Cooke, Jr. and R.M. Parlman, J. Org.
Chem., 40, 53 I ( I 975).
with caution in predicting the behavior of
( 1903); (b) F.C. Whitmore and T. Otterbacker.
Org. Synth., Coll. Vol. 2, 3 1 7 ( 1943). 48) S. Krishnamurthy and H.C. Brown, ibid., 41, 3064
greatly modified systems.
7) F.Y. Wiselogle and H. Sonneborn I ll , Org. Synth., ( 1 976).
Coll. Vol. /, 90 ( 1941). 49) S. Krishnamurthy, J. Organometa/. Chem., 1 56,
8) A. Verley, Bull. Soc. Chim. Fr., 37, 537, 871 ( 1925). 1 7 1 ( 1 978).
9) H. Meerwein and R. Schmidt, Justus Uebigs Ann. 50) H.C. Brown and S.C. Kim, J. Org. Chem., 42, 1482
VI. CONCLUSIONS
JO) W. Ponndorf, z. Angew. Chem., 39, 138 ( 1 926).
Chem., 444, 221 ( 1 925). ( 1978).
Forty years ago it was first discovered
5 1 ) H.C. Brown and S.C. Kim, Synthesis, 635 ( 1977).

that diborane reduces aldehydes and

I I) H. Lund, Ber., 70, 1 520 ( 1 937). 52) C.A. Brown and S. Krishnamurthy, J. Organo­
1 2) For an extensive review on Meerwein-Ponndorf­ metal. Chem., 1 56, 1 1 1 ( 1978).
keto n es rapidly. Unfortunately, the Verley reduction, see A.L. Wilds, Org. React .. 2, 53) P. Binger, G. Benedikt, G.W. Rotermund, and R.
chemical rarity of diborane at the time
178 ( 1944). Koster, Justus Liebigs Ann. Chem., 717, 2 1 ( 1968).
1 3) (a) L. Bouveault and G. Blanc, Bull. Soc. Chim.
prevented organic chemists from utilizing
54) E.J. Corey, S . M . Albonico, U. Koelliker, T.K.
Fr., 31, 674 ( 1 904); (b) P.A. Levene and C.H. Allen, Schaaf, and R.K. Varma, J. Am. Chem. Soc., 93,
this reagent as a reducing agent. Subse­
J. Biol. Chem., 27, 443 ( 19 1 6); (c) S.G. Ford and 1491 ( 1971).

quently, the development of practical syn­

C.S. Marvel, Org. Synth., Coll. Vol. 2, 372( 1943). 55) H.C. Brown, S. Krishnamurthy, and .J.L. H ub­
14) A.B. Burg and H . J . Schlesinger, J. Am. Chem. bard, J. Organometal. Chem., in press.
thetic routes to diborane, the discovery of Soc., 59, 780 ( 1937). 56) H.C. Brown and W.C. Dickason, J. Am. Chem.
sodium borohydride and, later, lithium
1 5) A. Stock, "Hydrides of Boron and Silicon," Cor­ Soc., 92, 709 ( 1970).

aluminum hydride made such hydride

nell University Press, Ithaca, N.Y., 1933. 57) H.C. Brown and S. Krishnamurthy, ibid., 94, 7 1 59
1 6) A. Stock and C. Massenze, Ber., 45, 3539 ( 19 1 2). ( 1 972).
reducing agents readily available. There 1 7) H . I . Schlesinger and AB. Burg, J. Am. Chem. 58) H.C. Brown, S. Krishnamurthy, and S.C. Kim, un­
then resulted rapid progress in the develop­
Soc., 53, 4321 ( 1 9 3 1 ). published results.
59) (a) B. Ganem, J. Org. Chem., 40, 2846 ( 1975); (b)
ment of new reducing agents and in the ex­
1 8) ff. I . Schlesinger, R.T. Sanderson, and A.B. Burg,
ibid., 62, 3421 ( 1940). J.M. Fortunato and B. Ganem, ibid., 41, 2 1 94
ploration of their scope and applicability in 19) H.J. Schlesinger and A.B. Burg, ibid., 62, 3425 ( 1976).

organic synthesis. Still, we are in constant

( 1940). 60) S. Krishnamurthy and H.C. Brown, J. Am. Chem.
20) H.I. Schlesinger, H.C. Brown, B.A. Abraham, N. Soc., 98, 3383 ( 1976).
search of new selective reducing agents that Davidson, A.E. Finholt, R.A. Lad, J. Knight, and 6 1 ) C.A. Brown and S. Krishnamurthy, Abstracts,
are capable of reacting with a specific func­
A.M. Schwartz, ibid., 75, 1 9 1 ( 1953). 1 75th National M eeting of the American Chemical

tional group. Today an organic chemist has

21) H . J . Schlesinger and H.C. Brown, ibid., 75, 219 Society, Anaheim, Ca., M arch 1978, ORGN 23.
( 1953). 62) S. Krishnamurthy, F. Vogel, and H.C. Brown, J.
a choice of specific hydride reagents for 22) H . I . Schlesinger, H.C. Brown, J.R. Gilbreath, and Org. Chem., 42, 2534 ( 1 977).
achieving specific synthetic transfor­
J.J. Katz, ibid., 75, 195 ( 1953). 63) (a) G. Wittig, Justus Uebigs Ann. Chem., 573, 209

mations. Even more important, the ma­

23) ff.I. Schlesinger, H.C. Brown, H.R. Hoekstra, and ( 195 1); (b) R.C. Wade, E.A. Sullivan, J.R.
L.R. Rapp, ibid., 75, 199 ( 1953). Berchied, Jr., and K.F. Purcell, lnorg. Chem., 9,
jority of these reagents are now commer­
24) H.J. Schlesinger, H.C. Brown, and E. K. Hyde, 2 I 46 ( I 970).

cially available to facilitate their applica­

ibid., 75, 209 ( 1 953). 64) R.O. H utchins, D. Kandasamy, C.A. Maryanoff,
25) H.C. Brown, H.J. Schlesinger, I. Sheft, and D.M. D. Masilamani, and B.E. Maryanoff, J. Org.
tion by c hemists. 92 Ritter, ibid., 75, 192 ( 1953). Chem., 42, 82 ( 1 977).
26) H.J. Schlesinger, H.C. Brown, and A.E. Finholt, 65) R . F. Barch, M .D. Bernstein, and H . D. Durst, J.
ibid., 75, 205 ( 1953). Am. Chem. Soc., 93, 2897 ( 1971).
ACKNOWLEDGEMENT 27) A.E. Finholt, A.C. Bond, Jr., and H.I. Schlesinger,
ibid., 69, 1 199 ( 1947).
66) R .O. H utchins, C.A. Milewski, and B.E.
Maryanoff, ibid., 95, 3662 ( 1973).
We wish to acknowledge the generous 28) W.G. Brown, Org. React., 6, 469 ( 1 95 1). 67) G. Zweifel and H.C. Brown, Org. React. , 1 3, I
financial support of the U.S. Army Re­
29) H.C. Brown, P.M. Weissman, and N.M. Yoon, J. ( 1 963).
A m. Chem. Soc., 88, 1458 ( 1966). 68) H.C. Brown and B.C. Subba Rao, J. Am. Chem.
search Office, North Carolina, through a 30) S.W. Chaikin and W.G. Brown, ibid., I, 1 22 Soc., 82, 68 1 ( I 960).
series of grants f or our program on "Selec­
( 1949). 69) H.C. Brown and W. Korytnik, ibid., 82, 3866

tive R eductions" from the inception of this

3 1 ) H.M. Bell and H.C. Brown, ibid., 88, 1473( 1966). ( 1960).
32) R.O. H utchins, F. Cistone, B. Goldsmith, and P. 70) H . C. Brown, P. H eim, and N.M. Yoon, ibid., 92,
program to the present. Heuman, J. Org. Chem .. 40, 201 8 ( 1 975). 1 637 ( 1970).
33) R . F. Nystrom, S.W. Chaikin, and W.G. Brown, J. 71) N.M. Yoon, C.S. Pak, H.C. Brown, S. Krishna­
References and Noles: Am. Chem. Soc., 71, 3245 ( 1949). murthy, and T.P. Stocky, J. Org. Chem., 38, 2786
I) Based in part on the symposium lecture delivered 34) N.M. Yoon and J.S. Cha, J. Korean Chem. Soc., ( 1973).
before the Organic Division at the Centennial 21, 108 ( I 977). 72) H.C. Brown and P. Heim, ibid., 38, 9 1 2 ( 1 973).
Meeting of the American Chemical Society, New 35) H.C. Brown and B.C. Subba Rao, J. Org. Chem.. 73) L.M. Braun, R. Braun, H . R . Crissman, M. Opper­
York (March 1976). 22, 1 1 36 ( 1 957). man, and R.M. Adams, ibid., 36, 2388 ( 1971).
2) H.C. Brown, H.J. Schlesinger, and A.B. Burg, J. 36) J. Ko!lonitsch, P. Fuchs, and V. Gabor, Nature, 74) (a) C.F. Lane, A ldrichimica Acta, 8, 20 ( 1975); (b)
Am. Chem. Soc., 61, 673 ( 1939). 173, 125 ( 1 954). S. Krishnamurthy and K.L. Thompson, J. Chem.
3) For an extensive review of our earlier results, see 37) J. Kollonitsch, P. Fuchs, and V. Gabor, ibid., 1 75, Educ., 54, 778 ( 1977); (c) C.F. Lane, H . L. Myatt, J.
(a) H.C. Brown, J. Chem. Educ., 38, 1 73 ( 1961); (b) 346 ( 1955). Daniels, and H. Hopps, J. Org. Chem., 39, 3052
H.C. Brown, Moderni Sivilupi Della Sintesi 38) (a) H .C. Brown and B.C. Subba Rao, J. Am. ( 1974).
Organica. Conferenze X, Corso Estivo di Chimica, Chem. Soc., 78, 2582 ( 1 956); (b) Recent 1 1 B N M R 75) H.C. Brown and G. Zweifel, J. Am. Chem. Soc.,
Academica Nationale dei Lincei, Rome. 1968, pp examination o f such solutions in diglyme indicates 83, 1241 ( 196 1 ).
31-50; (c) H.C. Brown, "Boranes in Organic the presence of NaBH,, NaB2 H 7 , NaAICl3 BH 4 76) G. Zweifel and H .C. Brown, ibid., 86, 393( 1964).
Chemistry," Cornell University Press, Ithaca, and NaAICJ3H-all present at the same time. 77) H.C. Brown and N.M. Yoon, Israel J. Chem., 1 5,
N.Y., 1972. diglyme 1 2 ( 1977).
4) (a) N.G. Gaylord, "Reduction with Complex Metal AIC13 + NaBH4 .===!- NaCl3Al· BH, 78) E.F. Knights and H.C. Brown, J. Am. Chem. Soc.,
Hydrides," lnterscience Publishers, Inc., New NaCl3A l · BH4 + NaBH4 - NaAICl3H + Na8 2 H 7 90, 5280, 5281 ( 1968).
York, N.Y., 1956; (b) E. Schenker, "Newer Further reaction will only proceed if this system is 79) (a) H.C. Brown, D.B. Bigley, S.K. Arora, and
Methods of Preparative Organic Chemistry," Vol. disturbed; see H. Niith, "Proceedings of H ydride N .M. Yoon, ibid., 92, 7 1 6 1 ( 1 970);(b) H.C. Brown,
IV, W. Foerst, Ed., Verlag Chemie GmbH, S y mposium. I I .," M etalgesellschaft AG, S. Krishnamurthy, and N.M. Yoon, J. Org. Chem.,
Weinheim/Bergstr., 1968, pp 196-335; (c) H .C. Frankfurt, 1 974, p 51. 41, 1 778 ( 1976).
Brown, "Organic Syntheses via Boranes," Wiley­ 39) N.M. Yoon, H.J. Lee, J. Kong, and J.S. Chung, J. 80) H.C. Brown and D.B. Bigley, J. Am. Chem. Soc.,
lnterscience, New York, N.Y., 1975; (d) G.M.L. Korean Chem. Soc., 19, 468 ( 1 975). 83, 486 ( 1 961).

10 Aldrichimica Acta, Vol. 12, No. 1, 1979

8 1) H.C. Brown and A.K. Manda!, J. Org. Chem., 42, 1 7,619-2 Borane-tetrahydrofuran com­ 1 9,789-0 Potassium triisopropoxyboro­
2996 ( 1 977).
plex, IM solution in THF hydride, IM solution in THF
82) (a) S. Krishnamurthy and H.C. Brown, J. Org. 500ml $39.60
Chem., 40, 1864 ( 1 975); (b) ibid., 42, 1 197 ( 1 977). 500ml $ 1 7. 30
83) H.C. Brown and V. Varma, ibid., 39, 1631 ( 1974). 1 7,550-1 Boron trifluoride etherate 1 9,807-2 Sodium borohydride
84) H.C. Brown and S.K. Gupta, J. Am. Chem. Soc., 1 kg $ 1 1 .00; 3kg $27.50 1 00g $ I 3. 1 0; 500g $38. 50
93, 1816 ( 1971).
1 8,89 1 -3 Catecholborane . ..... 25g $ 1 8.70 2kg $ 1 2 1 .00
85) C.F. Lane and G.W. Kabalka, Tetrahedron, 32, 20,097-2 Sodium borohydride, 0.5M
981 ( 1 976). 500g $275.00
86) G.W. Kabalka, J.D. Baker, Jr., and G.W. Neal, J. 1 8,525-6 Disiamylborane Preparation solution in diglyme
Org. Chem., 42, 5 I 2 ( 1977). Kit, ( I mole) . . ..... l kit $52.25 800ml $22. 50
87) G.W. Kabalka, D.T.C. Yang, and J.D. Baker, Jr., E2,740-8 Ethylene glycol dimethyl 1 5,6 1 5-9 Sodium cyanoborohydride
ibid., 41, 574 ( 1 976). 1 0g $5.20; 50g $21 .00
88) (a) H.C. Brown and P.A. Tierney, J. lnorg. Nuc/. ether (monoglyme)
Chem., 9, 5 1 ( 1 959); (b) D.J. Pasto and P. 1 00g $5.75; 500g $ 1 8.50 19,923-0 Sodium hydride, 5()(fo disper­
Balasubramanian, J. •Am. Chem. Soc., 89, 295 1 kg $25.00; 3kg $62.00 sion in mineral oil
( 1967); (c) H.C. Brown and N. Ravindran, J. Org.
18,014-9 K-Selectride® , 0.5M solution 500g $20. 65; 2kg $55.00
Chem., 42, 2533 ( I 977).
in THF ........ ... 500ml $26.40 1 8,086-6 Super-Deuteride® , IM solution
89) H.C. Brown and N. Ravindran, Synthesis, 42
( 1972). 20,934-1 KS-Selectride™ , 0.5M solution in THF ........... 1 00ml $ 1 5.05
90) (a) M.M. Midland, A. Tramontano, and S.A. in THF ........... 500ml $35.00 500ml $57.20
Zderic, J. Organometal. Chem., 1 56, 203 ( 1978);
1 9,987-7 Lithium aluminum hydride 1 7,972-8 Super-Hydride® , IM solution
(b) M.M. M idland, A. Tramontano, and S.A. in THF ........... 500ml $28.60
Zderic, J. Am. Chem. Soc., 99, 521 1 ( 1 977). ! Og $5.00; 25g $9.60
9 1) (a) Y. Yamamoto, H. Toi, S.l. Murahashi, and I . 1 00g $27.30 1 8,656-2 Tetrahydrofuran, anhydrous,
M oritani, J. Am. Chem. Soc., 97, 2558 ( 1 975); (b) 20, 1 04-9 Lithium hydride .... l O0g $ 1 3.50 99.9%. . . ............... I O0g $4.00
Y. Yamamoto, H. Toi, A. Sonoda, and S.l.
500g $44.00 500g $8.80
Murahashi, ibid., 98, 1965 ( 1976); Chem. Com­ T5,980-3 Triethylene glycol dimethyl
mun., 672 ( 1976). L290-4 Lithium tri-tert-butoxy-
92) Available from Aldrich Chemical Co., Inc., aluminohydride ...... 5g $7.50 ether (triglyme) ... 250g $9.00
Milwaukee, Wisconsin 53233. 25g $24.00 1 kg $24.00
1 7 ,849-7 L-Selectride® , I M solution 19,733-5 Triisopropyl borate
Aldrich offers these reagents cited by in THF ........... 500ml $33.65 1 00g $ 1 0.00; 500g $3 1 .80
Professor Brown and Dr. Krishna- M 1,410-2 2-M ethoxyethyl ether ( diglyme) T7565-5 Trimethyl borate
murthy: 500g $ 1 4. 50; 1kg $ 1 9.95 1 00g $4. 70; 500g $ 1 1 .70
20,691-1 Aluminum chloride, anhydrous 3kg $43.45 K- and L-Selectride, Super-Deuteride and Super­
Hydride are registered trademarks of Aldrich
1 00g $3.00; 1 kg $8.00 P4,568-0 (+)-a-Pinene ......... l O0g $1 l . 00 Chemical Company, Inc.
1 5, 107-6 9-BBN, 0.5M solution in THF [a)22 +47. ] O 500g $35.00 KS-Selectride is a trademark of Aldrich Chemical
500ml $ 1 8. 70 Company, Inc.

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Aldrichimica Acta, Vol. 12, No. 1, 1979 11

Trialkylborohydrides in
Organometallic Syntheses
Trialkylborohydrides in Organometallic Syntheses
J.A. Gladysz
Department of Chemistry J .A. Gladysz
University of California
Los Angeles California 90024
Department of Chemistry
University of California
Los Angeles, CA 90024

metallic syntheses, our studies impact upon ones of manipulation and handling. When
a broad front of synthetic chemistry. Na/ H g is utilized, mercury-containing by­
It was our interest in nucleophilic attack products are sometimes produced. 1 2 The
upon coordinated CO that first led us to use of Li(C2 H 5) 3 BH, however, enables the
study the reactions of trialkylborohydrides rapid, room-temperature, one-flask syn­
with metal carbonyl complexes. A variety thesis of anions Li[Co(CO)4), Li[(CsHs)­
of reactions had been observed previously Mo(COM and Li[Mn(CO)5] in near­
between NaBH4 and metal carbonyl quantitative yield under homogeneous
complexes. 8 We thought that a hydride conditions. Only the volatile by-products
source which was soluble in organic sol­ H2 and (C2 H5 )3B are produced ( eqs. 1-3).
vents and contained only one transferable
hydride per mole would yield better de­ Many elegant and useful synthetic trans­
fined chemistry. formations utilizing organometallics pre­
pared from [(C5 H5 )Fe(CO)2]- have been
One of the first useful reactions observed
described in the literature. 1 3 The genera­
was the cleavage of metal carbonyl dimers
Trialkylborohydrides have been well es­ tion of Li[(C5 H5)Fe(CO)2 ] via Li(C2 Hsk
to metal carbonyl anions ( eqs. 1-4).9, 1 0
tablished as potent hydride donors toward BH or Li(sec-C4 H9)3 BH (L-Selectride®),
Transition metal anions play a pivotal role
a variety of organic electrophiles. 1 Lithium however, requires longer reaction times
in the construction of metal-carbon and
triethylborohydride (Super-Hydride® ) has ( 2hr) and ::?':50% HMPA cosolvent (eq. 4).
metal-metal bonds. They are highly This is likely a consequence of the higher
been shown to be an exceptionally clean nucleophilic species which may be readily
reagent for the reductive displacement of reduction potential of [(C5 H5 )Fe(CO)2 J2
alkylated, acylated, or metalated by reac­ relative to the other metal carbonyl dimers.
alkyl halides2 and tosylates3 and reductive tion with an appropriate electrophile.
ring opening of epoxides.4 Hindered trial­ However, potassium trialkylborohydrides
kylborohydrides such as lithium trisiamyl­ Conventionally, 1% Na/ Hg a·malgam or are stronger hydride donors, and K(sec­
borohydride (siamyl = 3-methyl-2-butyl) other heterogeneous metal reductants have C4 H9)3BH and K(C2 H5) 3BH were found to
can reduce ketones such as 3-methylcyclo­ been employed for the conversion of metal effect the synthesis of K[(C5 H5 )Fe(CO)2 ] in
hexanone with �9.6% stereoselectivity. 5 carbonyl dimers to metal carbonyl an­ THF ( eq. 5). Reaction times were 3hr at
Other applications include the use of ions. I I The problems involved are mainly room temperature or 0. 5hr at 45-65°C.
K(sec-C4 H9)3BH (K-Selectride®) for the (C0)4Co-Co(C0)4 + 2Ll(CaHshBH ►
I 4-reduction of enones6 and chiral trial­
2Ll[Co(C0)4] + 2 (C2Hs)aB H2
(eq. 1 )
k�lborohydrides for executing asymmet­
+
ric reductions. 7
(CO)s M n-Mn(C0)5 + 2Ll(C2Hs hBH
A somewhat different line of research in­ 2Ll[Mn(C0)5] + 2 (CaHs hB H2
(eq. 2)
+
volving trialkylborohydride reagents has
(C5H5)(C0)3 Mo-Mo(CO)a(C5H5)
been under investigation in our laboratory.
+ 2Ll(C2Hs hBH
We have been interested in their reactivity
toward inorganic and organometallic elec­ 2Ll[(C5H 5)Mo(C0h] + 2 (C2HshB + H2 (eq. 3)

trophiles. With substrates containing

metal-metal or heteroatom-heteroatom (C5H5)(CO)afe-Fe(CO)a(C5H5) + 2Ll(C2Hs hBH HMPA
'"
bonds, rapid and high-yield cleavage to 2Li[(C5H5)Fe(C0h) 2 (C2Hs)aB H2
+ (eq. 4)
+
two nucleophilic anionic species occurs in
many cases. Since transition metal anions,
main-group metal anions, and metalloid (eq. 5)
anions are key intermediates in organo-
Aldrichimica Acta, Vol. 12, No. 1, 1979 13
 Potassium salts of other metal carbonyl
Figure 1
anions, (e.g., K[(C5 H5 )Mo(CO)3 ], K[Mn­
(CO)5]; eqs. 6 and 7) can also be prepared UNSTABLE ANIONIC FORMYL COMPLEXES
PREPARED WITH Li(C 2H 5 hBH
with K(sec-C4 H9)3 BH and K(C2 H5)3 BH.
Sodium trialkylborohydrides are readily H,
synthesized1 4 and can be used similarly. /C=O r. ;'\ - 0II
C 5H 5 �0)Fe 1,,COJ4�n -C-H
Thus, transition metal anions can be
prepared with a number of different ;C=O Sn(CsH5)3
R
counter-ions by the trialkylborohydride H,
method. Triethylborohydrides are prefer­ (co)sMn-Mn(co)4
able to tri-sec-butylborohydrides because (. ;'\ - II /C=O
1,,C014Re-C-H CsHs(co)2Mo I
of the greater volatility of the borane by­
'c=O w--c �o
Br
product. R/ 1
To demonstrate the preparative utility of
preparation of metal carbonyl anions from trates the variety of unstable metal formyl
these metal anion solutions, we have syn­
other organometallic precursors. 1 0 Eqs. IO complexes prepared by this method. 1 Ho
thesized a number of derivatives.9 , 1 0 These
and 1 1 provide two such examples. Not surprisingly, we believe anionic formyl
are compiled in Table I; full experimental
details have been published. 1 0 Entries I and We anticipate that such reactions may complexes are intermediates in many of
prove of occasional synthetic utility. For our metal carbonyl anion syntheses.
IO depict the actual isolation of two anions
as their air-stable "PPN•", or [(C6 H5 h­ instance, [Mn(CO)5]Br undergoes much Species 1 is formed in 99% yield when [Mn­
P]2 N+, salts. Acylation reactions are il­ more rapid exchange with DCO than [Mn­ (CO)5]2 is treated with one equivalent of Li­
lustrated in entries 4,5,7,9, 13, and 14. (CO)5 ]2 . Thus, the preparation of 1 3CO­ (C2 H5 )3 BH at -20° C; warming to room
labeled [Mn(CO)5]R species would be most temperature and the addition of a second
Alkylation reactions and the formation of
tin and silicon derivatives are also readily accomplished via initial conversion equivalent of Li(C2 H5 )3 BH affords two
of [Mn(CO)5]2 to [Mn(CO)5 ]Br. After equivalents of Li[Mn(CO)s] quanti­
tabulated. Isolated yields are uniformly
1 3CO exchange, the desired product could tatively. 9
good.
We have investigated the in situ prepara­
be obtained in a one-flask operation from The metal carbonyl dimer [Re(CO)5 ]2
labeled [Mn(CO)5]Br. did not cleave upon reaction with Li­
tion of other metal carbonyl anion
A major focus of research in our (C2 H5 )3 BH. Instead, a thermally stable bi­
derivatives. Protonation of Li[Mn(CO)s]
nuclear rhenium formyl complex was ob­
tained, which proved isolable (eq. 13). 2 1
and Li[(C5 H5)Mo(CO)3] with the non­ laboratory has been the preparation and
aqueous, nonoxidizing acid CF3 SO3 H af­ characterization of reactive ligand types
believed to be present on the reaction coor­ Rhenium is known to form stronger metal­
fords quantitative spectroscopic yields of
dinate between CO/ H2 and alkanes and metal and metal-ligand bonds than
H[Mn(C0)5] and H((C5 H5 )Mo(COh],
alcohols in Fischer-Tropsch-type process­ manganese.
respectively (eqs. 8 and 9). 1 5
es. 17 There has been a great deal of atten­ Anionic formyl complexes can undergo
Transition metal hydrides are key inter­
tion focused upon formyl ligands as the further reduction by trialkylborohydrides.
mediates in numerous stoichiometric and
probable initially formed catalyst-bound Organic products, presumably derived
catalytic reactions, and have been the ob­
species. 1 7 from the formyl ligand, include formal­
j ect of a variety of structural, spec­
troscopic, and theoretical studies. 8 Since dehyde and methanoJ. 2 1 When Fe(CO)s
was treated with 2 equivalents of K(sec­
Trialkylborohydrides provide an ex­
the conventional preparation of anhydrous cellent means of generating anionic formyl
complexes according to the generalized eq. C4 H9)3 BH, the formyl complex K[(C0)4-
H[Mn(C0)5] requires extensive vacuum­
line manipulations, 1 6 our in situ synthesis 12. Because most anionic formyl complex­ Fe(COH)] (2) was rapidly formed;22 re­
es rapidly decompose at room tempera­ fluxing the reaction mixture for 3hr in
offers obvious advantages. We have used it
ture, reactions must be carried out below THF afforded K2 [Fe(CO)4] in quantitative
to study several H[Mn(CO)5] reactions. 1 5
0° C and the products characterized by low yield as an analytically pure precipitate (eq.
Trialkylborohydrides also enable the temperature spectroscopy. Figure I illus- 14). 23 The highly nucleophilic tetracar­
bonylferrate dianion, [Fe(CO)4] = has been
(C1H1)(C0)3Mo-Mo(COh(C5H5) + 2 K(sec-C4 H9)3BH proven to be of considerable value in
(eq. 6 )
2 K[(CaHs)Mo(COh] + 2 (sec-C4 H9hB + H2 organic and inorganic syntheses. 1 1 ,24 A
number of useful organic transformations
employing Na2 [Fe(CO)4] or N a2 [Fe­
(CO)sMn-Mn(C0)5 + 2 K(sec-C4H9 )3BH
(eq. 7) (CO)4] · dioxane have been developed by
2 K[Mn(C0)5) + 2 (sec-C.H9 hB + H 2
Collman and coworkers. 24 Although
K2 [Fe(C0)4] has not been as extensively
(eq. 8) utilized, its preparation is distinctly easier
and it is not pyrophoric. To provide ad­
ditional characterization, we carried out
the homologation reaction depicted in eq.
15 and the derivatization with AuCl­
[Mn(C0)5] Br + 2 Li(C2H5 )aBH [P(C6 H5)3] depicted in eq. 16. 23
(eq. 1 0)
Li[Mn(C0)5] + LiBr + Trialkylborohydrides may prove useful
in the synthesis of other transition metal
[(CsH s )Mo(CO)a] CI + 2 Li(C2 H5 )aBH dianions. Following an initial report by
(eq. 1 1 ) Shore, 25 we were able to prepare the cluster
Li[(CsH s )Mo(CO h l + LiCI + 2 (C2 H 5 )a8 + H2
dianion Kz [H2 RuiCO) i z] according to eq.
14 Aldrichimica Acta, Vol. 12, No. 1, 1979
17.26 Exploratory reactions indicate that
trialkylborohydrides are not sufficiently (eq. 12)
strong reductants to produce metal car­
bonyl trianions and tetraanions of the type
reported by Ellis. 21 Li+(CO}5 Re-Re(CO)4 • THF
(CO)5 Re-Re(CO)5 (eq. 1 3)
Recently, we have found that trialkyl­ H-C=O
borohydrides can also be used to form
neutral formyl complexes from metal car­
Fe(CO)5
2 K (sec-C4 H9 )sB H
bonyl cations according to the generalized 100% (eq. 14)
3hr, THF, fl
eq. 18.28 These reactions, and the proper­
ties of the products, are under active in­

2) P(C6 H5 h (eq. 1 5)
vestigation. The neutral formyl (C5 H5)Re­
1-nonanal 1 00%
1 ) n -C8 H1 7 B r
(CO)(NO)(COH) (3), whose preparation is
depicted in Scheme I, has a half-life of ca. 3 ) CH3COOH
3hr at room temperature. The addition of a
2 AuCl P(C6 H5 h
[ ]
second equivalent of Li(C2 H5)3 BH affords
82% (eq. 16)
4, the first bis(formyl) complex prepared.
Reaction of 3 with BH3 • THF reduces the
formyl ligand to a methyl ligand (Scheme H4 Ru4 (CO) 14 + 2 K(sec-C4 H9 hBH
(eq. 17)
I). K2 [H 2 Ru 4 (CO h2 l + 2 (sec-C4 H 9 hB + 2 H2

In only one instance have we observed a

trialkylborohydride to cleanly attack a (eq. 1 8)
metal carbonyl complex at a site other than
coordinated CO. The reaction of 5 with
Li(C2H5)3BH afforded the novel metallo­ Scheme I. Formation and Further Reductions of Neutral Formyl 3
cycle 6, presumably via intermediate 7 (eq.
19).29 We undertook an X-ray crystal­
structure determination of the PPN• salt of
6 to confirm its structure. Metallocycle 6 is
Q
ON ,;1e ,CO
100'/o
not merely a curiosity; it serves as a pivotal CO BF4-
intermediate in our recently described ap­
proach to a-silyloxyalkyl and a-hydroxy­
alkyl metal complexes. 29 a-Hydroxyalkyl
ligands are believed to be key mechanistic
branch points in Fischer-Tropsch-type
processes. 1 7
Having established that trialkylborohy­
drides can effect the net cleavage of metal­
metal bonds, we decided to see if metalloid­ 4
metalloid bonds could be broken as well.
Gray, elemental selenium consists of
polymeric, unbranched helical chains.
TABLE I. SUMMARY OF TRANSITION METAL MONOANION DERIVATIVES PREPARED
Entry Starting Hydride Monoanion Electrophile Product Isolated
C arbonyl Reagent Produced Added Formed Yield (%)
1 [Co(CO)4l z Li(C2 H 5 )aBH Li[ Co(CO) 4] I (Ce HshPh N +Cf- [ (Ce HshPhN +[ Co(CO)4 J - 79
2 [Co(CO)4h Li(C2 HsbBH Li[Co(CO)4 ] (C6 H 5 )aSnCI [ Co(CO).] Sn(Ce H sb 83
3 [ (C5 H5 )Mo(CO)a]z Li(C2 H 5 )aBH Li[ (C 5 H 5 )Mo(CO)a] CHal [ (C5 Hs)Mo(CO)a] CH 3 77
4 [ (C5 H5 )Mo(CO)alz Li(C2 H 5 )aBH Li[ (C 5 H 5 )Mo(CO)a] (CH3 O)COCOCI [ (C5 H 5 ) Mo(CO)a] COCO2 CH 3 77
5 [ (C5 H5 )Mo(CObh Li(sec-C4 H 9 )aB H L i [ (C 5 H 5 )Mo(CO)a] (CH3 O)COCOCI [ (C5 H 5 ) Mo(CO)a] COCO2 C H 3 77
6 [ (C5 H5 )Mo(COh] 2 Li(C2 H 5 )aBH Li[ (C 5 H 5 )Mo(CO)a] (Ce H 5 )aSnCI I (CsH5 ) Mo(CO)a] Sn(C6 H5 )a 76
7 [Mn(CO)5)z Li(C2 H 5 )aBH Li[Mn (CO) 5] C6 H 5 COCOCI [ Mn(CO) 5 ] COCOC6 H 5 92
8 [ Mn(CO)5l z Li(C2 H 5 )aBH Li[ M n (CO)s] (Ce Hs)aS n C I [ M n (CO) 5] S n (C6 H 5 )a 88
9 [Mn(CO)sh Li(C2 H 5 )aBH Li[M n(CO) 5 ] (CH3 O)COCOCI [ Mn(CO)s] COCO 2 CH3 81
10 [ Mn(CO)5h K (sec-C4 H 9 )aBH K [ M n (CO) 5] [ (C6 H 5 )aP] N•Cf- [ (Ce HsbPhN•[ M n(CO)5 J - 78
11 [ Mn(CO)5)z K (sec-C4 H 9 )aBH K [ M n (CO) 5] (CH3 )aSiBr [ Mn (CO)5] S i(CHa b 60-80
12 I (Cs H s )Fe(COhl z K (sec-C4 H 9 )aBH K[ (C 5 H 5 )Fe(COh] (CsHsbSnCI I (C5 H 5 )Fe(COh] S n (C6 H 5 )a 93
13 I (CsHs )Fe (COhlz K (sec-C4 H 9 )aBH K[ (C 5 H 5 ) Fe(CO) 2J C6 H 5 CH=CHCOCI [ (C5 H 5 ) Fe(COh] COCH=CHC6 H 5 72
14 I (CsHs)Fe(COhlz K (sec-C4 H9 )aBH K [ (C5 H 5 ) Fe(COh] C6 H 5 COCI [ (CsH s) Fe(COh]COC6 H 5 67
15 I (Cs H s )Fe(CO hh K(C 2 H 5 )aBH K [ (C5 H 5 ) Fe(COh] CHal [ (CsHs) Fe(COh] CH3 56

Aldrichimica Acta, Vol. 12, No. 1, 1979 15

 While it is only partially reduced by
NaBH4,30 Li(C2 H5)3 BH rapidly converts
Se, to Li2Se or Li2Se2 (depending upon
stoichiometry) according to eqs. 20 and
22.3 1 Alkyl halides could then be added to
the heterogeneous suspensions (optimally
in the presence of t-butyl alcohol cosol­
vent) and dialkyl selenides and dialkyl di­
selenides obtained in 50-90% yields (eqs. 2 1
and 23). 31
Se + 2 Li(C2 H 5 hBH Li2Se + 2 (C2 Hs hB + H2 (eq. 20)
This one-flask preparation of R2Se and
R2 Sei compounds offers distinct advan­ Li2Se + 2 RX R2 Se + 2 LiX (eq. 2 1 )
tages over many previous methods. Alkali
metal-ammonia reduction converts Se, to
2 Se + 2 Li(C 2 H 5 hBH Li2Se2 + 2 (C2 H 5 hB + H2 (eq. 22)
Se = or Set , but is obviously a more
cumbersome procedure. Sodium formal­
dehyde sulfoxylate ("Rongalite") can also Li2 Se2 + 2 RX R2Se2 + 2 LIX (eq. 23)
reduce selenium but requires an aqueous
solvent system.3 1 s + 2 Li(C2 H 5 hBH ► Li2S + 2 (C2 H5 hB + H2 (eq. 24)
W e have undertaken a more extensive
investigation of the reaction of sulfur (S8) 2S + 2 Li(C2 H5 )aBH L i2S 2 + 2 (C2 Hs hB + H2 (eq. 25)
with trialkylborohydrides. 32 ,33 Although
there exists a variety of means for the in­ RSSR + 2 Li(C 2 H s hBH 2 RSLI + 2 (C2H 5 hB + H2 (eq. 26)
troduction of sulfur into organic mole­
cules, research continues on the develop­ RSeSeR + 2 Li(C 2 H5 hBH 2 RSeli + 2 (C2H s hB + H 2 (eq. 27)
ment of new sulfur transfer reagents and
methods. When Li(C2 H5)3 BH is simply
TABLE I I . R EPRESENTATIVE ORGANOSULFUR COMPOUNDS PREPARED
syringed onto sulfur or a sulfur/ THF
suspension, Li2 S or Li2 S2 formation occurs
over a two-minute period as depicted in Entry Product Electrophile Yield (%)" Reaction Conditionsb
eqs. 24 and 25. Significantly, these reaction A. Sulfides
mixtures are homogeneous, whereas com­
(CsHsCH 2 hS CsHsCH 2 CI [ 94] 3hr
mercial anhydrous Li2 S is insoluble in
THF. While there may be some association 2 (n-C 4 H 9 ) 2S n-C4 H 9 1 71 5hr
between the sulfur anions and the by­ 3 (n-Cs H 1 1 h S n-C5 H 1 1 Br 71 5hr
product (C2 H5)3 B, experiments33 indicate 4 (sec-C4 H 9 h S sec-C4 H 9 1 63 1 2hr reflux
that the homogeneity is primarily due to 5 (CH 3CO h S CH 3 COCI 87 2hr

0 0
supersaturation.
A variety of electrophiles have been add­
ed to these reaction mixtures. Some of the 6 .,....._o)l-.s)'u/'-. 51 2.5hr
organosulfur compounds thus prepared
are tabulated in Table 11. 32,33 Although the
synthesis of simple dialkyl sulfides is ade­ 7
[Xs [63] 1 .5hr
quately served by inexpensive N a2 S • 9H20,
this reagent is,of course,incompatible with
B. Disulfides
electrophiles requiring strictly anhydrous
conditions. Notably, our Li2 S preparation 8 [ 89] 5hr
undergoes facile acylation ( entries 5 and 6), 85
9 ( H 2 C==CHCH 2 l 2S 2 H 2 C==CHCH 2 Br [ 93] 2hr reflux
providing a distinct improvement over ex­
isting synthetic methods for diacyl sul­ 10 n-C4 H 9 1 [ 87] 1 hr
(n-C4 H g l 2S2
fides. 34 While anhydrous alkali metal sul­
78
fides are commercially available, they are
11 (n-Cs H 1 1 h S2 n-C 5 H 1 1 Br 99 2hr reflux
exceedingly hygroscopic, and thus, our
one-flask in situ synthesis offers obvious 12 (sec-C4 H 9 ) 2 S2 sec-C4 H 9 1 [ 73] 2hr reflux
advantages. 13 (CsHsCOl 2S2 C 6H 5COCI 85 1 hr reflux
14 (CH 3 C0 l 2 S2 CH 3 COCI [ 82] 0.5hr
Alkali metal disulfides are not commer­
cially available. Methods for their prepara­ "Yields are based upon starting sulfur and are not optimized. Bracketed values are 1 H NMR yields;
tion (e.g., Li/ NH3) are cumbersome and others are isolated yields.

sometimes afford mixtures of polysulfide bRoom temperature unless noted.

salts. Hence, alkylation of Na2 S2 has been
reported to proceed only in fair yield, 33 As containing precursors. Particularly for the Disulfides and diselenides are rapidly
is evident from Table 118, our disulfide diacyl disulfides (entries 1 3 and 1 4) are the cleaved by Li(C2 H 5)3 BH to thiolates and
yields are uniformly high. Thus, disulfides literature procedures markedly simpli­ selenolates, respectively (eqs. 26 and
may be readily prepared from nonsulfur- fied. 3 5 27). 3 H 3 These reactions enable facile syn-
16 Aldrichimica Acta, Vol. 12, No. 1, 1979
 4) H.C. Brown, S. Krishnamurthy, and R.A.
1 ) 2 Li(C 2H5 bBH
...
Coleman, J. Am. Chem. Soc., 94, 1 750 ( 1 972).

2) 2 CH3COCI
1 00% (eq. 28) 5) S. Krishnamurthy and H .C. Brown, ibid., 98, 3384
( 1976).
6) J.M. Fortunato and B. Ganem, J. Org. Chem., 41,
2 1 94 ( 1 976).

1) 2 Li(C 2H5 bBH

7) S. Krishnamurthy, F. Vogel, and H .C. Brown,

►
ibid., 42, 2534 ( 1 977).
2) 0 (eq. 29) 8) See H.D. Kaesz and R.B. Saillant, Chem. Rev., 72,

2
231 ( 1 972).

0c1
9) J.A. Gladysz, G . M . Williams, W. Tam, and D . L.
Johnson, J. Organometal. Chem., 140, Cl ( 1977).
IO) J.A. Gladysz, G.M. Williams, W. Tam, D.L. John­
son, D.W. Parker, and J.C. Selover, Inorg. Chem.,
18, in press ( 1979).
Figure II 1 1) J.E. Ellis, J. Organometal. Chem., 86, I ( 1 975).
APPARATUS FOR IR MONITORING OF REACTIONS 1 2) R.B. King, J. Inorg. Nuc/. Chem., 25, 1 296 ( 1 963).

/
1 3) M. Rosenblum, Acc. Chem. Res., 7, 1 22 ( 1 974).
Bubbler 14) H.C. Brown, S. Krishnamurthy, and J.L. Hub­
bard, J. Am. Chem. Soc., JOO, 3343 ( 1 978).
1 5) J.A. Gladysz, W. Tam, G . M . Williams, D. L. John­
son, and D.W. Parker, Inorg. Chem., 18, in press
( 1 979).
16) R.B. King and F.G.A. Stone, Inorg. Synth., 7, 198
( 1 963).
17) G.H. Olive and S. Olive, Angew. Chem., Int. Ed.
Engl., 1 5, 136 ( 1976); J. Mo/. Cata/., 3, 443
( 1977/78); W.A. Goddard, S.P. Walch, A . K .
Rappe, T . H . Upton, and C . F . Melius, J. Vac. Sci.
Technol., 14, 4 1 6 ( 1 977).
1 8) J.A. Gladysz and J.C. Selover, Tetrahedron Lett.,
3 1 9 ( 1 978).
19) D.W. Parker, unpublished results.
20) J.A. Gladysz and J . H . Merrifield, Inorg. Chim.
theses of unsymmetrical sulfides and lizing trialkylborohydrides have been Acta., 30, L 3 ! 7 ( 1 978).
2 1 ) J.A. Gladysz and W. Tam, J. Am. Chem. Soc., 100,
selenides. Thus, the sequential treatment of described. Most of the transformations 2545 ( 1 978).
dibenzyl disulfide with Li(C2 H5)3 BH and detailed result in the formation of a metal­ 22) Other researchers have also noted the formation of
CH3I gave benzyl methyl sulfide in 75% carbon or heteroatom-carbon bond. Other salts of 2 by the reaction of Fe(COJ, with
trialkylborohydrides or related hydride donors:
yield. Benzyl acetyl sulfide was obtained in applications include the synthesis of metal C.P. Casey and S . M . Neumann, J. Am. Chem.
100% yield by the reaction of dibenzyl di­ hydrides, mixed metal compounds, and Soc., 98, 5395 ( 1976); S.R. Winter, G.W. Cornett,
and E.A. Thompson, J. Organometal. Chem., 133,
sulfide with Li(C2 H5)3 BH and acetyl chlor­ formyl complexes.
399 ( 1977).
ide (eq. 28).32 ,33 Eq. 29 depicts the forma­ 23) J.A. Gladysz and W. Tam, J. Org. Chem., 43, 2279
tion of a vinyl sulfide via an addition­
We anticipate that trialkylborohydrides
( 1 978).
may also be of use in the generation of 24) J.P. Collman, Acc. Chem. Res., 8, 342 ( 1 975).
elimination reaction. 33 phosphorus- and silicon-based anions. Our 25) K . l nkrott and S.G. Shore. J. Am. Chem. Soc.,
APPARATUS own efforts are focused on the applications 100, 3955 ( 1978).
26) W.K. Wong, unpublished results.
Metal carbonyl compounds have strong of some of the organometallic species 27) J.E. Ellis, C.P. Parnell, and G.P. Hagen, J. Am.
and characteristic IR bands in the 1800- described herein to organic synthesis. Chem. Soc., 1 00, 3605 ( 1 978).
28) W. Tam, W.K. Wong, and J.A. Gladysz, J. Am.
2100 cm-I region. A lthough the reactions Although the potential of metal carbonyl Chem. Soc., IOI, in press ( 1979).
we describe can be run in good yield in the reagents has long been recognized by 29) J.A. Gladysz, J.C. Selover, and C.E. Strouse, J.
absence of spectroscopic monitoring, the organic chemists, their inaccessibility by Am. Chem. Soc., 100, 6766 ( 1 978).
30) J.M. Lalancette, A . Freche, J.R. Brindle, and M .
simple apparatus detailed in Figure II standard bench-top techniques has often Laliberte, Synthesis, 526 ( 1976).
enables reactions to be titrated to 100% discouraged their use. In light of the studies 3 1 ) J.A. Gladysz, J.L. Hornby, and J.E. Garbe. J. Org.
yields. Solutions of the metal carbonyl summarized in this article, we hope this will Chem., 43, 1 204 ( 1 978).
32) J.A. Gladysz, V.K. Wong, and B.S. Jick, Chem.
reactant are placed in a Schlenk flask no longer be the case. Commun., 838 ( 1978).
which is fitted with a septum and a Teflon ACKNOWLEDGEMENTS 33) J.A . Gladysz, V.K. Wong,and B.S. Jick, submitted
needle. A standard 0. 1-mm-cavity NaCl IR for publication in Tetrahedron.
I wish to thank the donors of the 34) M. M ikolajczyk, P. K ielbasinski, and H . M .
cell is mated to the other end of the needle Petroleum Research Fund, administered Schiebel, J. Chem. Soc., Perkin Trans. I , 564
with a machined Teflon plug. To the other ( 1 976); S. Motoki and H. Satsumabayashi, Bull.
by the American Chemical Society, The Chem. Soc. Jpn., 45, 2930 ( 1972); W.A. Bonner, J.
IR cell inlet is attached a (gas-tight) Department of Energy, The National Am. Chem. Soc., 72, 4270 ( 1 950).
syringe. A slight positive nitrogen pressure 35) R.L. Frank and J.R. Blegen, Org. Syn., Coll. Vol.
is maintained via the side arm of the
Science Foundation, and the UCLA 3, 1 1 6 ( 1 955); L. Field and J.E. Lawson, J. Am.
Research Committee for support of the Chem. Soc., 80, 838 ( 1 958).
Schlenk flask. Reagents and reactants are various investigations reported in this arti­
added as needed through the septum. By cle. Most importantly, I would like to ex­
pumping the syringe, the reaction mixture press my gratitude to the following
can be spectroscopically sampled at any John A. Gladysz is a native of
coworkers for bringing this chemistry to Galesburg, Michigan. He earned his B.S.
time. fruition: Jim Garbe, John Hornby, Bryan degree at the University of Michigan and
Such an apparatus might also see use in Jick, Dennis Johnson, Jim Merrifield, Jay his Ph.D. at Stanford University. In 1974,
purely organic transformations. For in­ Selover, Wilson Tam, Greg Williams, Rick he joined the UCLA Faculty as an Assis­
stance, it should be as (or more) effective as Wong, and Victor Wong. tant Professor. H is research interests en­
TLC in monitoring the disappearance of a compass a wide area of synthetic
carbonyl-containing compound. References and Notes:
1) S. Krishnamurthy, A ldrichimica Acta, 7, 5 5 ( 1974). chemistry, emphasizing organometallic
CONCLUSION AND PROGNOSIS 2) H.C. Brown and S. Krishnamurthy, J. Am. Chem. compounds and new preparative methods
Soc., 95, 1669 ( 1972).
A number of rapid, high-yield, multi­ 3) S. Krishnamurthy and H.C. Brown, J. Org. Chem., (high pressure chemistry, metal atom
step, single-flask synthetic sequences uti- 41, 3065 ( 1976). chemistry).

Aldrichimica Acta, Vol. 12, No. 1, 1979 17

 bla n k
P a g e i n te nt i a l ly
Aldrichimica Acta
Volume 12, Number 2, 1979 Volume 12 Number 2 1979

Spin Trapping. See page 23.

A Businessman's Look at PMN� See page 35.

chemr sts helping chem, sts in research & industry

aldrich chemical co_

 ®

Aldrichimica
Volume 12, Number 2, 1979

- -1
A publication ofALDRICH CHEMICAL COMPANY, INC.

Main
About Our Cover:
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Aldrichimica Acta, Vol. 12, No. 2, 1979 21

 In taking successive samples, the syringe
must be "pumped" several times to flush
l 55/50

traces of the previous sample from the

syringe and needle.
Michael D. Tufano
Corporate Research Laboratories
UOP Incorporated
Des Plaines, I L 60016
Editor's note:
This sampling assembly is easily con­
"1 -iiter
capacity '-...
Steam distillation of a compound of low
v
� - r,
structed from materials normally available
volatility requires condensation of a large in the laboratory. To chemists who would
volume of water; this normally makes make use of the described assembly fre­
isolation of the desired compound, by ex­ quently, we recommend Aldrich's septum­
traction or filtration, tedious. inlet adapter with Teflon stopcock.
l 24/40 l 24/40

to condenser

distillation stopcock

The accompanying drawing details an

apparatus which we use to sample a reac­
tion in progress without interruption of the
reaction, or if run under inert atmosphere,
without introduction of air.
The arrangement is particularly suitable Cat. No. I Price
for use with high-temperature reactions ZI0,228-8 14/20 $21.60
where hot organic solvents would attack a ZI0, 136-2 19/22 23.40
septum cap attached directly to the flask ZI0, 137-0 24/40 25.80
via a sidearm or adapter.
to flask
to flask of of boiling Cont'd on page 36
By attaching the septum cap to a Pyrex
water and CH2Cl2
material
being glass tube and inserting this into the
adapter (as one would a thermometer), the
steam distilled
The arrangement shown 1 obviates the
tube, which now extends out from the pot,
need to collect a large volume of water. The
acts as an air-<:ooled condenser, protecting
compound steam-distills into the con­
the septum.
denser where it undergoes continuous ex­
t r a c t i o n by dichloromethane. 2 A The needle is then inserted through the
progressively more concentrated solution septum cap and manipulated to allow sam­
of the compound accumulates in the ple removal . After a sample has been taken
CH2Cl2 flask; this s olution is simply run the needle is withdrawn from the solution
through a small cotton-wool plug and and the luer-lock is closed to allow syringe
evaporated3 leaving the desired material. removal without admitting air to the pot.
With this device we concentrated into J.
about 200ml of CH2 Cl2 a quantity of 1,5-

ntr-,
dibenzocyclooctadiene that would have re­
quired filtration from tens of liters of
3

water.4
\j -
,I,

References:
I) This device was designed by Dr. A.C. Mackey, then
a graduate student at the University of Toronto.

Recently Dr. Colin F. Chignell, the chief

2) CH 2 Cl 2 is the only common heavier-than-water

of the Laboratory of Environmental

organic solvent that seems to be noncarcinogenic
and nontoxic: Chemical and Engineering News,
Biophysics at the N . I . H . suggested that we

¥"-
July 24, 1978, p 7.
+
3) E. Lewars, A ldrichimica Acta, 8, 38 ( 1 975).
offer a-(4-pyridyl I-oxide)-N-tert-butyl­
nitrone (4-POBN), a new spin trap unique­
4) P. Yates, E.G. Lewars, and P . H . McCabe, Can. J.

ly useful for the identification of hydroxyl

Chem .. 48, 788 ( 1970).

Professor E. G. Lewars - -, radicals in solution, reported by Janzen et

Trent University / al., J. Am. Chem. Soc., 1 00, 2923 ( 1978).
Peterborough, Ontario K9J 7B8 Unfortunately, Professor Janzen's method
Canada of preparation given in a footnote of that
Editor's note: communication to the editor, is very
We have found this continuous steam sketchy. Well, when a compound as in­
distillation/ extraction apparatus quite teresting as 4-POBN is suggested to us, we
useful, so as a service to chemists who may don't let lack of experimental details deter
have need for it, we offer the device shown us - and we have now made it.
below, accompanied by an instruction It was no bother at all, just a pleasure to
sheet. (1) Thermometer adapter assembly be able to help.
Z I0,408-6 2 1,543-0 a-(4-Pyridyl 1-oxide)-N-tert­
(2) Pyrex glass tube of appropriate length and diameter
( ) Septum cap
Continuous steam distillation/extraction butylnitrone (4-POBN)
3
t4) Heavy-gauge needle of appropriate length

apparatus $ 1 55.00 100mg $6.00; lg $30. 00

(5) Luer-lock
(6) Syringe of appropriate volume

22 Aldrichimica Acta, Vol. 12, No. 2, 1979

 Spin Trapping
Spin Trapping
C. Anderson Evans
Varian Associates
East Coast EPR Applications Laboratory
25 Hanover Road
Florham Park New Jersey 07932 C. Anderson Evans
Varian Associates
East Coast EPR Applications Laboratory
25 Hanover Road
Florham Park, New Jersey 07932

J anzen's group at the U niversity of Georgia leisurely fashion.

as well as by other groups around the The spin traps that have been most com­
world, either simultaneously or a short monly employed are those designed so that
time afterwards. 5 Since that time pub­ on reaction with a free radical a nitroxide is
lications in this area have proliferated6 with produced. Typically, spin traps are either
applications appearing in the fields of nitroso compounds 1 1 " (eq. 2) or nitrones 1 i b
polymerization,7 radiation chemistry,8 (eq. 3).
biology,9 and general solution chemistry. w
The actual experimental procedure
Interest in biological applications of spin employed in spin-trapping experiments
trapping is picking up, with several depends on a number of factors such as the
laboratories presently devoting a signifi­ manner of radical production, the inertness
cant portion of their research effort to the of the solvent and reagents with respect to
detection of free-radical processes in the spin trap, the lifetime of the spin ad­
biological systems. Because of this in­ ducts, how much or what kind of deoxy­
creased interest and because existing genation (if any) is required. Usually
general reviews of the technique are now deoxygenation by bubbling purified
Since its discovery some thirty-four some eight years old, 1 1 it seems appropriate
years ago electron spin resonance (ESR) nitrogen or argon gas through the solution
to discuss some of the recent work that has is sufficient for spin-trapping purposes. In
has proven to be a useful tool for studies in been done using the spin-trapping tech­
chemical, physical, and biological sys­ some cases degassing by the freeze-pump­
nique. Particular attention will be given to thaw vacuum technique is necessary if a
tems. I The ability of ESR to detect low the spin traps that have been used.
concentrations of free radicals and its sen­ very low oxygen level is required or if
Biological applications will be discussed in volatile reagents are involved.
sitivity to their environment and molecular some detail and a cautionary note is given
motions have contributed greatly to its to help in avoiding potential pitfalls in the An apparatus that has proven rather
popularity. A limitation in the application application of the technique. generally useful for us in spin trapping and
of ESR to solution studies has been the dif­ other organic applications of electron spin
ficulty in producing sufficient quantities of
reactive free radicals to make possible kT
The technique of spin trapping makes
direct ESR detection. Various methods
R· + TRAP � SA·
use of a diamagnetic compound (the spin {eq. 1)
have been employed to overcome this trap) which reacts with a free radical (the
Free Spin Spin
problem including high-energy in situ spin) giving rise to a relatively stable, ESR­
Radical Trap Adduct
radiolyses,2 high-intensity photolyses, 3 and observable free radical (the spin adduct, eq.
rapid-flow techniques. 4 H owever, these
O·
1). In favorable cases the free radical, R · , + R'- N=O _,. R'-N-R (eq . 2 )
I

techniques are rather expensive or cumber­

R·
can be identified from the ESR parameters
some and do not appear to be generally [e.g. , hyperfine coupling constants (hfsc),
applicable. Until recently, therefore, most
research in ESR in the solution phase was
g-factor] of SA • . Thus spin trapping ex­
R· +
tends the capabilities of ESR in that ►
limited to that involving relatively stable previously unobservable free radicals (or, ( eq . 3)
free-radical systems.
at least, radicals observable only with dif­
�1
In 1968 the technique of spin trapping ficulty) can now be studied as their respec­
R- <r -�-R3
was introduced by Professor Edward tive spin adducts in a somewhat more R 2 0·
- - -- - - --- -- - -- ·------------- - ---- -----
© 1 979 by Aldrich Chemical Company, Inc. Aldrichimica Acta, Vol. 12, No. 2, 1979 23
 resonance is shown in figure 1. 1 2 This con­ well, its spin adducts generally consisting
sists of a "U"-tube (a) which connects via a of triplet of doublets with a relatively small
7/ 25 tapered ground-glass joint to a Varian variation in the doublet splitting as a func­
"flat cell" [Fig. 1 (b)] for aqueous or high tion of trapped radical. An example of a (eq. 4)
O·
dielectric solvents, or to a standard ESR typical ESR spectrum is shown in Fig. 2
(CH3)3 C-N-CH2CH3
round cell [Fig. 1 (c)] if a low dielectric (b) for the ethyl adduct of PBN (PBN-Et)

NtB-Et
(nonlossy) solvent is used. In a typical ex­ (eq. 5).
periment one positions the "U"-tube ver­ A nitrone which has shown more sen­
tically and a solution of the spin trap is sitivity to the structure of the radical is 5,5-
placed in one chamber of the "U"-tube and dimethyl- l -pyrroline-N-oxide (DMPO),
the radical producer in the other. The
chambers are stoppered with rubber septa CH�o
through which long (#18 or #20 ) syringe CH3 � (eq. 5)
needles are inserted. A stream of purified o-
nitrogen or argon gas is then passed
DMPO
through the solutions for 15-30 minutes. If
a flat cell is used it may be attached during introduced by Janzen in 1972. 13 Examples
the outgassing procedure since the gas can of the spectra obtained on trapping
escape through the opposite end of the cell. different types of radicals with DMPO are
Since the round cell has no secondary shown in Fig. 3.
opening it must be flushed with nitrogen or It is interesting to consider the origin of 82 cos28 (eq. 6)
argon gas just prior to attachment to the the variation in the proton hyperfine split­
"U"-tube. When outgassing is complete the ting observed as a function of structure of
system is stoppered and the contents of the AH,B for a number of adducts to DMPO
the trapped free radical. The magnitude of (Fig. 5). In this kind of plot, the better the
"U"-tube and sample cell are thoroughly this interaction is governed by the Heller­

= =
mixed and shaken down into the ESR cell, scatter the better is the spin trap for pur­
McConnell equation (eq. 6), 14 where B0 poses of identification of the trapped
which is inserted into the microwave cavity and B2 are constants (B0 0 and B2 26
of the ESR spectrometer. Relatively simple radical. The range of hfsc's for the same ad­
Gauss for nitroxides) and 0 is the dihedral ducts to PBN is indicated on the plot.
modifications of this basic experimental angle formed by the C-N p-orbital and the
design allow the use of vacuum degassing, N-C ,BH planes (Fig. 4). Thus, each group O·
three- (or more) component mixing, etc. R added to the spin trap will have different (CHJ,C-N-C,H,

SPIN TRAPS stereoelectronic characteristics and will

therefore give rise to a different value for 0.
As mentioned earlier spin traps are
usually either nitroso compounds or nit­ The spin trap DMPO is structured so
rones. By far the most popular nitroso that the conformation of its adducts places (a)

compound has been 2-methyl-2-nitroso­ the ,B-hydrogen in a nearly eclipsing rela­

propane or, trivially, nitroso-tert-butane tionship with the nitrogen p-orbital (i.e. , 0
(NtB). Nitroso compounds have an in­ is small and A H,B is large). As a result,
herent advantage over nitrones for radical small changes in the bulk of R · give rise to
identification in that the added group lies relatively large variations in AH,B· This is
immediately adjacent to the nitroxide illustrated in the "scatter plot" of AN vs.
center and therefore can easily give rise to
additional hyperfine splitting. For exam­ �
ple,reaction of ethyl radical with NtB gives (b)
the ethyl adduct of NtB (NtB-Et) (eq. 4).
The ESR spectrum of this nitroxide [Fig. 2
(a )
(a)] shows the unpaired electron resonance (c)
split first into three lines of equal intensity Figure 1 Figure 2
by interaction with the nitrogen (nuclear
spin = 1) and then into three lines of a 1: 2: I
intensity ratio by interaction with the two Dl:r + t-BuOH

equivalent methylene hydrogens of the

ethyl group. A long-range splitting from
the methyl hydrogens shows up as a 1: 3: 3: I
pattern superimposed on the nine major x � impurity
lines and helps to identify the radical
trapped.
The nitrone which has been used most in
spin-trapping studies is phenyl N-tert-butyl
nitrone (PBN). This is probably due to the
fact that it has a good shelf stability, has 10
been commercially available for a long
time,and was the first nitrone to be used in
this manner. However, PBN does not dis­ Figure 3
tinguish between alkyl radicals particularly
24 Aldrichimica Acta, Vol. 12, No. 2, 1979
 -�,-� -�- ----- ~,---'

Me R = -CH20H
2 R-N=O ..-
_,.
o-
I
R -N=N-R .---. 0
II
R -N- N-R Me-C -N=O
I
-C-Me
0
+ +I +
(eq. 7)
o-
I II
o- I
R
O· R = -C02Et
�H,)3C-N-OC(CH3)3 ... �H3)3C · + O=N-oc(CH3)3 (eq. 8)
R 1 = H; R 2 = Me
R, = H; R 2 = Ph
Me,COH
Q R 1 = R 2 = Me
n·PrCHOH
Cb

o <®)
in Benzene �HOH

@N=O t -Bu@N=O
22
H
PhC , Mo CH,OH
O
/ Et n·Bu
H

.In\_
<; " Ph

gN=O
O
F N=O
M
R•­ �e F F

,l
fo,PBN
R = -t-Bu
-OMe

-Cl
•Q-••o -CO 2 Me

R ·C s H s
-N0 2

Me
R -C-CH,OH
CH 20H
Me
R = -C-CH,OH
Me
Figure 4 Figure 5 Me o
-
R = v xM•
OTHER SPIN TRAPS group lies closer to the unpaired electron �o Me

R= ii- x:; M•
The three spin traps discussed above center. However nitroso compounds have
have been the ones most utilized by the disadvantage of being both thermally
�O
H

researchers up to this point. Although a and photochemically unstable. 1 1 b, 1 6 h, 1 s In

addition they possess a low-energy visible t-Bu
great deal of tailored synthesis has been
F \O_
+ ,/
absorption band which makes it nearly im­
done for the technique of spin labelling,1 5 N
very little has been done to configure spin possible to use them for photochemical Ar
studies. One of the consequences of this in­ . ,o
Ar = -@-No,
©
traps to suit the exact problem under in­
vestigation. With the advent of in­ stability is that the ES R spectra of spin ad­
vestigational activity in the biological area, ducts of nitroso compounds invariably
show the presence of impurity nitroxides
it is likely that this situation will be chang­ c,
which may obscure certain regions of the -@-
ing over the next few years. b
spectra and hinder interpretations. It
A number of other traps have been used should be noted that aromatic nitroso com­ @Me

OOMe !{$Me
0-Me
in problems investigated by spin trapping, pounds show much more desirable proper­
particularly in the early days of the ties in this regard. I 6b
development of the technique. 5, 1 6 These
will not be discussed specifically, but the
structures of some of these traps are shown
There are other problems associated
with the use of nitroso compounds in spin­
IQ} Me,N
Q
in Figure 6.
Janzen has recently published the
trapping applications. Nitroso compounds
have a tendency to form dimers which are
Q-o Q·n ·C,,H,.

preparations of a number of traps which inert towards radical trapping (eq. 7). I 6b
seem to be quite good for trapping hydrox­ Thus,in any quantitative applications it is
yl radicals. 1 7 necessary to take this equilibrium into ac­
count. Nitroso compounds seem somewhat
R ELATIVE M E RITS OF N unreliable in spin-trapping applications in­
VERSUS NITRONE SPIN volving oxygen-centered radicals. For ex­
Earlier it was mentioned that nitroso ample, it has been shown 1 8 that the tert­
compounds are generally more capable butoxy adduct of NtB is unstable,decom­
Me
than nitrones of providing a "fingerprint " posing to give a tert-butyl radical and tert­ I
butyl nitrite (eq. 8). Figure 6
of the trapped radical because the added
Aldrichimica Acta, Vol. 12, No. 2, 1979 25
 In contrast to nitroso compounds, and Ingold. 23 A limited amount of data has itial formation of a dimer which decom­
nitrones have absorption bands firmly in been made available by other workers in poses to products. The decay is rather fast
the ultraviolet which render them suitable the field24. This rate constant data is sum­ (k = I x 104 M - 1 sec- 1 at 25° in benzene).
for a number of photochemical studies. In marized in Table I. For more substituted nitroxides,the decay
general, use of wavelengths longer than All rate constants for the spin-trapping is slower (n-hexyl tert-butyl nitroxide: k :(
300nm completely avoids direct photolysis reaction have been measured either by 100 M- 1 sec- 1 at 40° in benzene)23 and is
a

of the spin trap. Indeed, photolysis of direct competition or by determining a rate probably "a straightforward dispropor­
benzene solutions of PBN for over two constant ratio in which some other rate tionation not involving the formation of an
hours with a low-pressure mercury lamp constant is a "known " quantity. Thus,it is intermediate dimer. " 26c Indeed, the
gives no detectable ESR signal. 1 9 Nitrones doubtful that any spin-trapping rate con­ decrease in decay rate seems to continue as
are monomeric and, to my knowledge, stant is correct to better than a factor of 2 the degree of substitution and size of at­
show no tendency to dimerize. Many of and a safer margin of error would be to say tached groups increase. 19, 27 In fact some
the spin adducts produced from nitrones that the listed quantities are correct to spin adducts, are so stable they are at least
are stable for long periods (the phenyl spin within an order of magnitude. All values so partially isolable. 19,27
adduct of PBN has a half-life of several far fall in the extremes of I x 105 to 5 x 108 In preliminary work aimed at studying
weeks; the dodecyl adduct,several years t9 ). M- 1 sec- 1 • the effect of the size of the added radical on
The most serious disadvantage of nitrones spin adduct lifetime,I have compared the
is their tendency to undergo reactions with It is appropriate to remark that pre­
liminary flash photolysis-ESR results25 on relative persistence of the phenyl adduct of
the system tert-butoxy-PBN (eq. IO) in­
nucleophiles. A weak signal of the acetoxyl PBN (I) and the dodecyl adduct of PBN
adduct of PBN can be detected from reac­ (II). The phenyl adduct has a half-life of
tion of sodium acetate with PBN. 20 This dicate a k T == 2 x 106 M- 1 sec- 1 at 25° ,in
good agreement with the earlier work of several months in benzene whereas the
probably arises from nucleophilic addition
of acetate to PBN with subsequent oxida­ Janzen and Evans. 22b
tion of the anion produced (eq. 9). Very little information on activation
One concludes from this discussion that parameters has been obtained for the spin­
there is no such thing as the ideal spin trap. trapping reaction, but it appears that
One trap will be good for a given applica­ energies of activation will fall in the range
tion and another will be good for a of 1-5 kcal/ mole. 23 b
different application. It seems, therefore, DECAY OF SPIN ADDUCTS
that it would be good to have a kit of spin
A number of decay routes are possible
traps from which a researcher could select
for spin adducts. In the following discus­
the trap appropriate for his experimental
sion,some reference will be made to nitrox­
ides which are not spin adducts,per se.
needs. This is one of the reasons that I hope
the custom design of spin traps will
However, it is felt that data which is
accelerate in order that a larger number of
spin traps will become available. available for these nitroxides has a bearing
on the decay of spin adducts.
SPIN ADDUCTS II
Spin adducts which have a hydrogen at­
The spin-trapping reaction has been tached to the a-carbon can decay by dis­ dodecyl adduct evidently has a half-life of
studied extensively within Janzen's group proportionation (eq. 11). The mechanism several years. 1 9 Similar results were ob­
and a review of this aspect of spin trapping for this decay pathway has been worked tained for the phenyl and dodecyl adducts
has appeared. 2 1 A large number of rate out by Ingold and co-workers. 26 For of DMPO, although these adducts were
constants have now been determined for diethyl nitroxide,the decay involves the in- much less stable. 19

TABLE I. RATE CONSTANTS FOR THE SPIN-TRAPPING REACTION

the formation reaction (eq. I) principally
by Janzen, Evans,et al. 22 and by Schmid
+-
PBN
R · + TRAP __. SA•
NaOC-CH, + � kT
8 O· ( eq . 9)
�ti,)3C-N-9H 0
jQ; Spin T rap Radical T (° C) k T (M•1sec-1) Reference
cscH, PBN t-BuO · 25 5 X 1 06 22,44
Ph • 25 2 X 1 07 22,44
3 X 1 07
�H,)3CO PBN 4 X 1 06
BzO · 40 22,44
► CH3 • 25 22,44
1 .3 X 105
�H3)3C-N-CH
9· 0
@
(eq. 10)
DMPO
RCH2 •
t-BuO •
40
25 4 X 1 08
7 X 1 07
23
22,44
ck{cH
�3 8 X 1 07
Ph • 25 22,44
BzO · 40 22,44
PhCH2 • 25 2 X 1 07 22,44
2.5 X 1 06
2 -C-N-C-
I I RCH 2 • 40 23
H O· 2 X 1 06
I I I ►
NtB t-BuO · 25 22,44
(eq. 1 1)
1 .3 X 1 08
1 X 1 06
CH30; -45 24e
-f-N-C- ;C=N-
C-
9 X 1 06
I ' + I
24a
I
(CH3 )JOC=O 40
H OH
+
I I I I
o- RCH2 • 40 23
·�·�-----,- ---�---�--------,--�-----

26 A ldrichimica Acta, Vol. 12, No. 2, 1979

 (eq. 13)
It may not be too obvious to remark that
[OJ
the stable nitroxides used for spin labels are ►
almost exclusively those in which all of the
hydrogens on the a-carbons have been sub­
stituted.
There are some other ways in which the

(eq. 14)
spin adduct can decay. One of the most
common is by means of a reduction of the
spin adduct (shown formally in equation 12
as reaction of the nitroxide with a
non radical
hydrogen atom). The observation of this
reaction is becoming more common now products
that the use of spin traps in biological
systems is increasing. This is, of course,
because of the endogenous reducing agents
(eq. 15)
present in many biological preparations.
The most common reductant is ascorbate,
HO (and similar radicals)
but there may be others (such as dithionite)
which are not naturally occurring, but may
have been added in the preparative pro­ radicals involved.In recent years spin trap­ nitrogen (AN 16.0 Gauss) and a proton
cedure. One positive aspect of the disap­ ping has spurred interest in the application (AN 2.0 Gauss), consistent with the basic
pearance of spin adduct due to reduction is of ESR to biological problems and several structure III. The reaction could also be
that the skeletal structure of the adduct is successful studies have been reported.One
'?tfa
HOCH2C-N-C-H
·generally preserved. Therefore, it may be of the more common kinds of studies con­ I

CH3 O·
possible to regenerate the ESR spectrum cerns free radicals produced by high­ I I I
by means of an appropriately chosen ox­ energy radiation of aqueous solutions of
idative procedure.It might even be possible peptides, 30 amino acids, 3 1 nucleic acids, 32 Ill
to isolate the reduced adduct and to study it etc., in the presence of a spin trap. These carried out anaerobically without the en­
by other techniques such as NMR. have been discussed in some detail in a re­ zyme. In this experiment, a degassed solu­
It is, of course, possible to oxidize cent review.33 tion of linoleic acid and spin trap was
nitroxides28 (eq.13), but this appears to be In this article I will briefly discuss the prepared and mixed with a degassed solu­
less common than reduction, particularly application of spin trapping to the study of tion of hydroperoxylinoleic acid.An ESR
in biological systems. It may well be that lipid peroxidation and to the detection of spectrum identical with the one described
nitroxides which have been one-electron superoxide (02;) and hydroxyl radicals. above was obtained.
oxidized are more prone to undergo This is in no way intended to be a com­ The workers were able to assi gn a more
cleavage than are the reduced species. If prehensive review.These papers and others precise structure to the radical giving rise to
this is the case, skeletal integrity will not be are discussed in considerably greater detail the ESR spectrum by means of exper­
preserved and it will be difficult to in the review by Janzen.33 iments using deuterated linoleic acids.
regenerate the original nitroxide. When 11, l l-d2 -linoleic acid was used in
Spin adducts may decay by means of place of linoleic acid the ESR spectrum was
cleavage of a portion of the nitroxide as a In one of the earliest applications of spin unchanged. However, when either
trapping to a problem of biological in­
terest, de Groot et al. examined the pro­
free radical. This was mentioned earlier for 9,10, 11, 11, 12, 13,-d6- or 9, 10, 12, 13-d4 -lino­
the tert-butoxy adduct of NtB (eq.8). This leic acids were used, the doublet splitting
may also be a problem when certain groups duction of radicals in the anaerobic reac­ disappeared and the ESR spectrum con­
which add to the spin trap contain weak tion of lipoxygenase with linoleic acid us­ sisted of three lines.The authors concluded
chemical bonds (e.g. , -0-0-, -N=N-). For ing 2-methyl-2-nitrosopropanol ( HONtB) that a linoleic acid radical at either C-13 or
9 H3
example, alkylperoxy radical adducts of C-9 appeared to have been trapped. Of
PBN are difficult to observe except at low HOCH2r -N=O course, there is no a priori reason to ex­
temperatures.29 One exception was the ad­ CH3 clude trapping at C-10 or C-12.Radicals
duct derived from n-C 18 H3702 • and PBN, HONtB derived from addition reactions to the dou­
which was observed at room temperature. ble bond (eq. 15) are consistent with the
The decay pathway for these adducts may as spin trap.34 The nitroso alcohol above experiments whereas radicals deriv­
well involve breaking of the 0-0 bond.At (HONtB) was chosen as spin trap because ed from hydrogen abstraction at C-11 are
room temperature, alkoxy radical adducts of its greater solubility in water over NtB. not.
are observed instead of alkylperoxy ad­ The reaction of interest in this work was Other experiments carried out with
ducts (eq.14). the formation of dimeric linoleic acid deuterated compounds established that the
which was shown to require hydroperoxy­
linoleic acid.Garssen et al.35 had proposed
SELECTED APPLICATIONS OF radical was derived from linoleic acid and
SPIN TRAPPING TO BIOLOGY not from the hydroperoxide.
a mechanism for this dimerization in­
The presence of free radicals in bio­ volving a linoleic acid radical.When lino­ It should be reemphasized at this point
logical systems has been postulated for leic acid was incubated aerobically with that nitroso compounds are notoriously
some time. Conventional ESR has not lipoxygenase and HONtB an ESR spec­ unreliable as traps of oxygen-centered
been heavily utilized to study these radical trum consisting of a triplet of doublets was radicals.It would perhaps be advisable to
processes because of the short lifetime and observed.The ESR spectrum indicated an reinvestigate this system using nitrone spin
consequent low concentrations of the free interaction of the unpaired electron with a traps to see if other radicals present in the
Aldrichimica Acta, Vol. 12, No. 2, 1979 27
 0
observed. Control experiments verify that
Spinach Chloroplasts
Qoo{H)
N N H (eq. 16)
the entire system is necessary to produce
I
+
O·
the signal, i.e., Fe•2 or bleomycin alone
o- with DMPO does not give rise to the ESR
spectrum. The authors propose that the
hydroxyl radical is the actual toxic species
CH1-0-CN-CH3
hv giving rise to the DNA strand breaks.
spinach
►
These strand breaks are somewhat "site­
methyl vlologen
chloroplasts
specific" because bleomycin is bound to
DNA and the hydroxyl radical is released

+ . �.
C�-N� -CH3 (eq. 18)
in the vicinity of the site of strand breakage.
SOM E CAUTIONARY N OTES TO
PRACTITIONERS SPIN TRAP­
PIN G
enzyme 1 6) resulted in the production of an ESR
ArNOa ►
(eq. 19)
ArNO: It seems t o be somewhat o f a law of
signal identical to that previously
observed 39 for the hydroperoxy radical ad­ nature that the easier a technique is to per­
ArNOi + <>z -+ ArN02 + Oi duct of DMPO. Oxygen was required fo r form, the more subject to abuse are the in­
the reaction and the observed signal was terpretations of the results. Spin trapping is
reaction could be detected. This system was in most cases rather easy to do experimen­
reexamined recently, but again, only a much larger in the presence of methyl
viologen, a species known to accept elec­ tally and, accordingly, may well fall under
nitroso trap was used. 36 the jurisdiction of the above law. It seems
trons from the primary acceptor of
Perhaps the most powerful application photosystem I. The methyl viologen func­ appropriate, therefore, to lay out some
of spin trapping to the lipid peroxidation tions by taking the electron from the guidelines which may be helpful in
area has been due to Piette and co­ photosynthetic chain and forming the avoiding some of the more common pit­
workers. 37 These workers have explored methyl viologen radical cation (eq. 1 7). falls.
radical production in rat liver microsomes This radical in turn reduces molecular oxy­ I. The observation of an ESR
using both PBN and DMPO as spin traps. gen to form the superoxide radical (eq. 18). signal in a spin-trapping experi­
The liver microsomal NADPH-dependent ment is not prima facie evidence
lipid peroxidation system was shown to A recent work from the National
Biomedical ESR Center describes the de­ that one has trapped the radical of
produce free radicals from a variety of sub­ greatest interest to the researcher.
strates, viz., methanol, ethanol, propanol, tection of superoxide during the aerobic
acetone, acetonitrile, DMSO, linoleic acid liver microsomal reduction of nitro com­ Thus, the highest priority in any spin­
and the well known carcinogens, di­ pounds40 (eq. 19). Both DMPO and PBN trapping experiment is assignment of the
methylnitro samine and diethylnitro­ were used as spin traps. The mechanism for ES R signal(s).
samine. 370 The authors also showed that a production of superoxide is very similar to 2. The observation of a spin adduct
good signal could be obtained when the that given above for methyl viologen. corresponding to the radical of
common buffering agent, Tris, was used. Buettner and Oberley have published a greatest interest to the researcher
This latter result further demonstrates that paper in which lifetimes of the 02° (or does not necessarily mean that the
all components of the system must be HO2 · ) adduct of DMPO were measured ESR signal arose by means of the
checked in order that the true source of under a variety of conditions. 4 1 A method pathway of greatest interest to the
radicals giving rise to a particular spin ad­ for quickly purifying the commercially observer.
duct be identified. available DMPO is presented. This paper Considerable testing needs to be done to
Lai and Piette37h have also demon­ should prove to be valuable since it aids in assure that the spin adduct did indeed get
strated hydroxyl radical production in the defining the limits of ot>servation of there by the proposed mechanism. One
microsomal system. superoxide by spin trapping. simple test is to vary the concentration of
HYDR O XYL RADICAL the spin trap to determine the kinetic order
SUPEROXIDE DETECTION TION of the reaction in spin trap. It should be
S ingly-reduced oxygen, superoxide Hydroxyl radical is one of the most quite general that the overall reaction
(02;), has been postulated as an in­ powerful oxidizing radicals occurring in should tend toward zeroth order in spin
termediate in a host of biochemical redox biological systems. DMPO and PBN have trap as the concentration of spin trap is in­
reactions. Because of its importance, a been shown39 to be effective traps for this creased.44 It may not be too obvious to
great deal of attention is being paid to the radical. remark that observation of zero order
detection of superoxide anion by spin trap­ One of the more intriguing observations dependence of spin trap is not 100%
ping. 33 of hydroxyl has been in the Fe•2-bleo­ assurance of the radical nature of the ad­
The first paper in this area was the paper mycin-DMPO system.42 Bleomycin43 is a duct formation. It is, however, a step in the
by Harbour and Bolton,38 who studied multifunctional anticancer antibiotic right direction.
superoxide production in spinach chloro­ known to induce strand breakage in DNA. 3. Corollary to # 1 . The lack of
plasts. Indeed, it now appears that this The efficiency of strand breakage is observation of an ESR signal does
paper was the one which triggered much of markedly increased when reducing agents not mean that the radical of in­
the current interest in spin-trapping are added. terest is not present.
applications to biological problems. W hen a solution of FeS04, bleomycin It may be that the spin adduct is un­
Harbour and Bolton found that red light and DMPO is placed in the cavity of an stable, the trapping rate is too slow relative
(A >600nm) illumination of spinach ESR spectrometer the characteristic signal to other pathways fo r the radical, or there
chloroplasts in the presence of DMPO ( eq. of the hydroxyl radical adduct to DMPO is might be a number of other reasons for the
28 Aldrichimica Acta, Vol. 12, No. 2, 1979
failure to observe the adduct of interest. Janzen, C.A. Evans, and J.I.-P. Liu, (b) M. Iwamura and N. Inamoto, ibid.,
Some ideas for dealing with this and the ibid., 9, 5 13 ( 1973). 43, 856, 860 ( 1970).
other problems above are discussed in 14) C. Heller and H.M. McConnell, J. 28) A.R. Forrester, J.M. Hay, and R. H.
Janzen's review.33 Chem. Phys., 32, 1535 ( 1960). Thomson, "Organic Chemistry of
To summarize, spin trapping is a power­ 15) (a) C. Chignell, Aldrichimica Acta, 1, I Stable Free Radicals," Academic
ful technique for the indirect ES R observa­ ( 1974); (b) L. Berliner, Ed., Spin Press, London, 1968, p 225.
tion of many reactive free radicals. As with Labelling, Vol. I and 2, Academic 29) M.V. Merritt and R.A. Johnson, J.
all techniques, some care should be taken Press, New York, 1976; (c) I.C.P. Am. Chem. Soc., 99, 3713 ( 1977).
to cross-check results whenever possible. Smith, ref. I (b ), pp 483-539. 30) H. Taniguchi and H. Hatano, Chem.
16) (a) W. Ahrens and A. Berndt, Lett., 53 1 ( 1974); ibid., 9 ( 1975).
References and Notes: Tetrahedron Lett. , 428 1 ( 1973); (b) S. 3 1) (a) C. Lagercrantz and S. Forschult,
I) (a) J.E. Wertz and J.R. Bolton, " Elec­ Terabe, K. Kuruma, and R. Konaka, Nature, 218, 1247 ( 1968); (b) S. Rustgi,
tron Spin Resonance," McGraw-Hill, J. Chem. Soc. Perkin Trans. fl 1252 A. Joshi, H. Moss, and P. Riesz, Int. J.
New York, 1972; (b) H.M. Swartz, ( 1973); (c) E.G. Janzen, R. L. Dudley, Radiat. Biol., 31, 415 ( 1977).
J.R. Bolton, and D.C. Borg, "Biolog­ and R. V. Shetty, J. Am. Chem. Soc., 32) A. Joshi, S. Rustgi, and P. Riesz, Int.
ical Applications of Electron Spin 101, 243 ( 1979). J. Radiat. Biol., 30 , 15 1 ( I976).
Resonance," Wiley-Interscience, New 17) E.G. Janzen, Y.Y. Wang, and R.V. 33) E.G. Janzen in "Free Radicals in
York, 1972. Shetty, J. Am. Chem. Soc., 100, 2923 Biology," Volume IV, W. A. Pryor,
2) See, for example, the classic paper by ( 1978) and refe rences therein. Ed. , 1979.
R.W. Fessenden and R.H. Schuler, J. 18) A. Macker, Th.A.J.W. Wajer, and 34) J.J. M.C. de Groot, G.J. Garssen,
Chem. Phys., 39, 2 147 ( 1963). Th.J. DeBoer, Tetrahedron, 24, 1623 J.F.G. Vliegenthart, and J. Boldingh,
3) A representative paper is by J.K. ( 1968). Biochim. Biophys. Acta, 326, 297
K ochi and P. Krusic, J. Am. Chem. 19) C.A. Evans, unpublished work. ( 1973).
Soc., 93, 846 ( 197 1). 20) A.R. Forrester, quoted in ref. l l (b), p 35) G .J. Garssen, J. Vliegenthart, and J.
4) See, for example, W.T. Dixon and 1 15. In reproducing this experiment Boldingh, Biochem. J., 122, 327
R.O.C. Norman, Proc. R. Soc. Lon­ only very low levels of nitroxides were ( 197 1).
don Ser. A., 97 ( 1963). produced (ref. 19). 36) H. Aoshima , T. Kajiwara, A.
5) (a) E.G. Janzen and B.J. Blackburn, 2 1) E.G. Janzen, C.A. Evans, and E. R. H atanaka, and H. Hatano, J. /Ji,o­
Abstracts of the 156th Meeting of the Davis in "Organic Free Radicals," chem., 82, 1559 ( 1977).
ACS, Atlantic City, N.J., Sept. , 1968, W. A. Pryor, Ed. , A CS Symposium 37) (a) A.N. Saprin and L.H. Piette, Arch.
N o. ORGN-86; (b) E.G. Janzen and Series, 69, 433 ( 1978). Biochem. Biophys., 180, 480 ( 1977);
B.J. Blackbum, J. Am. Chem. Soc., 22) (a) E.G. Janzen, C.A. Evans, and Y. (b) C.-S. Lai and L.H. Piette, Bi,o­
90 , 5909 ( 1968); (c) G.R. Chalfont, Nishi, J. Am. Chem. Soc., 94, 8236 chem. Biophys. Res. Commun., 78, 51
M.J. Perkins, and A. Horsfield, ibid., ( 1972); (b) E.G. Janzen and C. A. ( 1977).
90 , 7 14 1 ( 1968); (d) C. Lagercrantz and Evans, ibid., 95, 8205 ( 1973); (c) E.G. 38) J . R. Harbour and J . R. Bolton, Bi,o­
S. Forschult, Nature, 218, 1247( 1968). Janzen and C.A. Evans, ibid., 97, 205 chem. Biophys. Res. Commun., 64,
6) It now appears that there are some 200 ( 1975); (d) E.G. Janzen, D. E. Nutter, 803 ( 1975).
publications in spin trapping and Jr., and C.A. Evans, J. Phys. Chem., 39) J.R. Harbour, V. Chow, and J. R.
applications. A complete list in the 79, 1983 ( 1975). Bolton, Can. J. Chem., 52, 3549
form of a titled bibliography will be 23) (a) P. Schmid and K.U. Ingold, J. Am. ( 1974).
available soon from the author. Chem. Soc., 99, 6434 ( 1977); (b) P. 40) R.C. Sealy, H . M. Swartz, and P. L.
7) Polymerization example: T. Kunitake Schmid and K . U. Ingold, ibid., 10 0, Olive, Biochem. Biophys. Res. Com­
and S. Murakami, J. Polym. Sci., 2493 ( 1978). mun., 82, 680 ( 1978).
Polym. Chem. &L, 12, 67 ( 1974). 24) (a) M.J. Perkins and B.P. Roberts, 4 1) G.R. Buettner and L.W. Oberley,
8) Radiation chemistry example: F.P. Chem. Commun., 173 ( 1973); (b) M.J. ibid., 83, 69 ( 1978).
Sargent and E.M. Gardy, Can. J. Perkins and B.P. Roberts, J. Chem. 42) L.W. Oberley and G.R. Buettner,
Chem., 54, 275 ( 1976). Soc. Perkin Trans. fl, 297 ( 1974); (c) FE ES Lett., 91, 47 ( 1979).
9) Biological chemistry example: G. R. M.J. Perkins and B.P. Roberts, ibid., 43) J.L. Fox, Chem. Eng. News, 56, 2 1
B ue t t n e r , L.W. Oberley , and 77 ( 1975); (d) P. Ledwith, P.J. Russell, ( 1978).
S.W.H.C. Leuthauser, Photochem. and L. H. Sutcliffe, Proc. R. Soc. Lon­ 44) C.A. Evans, Ph. D. Thesis, University
Photobiol., 28, 693 ( I978). don Ser. A . 332, 15 1 ( 1973). (e) P. of Georgia, 1974.
IO) Solution chemistry example: C. Lager­ Sargent, J. Phys. Chem., 81, 89 ( 1977).
crantz and S. Forschult, Acta Chem. 25) T.M. Chiu, C.A. Evans, J. R. Bolton,
Scand., 23, 8 1 I ( 1969). and S.K. Wong, unpublished work at C. Anderson Evans received his P h.D.
I I) (a) M.J. Perkins, in " Essays on Free the University of Western Ontario, degree from the University of Georgia in
Radical Chemistry," R.O.C. Norman, London, Ontario. 1974. He received his post doctoral train­
Ed., Chem. Soc. Spec. Pub/., 24, 97 26) (a) K. Adamic, D.F. Bowman, T. ing at the Centre D'Etudes N ucleaire,
( 1970); (b) E.G. Janzen, Acc. Chem. Gillan, and K.U. Ingold, J. Am. Chem. Grenoble, France under a Fulbright-Hays
Res., 4, 31 ( 197 1); (c) C. Lagercrantz, Soc., 93, 902 ( 197 1); (b) D. F. Bowman, Fellowship, 1973-1974 and at the U niversi­
J. Phys. Chem., 15, 3466 ( 197 1). J .L. Brokenshire, T. Gillan, and K. U. ty of Western Ontario, L ondon, Ontario,
12) G.A. R ussell, E.G. Janzen, and E.T. Ingold, ibid., 93, 655 1 ( 197 1); (c) D. F. 1974-1976. His current interests include
Strom, J. Am. Chem. Soc., 86, 1807 Bowman, T. Gillan, and K. U. Ingold, magnetic resonance, spin trapping,
( 1964). ibid., 93, 6555 ( 197 1). NMR/ ESR applications to biological
13) (a) E . G. Janzen and J.I. -P. Liu, J. 27) (a) M. Iwamura and N. Inamoto, Bull. problems and computer applications to in­
Mag. Res., 9, 5 10 ( 1973); (b) E.G. Chem. Soc. Jpn., 40, 702, 703 ( 1967); strumentation.

Aldrichimica Acta, Vol. 12, No. 2, 1979 29

 A Small Chemical Businessman
Looks At Premanufadure
Notification (PMN)
A Small Chemical Businessman Looks At Premanufacture Notification (PMN)
Kenneth W. Greenlee
President
Chemsampco Inc. Kenneth W. Greenlee
4692 Kenny Road
Columbus Ohio 43214 President, Chemsampco, Inc.
4692 Kenny Road
Columbus, Ohio 43214

One of the most worrisome aspects of produced in less than 1 0, 000!bs. , across the tification or registration program . . . .
o peratin g a small- or medium-size board. rather it requires a manufacturer to notify
chemical company today is the enormous
At first, PMN sounded so simple. I EPA . . . . and submit information . . .
proliferation of government regulations.
visualized sending a postcard or short letter which EPA can use." But another section
Of these, the PMN (premanufacturing no­
to EPA s aying, "I plan to m ake u-name-it declares that the statutory 90-day waiting
period can be extended even for minor
tification) proposed by TOS CA for all new
acid for commercial purposes in 90 days
technical fl aws . . . indefinitely . . . until
products to be used individually regard­
less of quantity is the most serious: iffinal­ unless you object. " EPA would look at it
ized as now proposed, it is bound to stifle briefly and generally reply "Okay. " Such a EPA determines that the flaws are mended.
innovation. quick answer could be possible if EPA will Now I ask you, doesn't that sound just like
a bona fide certifica tion dea l?
Perhaps the clearest analysis we have hire practical chemists, biologists and tox-
seen of this has been Dr. Ken Greenlee's icologists ca pa ble of "separ ating the sheep TOSCA specifies that the application of
presentation at a public meeting called by from the goats." PMN must not be unduly burdensome on
the E PA in Cleveland, Ohio on February 7, industry. Yet EPA estimates that the cost
On the other hand, one couldn't fault
1 979. Dr. Greenlee is one of the country's
EPA for asking for a little help. It is of completing their forms will be in the
range of $2, 500 to $4 1 , 400; and presumably
ablest chemists running a chemical com­
reasonable for them to ask us to share
this is just for the clerical and "library
pany, Chemsampco, in Columbus, Ohio.
whatever property a nd toxicology data we
research" work of assembling existing data
Dr. Greenlee's presentation would be
hilariouslyfunny ifonly the problem were may have on hand. But the depth and
a nd "paper" projections. Crea ting data to
not so serious: we have to smile reading breadth of the questioning in those for-
this, despite our worries. mida ble 38 pages of PMN forms make it complete the forms could cost (according
clear that they w ant much, much more than to some estimates) one-quarter-of-a-
million dollars.
Alfred Bader
you arc likely to have on hand.
As head of a small chemical compa ny I It is clear that PMN is bad news for small
am well aware that chemicals ca n be Also, they make it clear that they mean
to have it. On page 222 5 of the document chemical companies. My own had to grow
dangerous, but also that they can be a dozen years before it m ade an annual
handled with safety. I am also well aware which we're here to discuss I read "Section
5 a nd these rules require m a nufacturers to
profit as large as EPA's estimated max-
that staying in business is a precarious ven- imum cost of PMN for just one product.
ture, and small economic changes may submit complete and valid notices . . . . . . . if
a person does not s ubmit a complete and Large companies m ay anticipate sales
spell life or death for a company. The volumes large enough to justify such costs
proposed PMN rules could make a large va lid notice he may be subject to penalties
up to $2 5 , 000 per day. " (!) in addition to the usual R & D costs, but
change. small ones cannot.
I am appalled by what EPA seems to be Now I ask you: who devises the notice
forms? Who decides what information to We small companies ca n continue to
laying on us . . . what will be especially operate in the research and development
ask for? Who decides whether the notices
severe upon small chemical businesses . . . a rea of chemistry, until that, too, becomes
a re complete a nd va lid? You know; not a n
and I predict that it will cut chemical in- overregulated. But, how can we hope to
novation in half. Before you scorn this independent firm of experts, not a panel of
referees; EPA does it all! brea k through that medium-volume range
"wild guess" of mine, take a good look at where PMN is required but the costs are
the wild guesses EPA is ask,· ng us to make sect10n
• 5 of TOSCA (Toxic Substances too high for us to bear?
in the proposed forms for PMN ( pre- Control Act) makes it clear that no
manufacturing notification) procedures! registration procedure is intended to be set On page 2263 of the preamble we see that
Now, besides criticizing the proposed rules, up under PMN . Moreover, EPA affirms, the E PA Administrator, D ouglas Costle,
I mean to offer some specific remedies; for in the preamble to their proposed rules, has determined that " . . . . . this document
a starter, I'd say to exempt quantities that "Section 5 does not establish a cer- does not . . . require prepar ation of an
'"-------------�------ ---- --------------------'
© 1979 by Aldrich Chemical Company, Inc. Afdrichimica Acta, Vol. 12, No. 2, 1979 35
 economic impact analysis . . . . ," because (it subjective that you would be Changes in processes mean new in­
appears) of its low cost to industry. Well, justified in contacting none termediates, some of which will be subject
its impact on the small chemical business at all! to PMN rules. A 90-to 180-day delay in
community may be like that of a ton of Page 2269 "Submitter must state (to manufacture of such an intermediate could
brick. said person) that he is not cause a critical interruption in output of the
Anyone who has carefully read the under legal obligation to final product, and conceivably could make
proposed rules, explanations and forms provide . . . . (but) . . . EPA . .. the new intermediate a dead letter before its
(an ordeal that takes hours) gets these im­ may require (him) to provide production could begin!
pressions about the questions and the data . . . . " In the upshot, is it a To be considered a nonisolated in­
they ask for: legal obligation, or is it not? termediate, the chemical (it seems) must
l) . Some will require great expense. Page 2305 "Are there any structurally not be removed from the reactor in which it
2) Some can't be obtained until after related chemical substances is made (page 2248), and at first this seems
you're in production. which you have not discuss­ reasonable. But, frequently reversed addi­
3) Some open up the realm of pure con­ ed here? ( )yes ( )no. If tion is required for good yields or safety; in
jecture. yes, explain why." Does this that case, the intermediate chemical must
4) Some violate the traditions and prac­ refer to substances which be pumped from the original reactor into
tices of confidentiality. Here, a prime have been made (or found) another one, or to a holding tank from
example is the requirement of process and studied, or to all such which it is added back (at a controlled rate)
flow diagrams which are among our (there could be thousands) to the same reactor, now charged with a
most closely guarded secrets. which are capable of ex­ different reactant. Such slightly variant
istence? Does it ask why they procedures should not make these in­
Honestly, it seems as if EPA is asking for exist or why you didn't dis­
every conceivable piece of information no termediates subject to PMN.
cuss them? The implication
matter how difficult it is to obtain or how is that you should know My own company has submitted 66
sacred or how ridiculous. If they were con­ about them all and discuss chemicals for the "inventory", half of
sciously trying to stifle innovation (hence them. which are intended for intermediate use
progress) in the chemical industry (at least My preannounced topic of major con­ only. We are generating new ones at a rate
in the small business area), they would be cern was the treatment of chemical in­ of I or 2 per month, some with useful lives
on the right track. termediates in PMN. Now, in small of less than 6 months. It actually seems that
In their eagerness to cover the whole chemical manufacturing businesses, quick PMN treatment for just one of them could
waterfront they have come up with many turnabouts in customer requirements, raw consume our entire R & D budget for a
ambiguities and contradictions which call material availability and costs, actions by whole year. Is there any wonder that I am
for rethinking or rewriting. competitors, etc. call for rapid adaptation apprehensive?
Examples: by the manufacturer. New processes or With that question, which is really a cry
Page 2269 "Submitter must contact radical changes in old ones may be needed ­ for help, l should stop. I could go on and
each person whom he firmly - - and accomplished - - - almost overnight. on. But, others should get their chance to
believes will purchase . . . " Our ability to move fast is the chief reason speak up and I hope they will.
Now, "firmly believes" is so for our success - - - our existence.
syringe barrel filled with solvent. Barrels of
Lab Notes, con t'd long-term Fourier Transform acquisition.
different sizes may be used according to the
Joseph Piaru/li
Sterling Chemical Laboratories amount of solvent desired. Without the
The problems associated with cleaning "quick disconnect" and using a somewhat
· and drying dirty NMR tubes have been Yale University
shorter needle, the system may be used for
alleviated by the following procedure. New Haven, CT 06520
rinsing uv spectrophotometer cells.
Commercially available washers for Edward W. Sheppard, Sr.

8.r -·
NMR tubes are convenient, but also fragile Research Chemist, Mobil Corp.
and expensive.An almost unbreakable ver­ Corporate Research and Development
sion can be made quickly from a rubber Princeton, NJ 08540
NMR lube ..... t 6"" or 9"" stopper, a syringe barrel, a long ( 12-in) 14-
or 16-gauge blunt needle, and a polyethyl­ Most devices for cleaning NMR tubes
tncllned �.,- Paateur pipetle ene"quick disconnect," used to join lengths are fragile and/ or cumbersome. Here is a
of rubber tubing.Assembled as shown in practical version which is easily con­
..........
block -+
_
�------� "'- N,
the accompanying diagram, with theNMR structed and used:
The soiled tubes are rinsed several times tube to be washed resting on the inner ledge
with a solvent which solubilizes the residue of the "quick disconnect," the apparatus is

·-­
(if any), then twice with acetone. The inserted into a vacuum flask and the 0,3 fflffl 00 tuoea

problem now arises as to the mode of dry­

ing. Oven drying is time consuming and
not very efficient. One solution is to dry the
- to
NMA ....

NMR tubes under an infrared heat lamp at

a distance of 6 to 9 inches. Dry N2 gas is cir­
culated through the tubes via a long (9-in)
Pasteur pipette. The tubes are positioned
for drying on a grooved and inclined
wooden block. Drying is completed in One end of an inverted U of 3-mm o.d.
about ten minutes. Spectra run after this glass tubing is inserted through a stopper
into a filter flask. The NMR tube is filled
procedure do not show any residual water
or acetone peaks even under conditions of Cont'd on page 38
36 Aldrichimica Acta, Vol. 12, No. 2, 1979
 bla n k
P a g e i n te nt i a l ly
 bla n k
P a g e i n te nt i a l ly
Aldrichimica Acta
Volume 12, Number 3, 1979 Volume 12 Number 3 1979

New Synthetic Reagents and Reactions. See page 43.

Choosing and Using Noble Metal Hydrogenation Catalysts.
See page 53.
chemists helpi ng chemists 1n resear,ch & industry

aldrich chemical co_

 ®

Aldrichimica
Volume 12, Number 3, 1979
A publication of ALDRICH CHEMICAL COMPANY, INC.

Main Sales Office:

940 West Saint Paul Ave. About Our Cover: Abraham Bloemaert
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Telephone: (414) 273-3850 When we first looked at the painting reproduced on our cover, we
Order Desk: (800) 558-9 160 Toll-free were reminded of what wc had written about another Acta cover
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Telex: 26 843 collector did not limit himself to one painting per subject.
East Coast Service and Distribution Center: "The Bible is the book of dreams, par excellence: dreams of in­
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The vision of a ladder with angels going up and down on it is unique
1500 Stanley Street, Suite 405
Montreal, Quebec H3A IR3 in Biblical imagery, and so Jacob's Dream has aroused artists' im­
Telephone: (5 14) 845-9289 agination for centuries." This depiction (oil on canvas, 29 x 331/ 2 in­
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The Old Brickyard, New Road to bring out its original beauty. If only our chemist could find a good
Gillingham, Dorset many more such dreams of paintings.
SP8 4JL, England This painting and those on five other Acta covers are among twenty­
Telephone: 074-76 22 1 1 four Dutch and Flemish paintings in an exhibition in honor of
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In Belgium/Continental Europe: Are you interested in our Acta covers? Selections from the Bader
Aldrich-Europe Collection, with 30 duotone reproductions, many of previous Acta
B-2340 Beerse covers, and an introduction by Professor Wolfgang Stechow is
Belgium available to all chemist art-lovers.
Telephone: 0 14/6 1 143 1
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In Japan: Also, many paintings reproduced on our Acta covers were shown at
Aldrich Japan the Milwaukee Art Center in an exhibition, "The Bible Through Dutch
c/ o Tokyo Danchi Sohko Kanrito Eyes," arranged by Dr. Bader in 1976. The fully illustrated catalog with
4- 1, 3-chome, Heiwajima, Ohta-ku 66 black-and-white and 4 full-color reproductions contains many art
Tokyo, Japan historical and Biblical comments.
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In Israel: Many of the early issues of the A ldrichimica A cta have become very
Sigma Israel Chemical Co. rare. Please do not throw your issues away. In time, we believe that
P.O. Box 37673 complete sets will become valuable, and � - if you do not want to keep
Tel Aviv, Israel 6 1360 them - there probably arc chemists near you who would be interested.
Telephone: 03-6 123 15
Telex: (922) 35645 © 1979 by Aldrich Chemical Company, Inc.
 chemical coatings themselves represent The reciprocating motor supplied as part
contaminants since they dissolve in certain of the Aldrich Kugelrohr Distillation Ap­
organic solvents, and Teflon sleeves often paratus (Cat. No. Z I0,046-3) makes an ex­
leak and collect contaminants. This note tremely useful substitute for a conventional
describes a modification to the Kuderna­ rotary motor used to drive the paddle
Danish concentrator which does away with stirrer in a reaction flask. Since the os­
the outside ground-glass joint between cillating motor is either air- or vacuum­
receiver tube and flask. driven, there is little danger from electrical
sparking and the motor will not burn out if
The modified apparatus is illustrated in
the stirrer should stall.
Figure I. Instead of being detachable the
charcoal receiver tube is now physically joined to the Cont'd on page 49
There are many instances where it is dif­ evaporator flask and contains a ground­
ficult to prevent charcoal from passing glass joint inside the tube using a Quickfit
through a filter bed prepared from many of socket and cup piece. When the solution
the commonly used filter aids. This is par­ has been concentrated to a small enough
ticularly true, for example, when DMF is volume to be contained in the receiver tube
used as a solvent for a catalytic reduction (usually about 4ml) the Snyder column is
with Pt or Pd on charcoal. In such cases, removed and a micro-Snyder column with
the use of a bed of magnesium sulfate an extension tube if necessary, is lowered
(anhydrous reagent powder) helps over­ through the top of the evaporator flask and
come this difficulty. inserted into the ground-glass joint leading
Jules Freedman, Ph.D. to the receiver tube. Concentration of the
Organic Chemistry Department solution is continued until the desired
Merrell Research Center volume is obtained. Alternatively, the final
110 Amity Road concentration can be performed under
C incinnati, Ohio 45215 reduced pressure or using a stream of
nitrogen. The final concentrate is removed
by pipette and either injected directly into
the gas chromatograph or transferred for
A common problem is the vacuum filtra­ the next step, e.g., the clean-up stage in
tion of products from hot, highly acidic pesticide residue analysis.
solutions. It always seems that the filtra­
To conden sing
tion is 90% complete and then the filter
system
paper disintegrates. Hot, highly caustic
1 24/29
solutions and/ or slurries are equally hard
to handle. A convenient solution to this Earlier this year I received a very in­
problem is to use polypropylene filter teresting letter from Dr. J.A. Cotruvo,
cloth. Impervious to most mineral acids Director, Criteria and Standards Division
and strong bases, it is easily cut with a pair of the Office of Drinking Water of the EPA
of scissors into any size using the appro­ in Washington, expressing his deep con­
Evaporator
priate-size filter paper as a model. It is in­ cern about the unavailability of Basic
flask
soluble in almost all organic solvents, and Fuchsin. Dr. Cotruvo explained that "this
therefore can be used again and again. A dye is used as an ingredient in the
bed of Filter-Ce!® or Dicalite® on the cloth bacteriological medium m-Endo agar,

1 14/23
works beautifully in clarifying solutions which is used by most water treatment
facilities on a regular basis for the
Receiver tube
with activated charcoal. The cloth can be
easily cleaned by washing or even boiling in enumeration of certain bacterial indicators
Boiling chip
a solvent like acetone. of fecal pollution. National drinking water
regulations allow for only one other alter­
Henry C. Koppel Fig. 1. Modified Kuderna-Danish concentrator show­ native procedure (the Most Probable
Vice President, Production ing the position of the micro-Snyder column for the Number test), but this test is less precise
Aldrich Chemical Company final stage of the concentration process. and more expensive than that using m­
Editor's Note: Endo agar." I replied that the problem
For the convenience of our customers, Apart from obviating the need for an might have seemed funny if it wasn't so sad
Aldrich offers this filter cloth. outside joint between the receiver tube and and serious. Basic Fuchsin used to be made
evaporator flask the modification has by two large American companies which
Zl0,425-6 Polypropylene filter cloth, another advantage. The micro-Snyder have discontinued its production (and that
94cm wide 1 meter $5.25 column, being enclosed completely by the
5 meters $21.00
of many other low-volume stains and dyes)
evaporator flask, can operate more ef­ because of regulatory pressures!
ficiently especially if the flask is evacuated In this case we were able to help. We are
by use of an adapter with vacuum take-off now manufacturing Basic Fuchsin on a
and outlet (e.g., Quickfit plastic screwcap­ modest scale, and will continue unless the
The Kuderna-Danish concentrator suf­ type) for the top of the Snyder column EPA stops us.
placed at the outlet from the flask. Im­
85, 734-3 Basic Fuchsin, certified
fers from the disadvantage that the ground­
proving the efficiency of fractional distilla­
25g $18.00; lO0g $ 50 .00
glass joint between the evaporator flask
tion at this stage is vital if pesticides are not
86,108-1 Basic Fuchsin, special for
and receiver tube represents a potential
to be lost in the process.
Sg $6.00
contamination site. Unless grease, a
flagella, certified
25g $ 20 .00
chemical spray coating (e.g., Teflon®) or a R.D. Davies
Teflon sleeve is used to render the joint Fuel Research Institute
watertight, water vapor seeps in depositing P . O. Box 217 It was no bother at all, just a pleasure to be
chlorides and other salts. Both grease and Pretoria, South Africa able to help.

42 Aldrichimica Acta, Vol. 12, No. 3 , 1979

 New Synthetic Reagents
and Reactions *
New Synthetic Reagents and Reactions
George A. Olah
Hydrocarbon Research Institute
and Department of Chemistry
University of Southern California
Los Angeles California 90007 George A. Olah
Hydrocarbon Research Institute
and Department of Chemistry
University of Southern California
Los Angeles, California 90007

I. INTRODUCTION nitronium salts as nitrating agents enables,

Synthetic organic chemistry encom­ for example, even trinitration5 of benzene
passes, besides multistep synthesis of com­ to trinitrobenzene. ArH
plex target molecules (frequently natural
products with specific stereochemistry),
the development of simple, basic reactions
and new methods for carrying out in­
dividual steps or preparing products.
It is in this latter area that our synthetic
investigations are centered, encompassing Nitro-onium ions, such as C5 H5 N+N02 ,
the study of basic (unit) reactions as well as readily prepared6 " · 0 from suitable donors R-OH + ►
development of new reagents. and nitronium s'alts, act as convenient
transfer nitrating reagents in generally
II. NITRATION
selective, clean reactions. Transfer nitra­
Conventional nitration 1 of aromatic
tions are equally applicable to C- as well as
compounds uses mixed acid (mixture of
to 0-nitrations allowing, for example, safe, +
nitric and sulfuric acid). In the reaction the
RON02
acid-free preparation of alkyl nitrates and
water formed dilutes the acid; further, due
polynitrates from alcohols (polyols). 6c
to its strong oxidizing ability, mixed acid is
ill-suited to nitrate many sensitive com­
pounds. It also presents serious problems
in spent-acid disposal. We have developed a
series of efficient new nitrating agents and
methods to overcome these difficulties.
Readily prepared and isolated stable
nitronium salts, such as N02BF4 and
NOiPF6, nitrate aromatics2 in organic
solvents generally in close-to-quantitative
yields. Alkyl nitrates, such as MeON02 , 3
BuON02 or acetone cyanohydrin nitrate,
MezC(CN)ON02 ,4 with BF3 as catalyst are
similarly effective and more selective
nitrating agents. The powerful nature of

ArH + CH30N02
or
(CH 3)2 c(cN)ON02

• Based on Lecture given upon receipt of the American

Chemical Society Award for Creative Work in Syn­
thetic Organic Chemistry, 1979, sponsored by the Al­
drich Chemical Company, delivered at the ACS/CSJ Professor George A. Olah (right) receiving the A CS A ward/or Creative Work in Synthetic Organic
Chemical Congress in Honolulu, Hawaii, April 4, 1 979 Chemistry sponsored by Aldrich, from Dr. Irwin Klundt, vice-president of Aldrich.
(Paper ORGN 236).

© ) 979 by Aldrich Chemical Company, Inc. Aldrichimica Acta, Vol. 12, No. 3, 1979 43
 A new nitration system in the form of III. HALOGENATION
nitrosonium (NO)' salts in DMSO was Fluorination of organic compounds still Fluorinations with Pyridinium
developed.7 The S-nitro � S-nitrito requires special techniques not generally Polyhydrogen Fluoride
equilibrium was also directly observed by feasible in the average laboratory. Reac­
1 3C and 1 5N N MR spectroscopy. tions with the industrially most generally
C 5H 5NH{HF),F
used and inexpensive fluorinating agent,
+

RNCO ► RNHC OF
- S - ONO anhydrous hydrogen fluoride, must be
+

carried out under pressure in special equip­

CH
3 I

ment due to its relatively low boiling point ROH ► RF

C H3

1� (20" C) and corrosive nature.

ArN02 ◄ ArH CH3- � -N02
+
We have found a simple way to enable HgO ►
RCH RCH F2
;X
carrying out anhydrous hydrogen fluoride ,y
reactions at atmospheric pressure in or­
CH3

Solid superacid catalysts, comparable to dinary laboratory equipment (polyolefin

o_r stronger than sulfuric acid, play a or even glass) - by using the remarkably R2C N2 ► R 2C H F
significant role in replacing conventional stable complex formed between pyridine
liquid acid (protic and Friedel-Crafts-type and excess hydrogen fluoride. HF (70%
w/w) and pyridine (30%) form a liquid com­ RCOCHN2 ► RCOCH2 F
Lewis) catalysts in developing novel, clean,
heterogeneous reactions. In the case of plex, C5 H5 NH +(HF).F-, showing little
vapor pressure at temperatures up to Where X and Y = Cl, Br, I
nitration, not only were alkyl nitrate
nitrations carried out in this way, but also 60° C .8 T h e reagent (pyridinium
b

the azeotropic nitration of aromatic com­ polyhydrogen fluoride) thus enablesB<b - n Oeaminative Fluorination Reactions in

pounds with nitric acid was developed4,5 �me to carry out a wide variety of synthet­ Pyridinium Polyhydrogen Fluoride
JCally very useful fluorination reactions at
Solution
over solid perfluorinated sulfonic acid
catalysts (Nafion-H). atmospheric pressure under very simple ex­ NaNO2 ►
perimental conditions. Examples of the Arf
usually high-yield reactions are:

N H2 FI
Water f ormed is continuously azeotroped
Hydro- and Halofluorination of Olefins
NaNO 2
and Acetylenes
R CHC02H RCHC02H
off by excess of aromatics, thus preventing
I
►
dilution of acid and allowing its extensive
utilization. NaNO2
ROC N H2 ► ROCII F
Electrophilic nitration of olefins is also
0 0
II
readily carried out8 0 with nitronium salts in
pyridinium polyhydrogen fluoride as sol­ The pyridinium polyhydrogen fluoride
vent. The reaction gives high yields of reagent is also very convenient for the in
nitrofluorinated alkanes which subse­ situ preparation of inorganic fluorides such
quently can be dehydrofluorinated to as SF4 .9 Due to the good solvent properties
nitroolefin.
C5H 5NH(H F ) ,F ►
NOt BF, S2C l2 SF4
+

'c - c/
x
Q-
pyridine-(HF ), ► / I 1 '- R2CO -
R 2CF2
►
f N02
Some of the characteristic reactions of of pyridinium polyhydrogen fluoride, SF4
NO2 and NO+ salts are depicted in Figures I X = C l, Br, I ► fluorinations can be carried out in situ at
and II, respectively. atmospheric pressure.
Figure I. Figure II. ArN;
+
H 20
ArN02

ArNSO

ArH
RNH2 NO
0
ArR RC02H
+
RCNH2
ArH

R0N02
ROH NO; 0 O
N02 RON0
ROH
SbCl;orBF4-
or PF; RNSO
R + N2 + S02
+

a
PF;or BF;
CsHsC H( CH 3) 2
R C02H Ph3C H
RC H=C H 2 N

,o

0
R R' /C H3
R- c'
RCO0N02
RCH=CH-N02 R -C
� N-N02 MN
N Ph3C
+ o c+
' c H3
'o H
N
CH 3 NO
"f'

- ---�---,,--

44 Aldrichimica Acta, Vol. 12, No. 3, 1979

 IV. ALKYLATION
Nafion -H ►
An alternative reagent, selenium tetra­ 0
fluoride (SeF4 ), which has an atmospheric In the Friedel-Crafts alkylation method R -C -OH + R 0H
� 1
R - C -OR
1

boiling point of 106 , was also developed.

° 10 using aluminum chloride or related metal
halide catalysts, complex mixtures of
Nafion-H ►
Fluorination of ketones, aldehydes, etc.,
0
R-C-R + MeC(OMe)3
proceeds in high yield.Since selenium com­ products are generally formed due to con­ 1
pounds are generally toxic, the reagent secutive and concurrent polyalkylation
must be handled with great care. and isomeriza tion-disproportionation OMe OMe
processes.They are promoted by extensive R�C'.'.'.:_R,
►
SeF4 carbocationic complex formation with the
catalyst.1 6 CH2-XH Nafion-H
Cyanuric fluoride, another easily prepared R-C-R + ►
�

CH2-XH
In order to avoid much o f the side reac­
1
I
r-,
fluorinating agent, is particularly advan­
\ X
tions and complex formation that neces­
tageous in the preparation of acyl sitate aqueous acid/ caustic workup (gen­
R - C�R'
fluorides, including formyl fluoride. 1 1 erally accompanied by loss of the catalytic X = O,S

N-<F
)CX
X
halide), high-acidity solid acid catalysts

3R
P.
-C-OH
which allow clean heterogeneous reac­
+
Ff�\\ tions without workup problems have been
used increasingly. My group 1 7 has found of
+ ( N,fioo-H ►
F particular utility, solid perfluorinated sul­
fonic acids such as the acid form of R Nafion-H
R t-+R ► )-f. R
R R

3R-C-F
DuPont's ion-membrane Nafion resin R

OH OH 0
+ (Nafion-H) or longer-chain perfluorinated R

0
alkanesulfonic acids such as perfluoro­
Nafion- H ►
decanesulfonic acid (PDSA). If needed, the
Uranium hexafluoride depleted of U235 is R -C:C-R R-C-CH2 R
H20
II 1

an abundant by-product of enrichment Solid Superacid Catalysts

plants. It was found 1 2 to be highly soluble For selective laboratory alkylations, we
in fluorocarbons and halofluorocarbons, have also developed a series of ionic
thus allowing its convenient use in alkylating agents. Although Meerwein's22
atmospheric-pressure fluorination reac­ trialkyloxonium and dialkoxycarbenium
tions (as well as in oxidations, vide irifra). tetrafluoroborate and hexachloroanti­
monate salts (as well as the conveniently
Nafion-H soluble hexafluorophosphate salts used in

jf;J
UFs
CF2CICFCl 2
► our work23) are widely used as transfer
alkylating agents, they lack selectivity and
generally are incapable of C-alkylation.
CF3(CF2)9S03H

J[J· PDSA
acidity of these acids, which is similar to
that of liquid Magic Acid® (FSO3 H-SbF5 ),
+
Dialkylhalonium salts such as di­
P.
R C-H RC-F
II
can be further increased by complexing
with higher-valency fluorides such as SbF5 ,
methylbromonium and dimethyliodonium
fluoroantimonate, prepared from excess
TaF5 , and NbF5 . t 8 alkyl halide with antimony pentafluoride
Due to the high carcinogenic activity of or fluoroantimonic acid and isolated as
Alkylation of aromatics with olefins,
chloromethyl ethers, 1 3 chloromethylation alkyl halides, alcohols (including methyl
stable salts, as well as the less stable
reactions have presented significant prob­ chloronium salts obtainable in solution,
alcohol), esters and the like takes place
with ease over these catalysts.1 9
2 RX
lems in recent years.A simple substitute for
the preparation of chloromethylarenes is
the selective side-chain chlorination of RCH=CH2
R 0H RX R + Nu­ ---t► RNu + RX
1 +
methylarenes. Whereas many radical •
chlorinations are known, an exceedingly 1 1
ArH + R X ----;�==-�► ArR R = CH3, C2H 5, etc. X = I, Br, Cl
R'OCX
simple and efficient PCkcatalyzed side­
chain chlorination of alkylbenzenes (and 11 are very effective alkylating agents for
alkanes) was found. ' 4 0 heteroatom compounds (Nu = R2 O, R2 S,
(co2 R')2 R3N, R3P, etc.), and for C-alkylation
(arenes, alkenes). As the nature of the
Transalkylation of aromatics with di- or halogen atom can be varied, these salts
polyalkylbenzenes can be carried out with provide useful selectivity in their alkylation
equal ease. 20 reactions.24
An alternative chloromethylating agent, A great variety of other halonium ions
CeH6 + R R C 6H4
1 11
l -chloro-4-chloromethoxybutane, react­
ing via oxygen participation to give
was also prepared, including the following:
CsHs R'+ R" CsHs
tetrahydrofuran as the by-product, is also
very effective. 1 5 Solid superacid catalysts of the Nafion­ [>-x-cH3 Q Qx-cH3

►
H type also efficiently catalyze various
ZnCl2
SnC1 4
reactions such as esterification, ketal X = I, Br
-HCI
( acetal) formation, Diels-Alder reactions,
pinacol-pinacolone rearrangement and Their alkylating abilities were also
hydration of alkynes. 2 1 studied.24'; z 5
Aldrichimica Acta, Vol. 12, No. 3, 1979 45
 Not only onium ions,but also carbocat­ Formic anhydride was also prepared, Benzyl and benzhydryl ethers are cleav­
ion salts, can be prepared and used as high­ characterized (by NMR and IR spec­ ed to the corresponding alcohols and benz­
ly reactive alkylating agents. The remark­ troscopy), and used as a new formylating aldehyde or benzophenone, respectively.
ably stable triphenylcarbenium salts are agent.32 Benzyl alcohols are further readily oxi­
widely used as hydride-abstracting agents
H �
0 o 0II dized to the corresponding carbonyl com­
and as initiators for cationic polymeriza­ II + -
pounds.
tions. Using methods developed for pre­ H-C-F + NaO -C-H �

DCC
paring stable carbocations in superacidic + -
0 PhCHROH + UF6 -. PhCHROHF
/ ether
media and isolating the salts generally by ► H-C� I
UF5
addition of Freon-type solvents or by
f? SOCl 2, pyridine
'o - HF
► H-C/ -UF4
evaporation of solvent SO2 , SO2 ClF or ► PhCR=OHF- � PhCR=O
ether
S02 F2 , we have isolated a series of stable 2 H-C-OH
-::::.o
'-.. CISO,NCO, Et3N �
salts. 26 Typical carbocation salts,general­
Oxidative cleavage of protected car­
ether
ly isolated as the fluoroantimonates, in­
clude such simple tertiary ions as the tert­ bonyl compounds such as tosylhydrazones
butyl and adamantyl cations,27 as well as and N, N-dimethylhydrazones also takes
stabilized secondary ions,such as the nor­ VI. OXIDATION AND OXYGENA­ place with ease upon aqueous quenching of
bornyl cation. TION the initially formed UF6 adducts.

£0
During investigations of oxidation reac­
(CH3)3 c• Sb2F11-

JQ
tions, including electrophilic oxygenation
of hydrocarbons,we have studied new oxi­
dations with higher-valency fluorides N, N-Dimethylalkyl(cycloalkyl)amines
SbF; (UF6 ,WF6 ,MoF5 ,IF5 and CoF3 ),I2, 33 per­ are also oxidized by UF6 yielding, upon
oxy compounds (UO4 • 2H2 O),34 super­ aqueous quenching,the corresponding car­
acid-catalyzed hydrogen peroxide 35 and bonyl compounds.
ozone reactions36 (i.e. , with H3 O2 and
A particularly advantageous new tech­
nique is to carry out alkylation reactions 1
O H•),as well as oxidations with NO2 •. , 7 37
RRCHN-CH3 + UF6
with alkyl halides by initiation with 3
I
nitrosonium salts. Using this reaction, a In spite of the availability of uranium CH3
very mild form of the Ritter reaction was hexafluoride depleted of fissionable 23 5 U + H 20
► 1
I

developed. 28 RRC=N-CH3 RRCO

and its remarkable properties,the study of I
c�
NOPF6 R'CN
R-X ► �-X-N� PF&- ► WF6 ,MoF5 , IF5 ,and CoF3 are capable

•NOX S N 1
of oxidations similar to those with UF6 but
�
are considerably less easily available and
also tend to give more fluorination side
,:,0 reactions.
R-NH-C '
'R Both hydrogen peroxide and ozone
[R•] ---
► �'j readily protonate in superacids,giving the
R 'CN
i
reactive electrophilic oxygenating agents
A = alkyl, aralkyl Hp•-OH and O==O•-OH,respectively.

X F , Cl, Br, I
R' = Me, Et, Pr, Ph, Bzl Protonated ozone,upon reaction with a
H2
[it·N=C-Rj tertiary alkane via front-side insertion into
0

►
the C-H bond, gives a very unstable tri­
V. ACYLATION, SULFONYLATION the reactions of UF6 with organic com­ oxide which immediately undergoes acid­
Solid superacidic catalysts of the pounds remained virtually unexplored. catalyzed cleavage rearrangement leading
Nafion-H type are also effective in bringing The highly covalent nature of UF6 makes it to the corresponding ketone and alcohol.
+

P�
about Friedel-Crafts-type acylations with particularly suitable for reaction in non­
aroyl halides. 2 9 Interestingly, acetyl aqueous solvents. Stable solutions of UF6 H• ►
· "s:o
+
Nafion - H ►
•
in chlorofluorocarbons (Freons) or chloro­ o
+ +
ArH + R'COCI ArCOR' hydrocarbons (methylene chloride or HO-O=O ► HO-O-O

f
chloroform) can be used conveniently as
chloride gives predominantly ketene under they do not attack glass and are generally R
easy to handle. I +
the reaction conditions. R - C -H + O-O-OH ►
R
I
Isolated acyl salts, such as acetyl, pro­ Ethers undergo oxidative cleavage to
pionyl and benzoyl salts,as well as similar­ form carbonyl compounds and alcohols.
ly isolated sulfonyl halide-antimony pen­ Furthermore, the direction of cleavage is RI o-o-oj·
,,
tafl uo ride complexes, are effective predictable,thus the utility of ethers (such R -C 1 1 1 t
R
acylating (sulfonylating) agents. 30 as benzyl or benzhydryl ethers) as protect­ I ',H
ing groups for alcohols is broadened. The
oxidation of methyl ethers is of high yield
and regiospecific. Trapping experiments RI
+H+
RI H
RSO2F•Sbfs + ArH __.. ArSOzR with phenyllithium suggest the inter­ R-C-O-O-OH ---1►
� R-C-O-O-OH
I I +
mediacy of methoxycarbenium ions in the R R
Acylation3 1 " withacyl fluorides,general­ reaction.
ly catalyzed by boron trifluoride, also 1 ►
allows formylation,as formyl fluoride is a R R'CHOMe + UF6 � RRCHOMeF-
1
stable acyl halide of formic acid. Ufs
1
ArH + FCHO ArCHO RR'C =OMe � R R C=O

46 Aldrichimica Acta, Vol. 12, No. 3, 1979

 The reaction can be considered as the examples are: Other recently40 developed reagents
aliphatic equivalent of the well known from our laboratory include the solid,
cumene hydroperoxide reaction giving
+
stable and quite soluble trimethyl(ethyl)­
phenol and acetone. aminesulfur dioxide complexes R 3N · S02 .
N 0 2 PFa(B F .)
Ar3CH Ar3CPF; + [HN<?]
These "solid forms" of S02 make many de­
►

Protonated hydrogen peroxide similarly hydrogenation, reduction, and halo­

acts as an electrophilic hydroxylating
0 0
II
genation reactions readily available,
agent, forming alcohols which can react
II
NO+
Ar - CH2-0-C-R ► RC-OH
avoiding the use of inconvenient, low­
further with hydrogen peroxide giving boiling, and difficult-to-handle sulfur di­
hydroperoxides and thus, acid-catalyzed ArCH20H
N O+
ArCHO oxide. Examples are:
cleavage rearrangement products.
►

0 R-CH2-N02 ► R-C:N
H+ H N 0 2+ II
HOOH .= HO-OH R1-9H-OCR3 R,-C-R2

t l
+
►

R2 R-CH2-CHNOH
CH3 CH3 0
► ,, H Nal II
I H aO2+ I N O2 II
CH -C-H CHrC I 11•�, R,-9=N-OH R 1 -C-R 2 ►
-78° C R-C-CH,
+
3 I
or N O ►

CH3 'OH
I
CH3 R2
Acknowledgment
Support of our research by the National
-H,0
9H3 0
Science Foundation, the National In­
N O+ or N O 2 II

�
�
R,-C=N-CH3 ► R 1C-R 2
stitutes of Health and the U.S. Army Office
I
9H3 CH3 R2
CH3-C -OH
H+
► CH3-c: N 02
of Research is gratefully acknowledged.
I -H 2O I
CH3 CH3 ►

References:
H 2
i P r7
s s
1) N O+ or N O 2
►
0
II
R-C-R 1) J.G. Hoggett, R.B. Moodie, J.R.
RxR
2) H,0
Penton, and K. Schofield, "Nitration
and Aromatic Reactivity," Cam­
VII. MISCELLANEOUS REAGENTS bridge University Press, Cambridge,
The utilization of iodotrimethylsilane, 197 1 .
( CH3 )3Sil, 38 (also studied independently by 2) a) G.A. Olah, S.J . Kuhn, and S.H.
M. Jung39) and its simplified in situ analogs Flood, J. Am. Chem. Soc. , 83,
458 1 ( 1961).
In situ lodotrimethylsilane Reagents b) G.A. Olah and S.J. Kuhn, ibid. ,
84, 3684 ( 1962).
Benzene and alkylbenzenes are hydrox­ c) G.A. Olah, S.J. Kuhn, S.H.
ylated to phenols with high selectivity as Flood, and J.C. Evans, ibid., 84,
the products are protonated in the acidic 3687 ( 1962).
3) a) G . A . Olah and H.C. Lin,
C6H 5Si�H3)3 + 12
media and thus, are protected from further
oxidation. Synthesis, 489 ( 1973).
CISi�H3)3 + Nal (in CH3CN)
b) G.A. Olah and H.C. Lin, J. Am.
Chem. Soc. , 96, 2892 ( 1974).
ArH offer excellent preparative possibilities for 4) a) G.A. Olah and S.C. Narang,
mild, neutral, nonaqueous cleavage-hy­ Synthesis, 690 ( 1978).
The nitronium ion, N02 , is generally drolysis reactions, deoxygenations, oxida­ b) G.A. Olah, R. Malhotra, and
considered to function only as a nitrating tions, halogenations, and the like. Some S.C. Narang, J. Org. Chem. , 43,
agent. It was found, 7 however, that it examples are:
possesses significant ambident reactivity 4628 ( 1978).
c) S.C. Narang and M.J. Thomp­
and acts as an oxidizing agent. Dialkyl I
son, Aust. J. Chem. , 31, 1839
(aryl) sulfides and selenides, as well as R-O-R
( 1978).
trialkyl(aryl)phosphines, react with nitro­
or M e3S iC I/I­
5) G.A. Olah and H.C. Lin, Synthesis,
1 I
nium salts to give the corresponding ox­
R-OH + R0H + RI + RI
444 ( 1974).
ides.
0 0 6) a) G.A. Olah, J . A. Olah, and N.A.
• R-c!-o H +
R-c -o -R' --....► R1
1
Overchuk, J. Org. Chem., 30,
R-S-R R-S - R 3373 ( 1965).
t 0 b) C.A. Cupas and R.L. Pearson, J.
0
R-S-R
II
R-S-R
1 Am. Chem. Soc., 90, 4742 ( 1968).
c) G.A. Olah, S.C. Narang, R.L.
I

Pearson, and C . A. Cupas,

R-Se-R R-Se-R R-OH R-1 Synthesis, 452 ( 1978).
7) G.A. Olah, B.G.B. Gupta, and S.C.
►

♦
Narang, J. Am. Chem. Soc. , in press.
0 0
R -N-C-0-R" --+ R-NH + R"-I 8) a) G.A. Olah and M. Noj ima,
Synthesis, 785 ( 1973).
I I
R'
b) G.A. Olah, M. Nojima, and I .
R'
Another interesting aspect of our work Kerekes, ibid., 7 7 9 ( 1973).
relates to the utilization of stable nitronium c) Idem, ibid. , 780 ( 1973).
CISi Me3/Li ,S
R-OH ►
- R- O - S"M
d) G.A. Olah and M. Noj ima, ibid.,
I e3
(NO!) and nitrosonium (NO+) salts, par­
ticularly the PF6 and BF4 salts, as mild and 786 ( 1973).
selective hydride-abstraction and oxi­ e) G.A. Olah and J. Welch, ibid. ,
dative cleavage agents. 37 Representative 652 ( 1974).

Aldrichimica Acta, Vol. 12, No. 3, 1979 47

 f) Idem, ibid., 653 ( 1 974). ( 1966) . c) G.A. Olah and T.L. Ho, J. Org.
g) Idem, ibid., 654 ( 1 974). b) H. Meerwein, E. Battenberg, H. Chem., 42, 3097 ( 1 977).
h) Idem, ibid., 896 ( 1 974). Gold, E. Pfeil, and G. Willfang, J. d) T.L. Ho and G .A. Olah,
i) G.A. Olah and J. Welch, J. Am. Prakt. Chem. [2], 154, 83 ( 1 940). Synthesis, 4 I 8 ( 1 977) .
Chem. Soc., 97, 208 ( 1 975). 23) a) G.A. Olah and J.J. Svoboda, e) G.A. Olah, S.C. Narang, G.F.
j) G.A. Olah, J. Welch, Y.D. Synthesis, 52 ( 1 973). Salem, and B.G.B. Gupta, ibid.,
Vankar, M. Nojima, I. Kerekes, b) G.A. Olah, J.A. Olah, and J.J. 273 ( 1 979).
and J. A. Olah, J. Org. Chem., in Svoboda, ibid., 490 ( 1973). 38) a) T.L. Ho and G.A. Olah, Angew.
press. 24) a) G.A. Olah and J .J. Svoboda, Chem., Int. Ed. Engl., 15, 774
9) G.A. Olah, M . R. Bruce, and J. ibid., 203 ( 1 973) . ( 1 976) .
Welch, lnorg. Chem., 16, 2637 ( 1 977). b) G.A. Olah and Y.K. Mo, J. Am. b) G.A. Olah and T.L. Ho,
IO) G.A. Olah, M. Nojima, and I. Chem. Soc., 96, 3560 ( 1 974). Synthesis, 4 I 7 ( 1 977) .
Kerekes, J. Am. Chem. Soc., 96, 925 c) G.A. Olah, "Halonium Ions," c) G.A. Olah and T.L. Ho, Proc.
( 1974). Wiley-Interscience, New York, Nat. Acad. Sci. U. S.A., 75, 4
1 1) G.A. Olah, M. Nojima, and I . N.Y., 1975, and references cited ( 1978).
Kerekes, Synthesis, 487 ( 1 973). therein. d) G.A. Olah, B.G.B. Gupta, and
1 2) a) G.A. Olah, J. Welch, and T.L. 25) G.A. Olah, G.K.S. Prakash, and S.C. Narang, Synthesis, 583
Ho, J. Am. Chem. Soc., 98, 67 1 7 M.R. Bruce, J. Am. Chem. Soc., in ( 1977).
( 1976). press. e) G.A. Olah, S.C. Narang, B.G.B.
b) G.A. Olah and J. Welch, ibid., 26) a) G.A. Olah, Angew. Chem., 85, Gupta, and R. Malhotra, ibid., 6 1
100, 5396 ( 1 978) . 1 83 ( 1 973) . ( 1979).
1 3) a) B.L. Van Duisen, A. Sivak. B.M. b) G.A. Olah, Aldrichimica Acta, 6, f) G.A. Olah, S.C. Narang, B.G.B.
Goldschmidt, C. Katz, and S. 7 ( 1 973) . Gupta, and R. Malhotra, J. Org.
M elchionne, J. Nat. Cancer Inst., 27) G.A. Olah, J.J. Svoboda, and A.T. Chem., 44, 1 247 ( 1 978) .
43, 48 1 ( 1 969). Ku, Synthesis, 492 ( 1 973). g) Idem, ibid., in press.
b) R.T. Drew, V. Cappiello, S . 28) G.A. Olah, B.G.B. Gupta, and S.C. h) G.A. Olah, S.C. Narang, B.G.B.
Larkin, and M. Kuschner, 1970 Narang, ibid., 274 ( 1 979) . Gupta, and R . Malhotra; Angew.
Conference of the American In­ 29) G.A. Olah, R. Malhotra, S.C. Chem., in press.
dustrial Hygiene Association, Narang, and J.A. Olah, ibid., 672 39) a) M.E. Jung, W.A. Andrus, and
Abstract 164. ( 1978). P.L. Ornstein, Tetrahedron Lett.,
1 4) G.A. Olah, P. Schilling, R. Renner, 30) a) G.A. Olah and H.C. Lin, ibid., 4 1 75 ( 1 977) and references cited
and I. Kerekes, J. Org. Chem., 39, 342 ( 1 974) . therein.
3472 ( 1974). b) G.A. Olah, H.C. Lin, and A. Ger­ b) M.E. Jung, M.A. Muzarek, and
1 5) a) G.A. Olah, D.A. Beal, S. H. Yu, main, ibid., 895 ( 1 974). R.M. Lim, Synthesis, 588 ( 1 978).
and J.A. Olah, Synthesis, 560 3 1) a) See reference 1 6. 40) a) G.A. Olah and Y. D. Vankar,
( 1974). b) G.A. Olah and S .J. Kuhn, J. Am. ibid., 702 ( 1 978) .
b) G.A. Olah, D.A. Beal, and J.A. Chem. Soc., 82, 2380 ( 1 960) . b) G.A. Olah, Y.D. Vankar, and
Olah, J. Org. Chem., 41, 1 627 32) G.A. Olah, Y.D. Vankar, M. Ar­ B.G.B. Gupta, ibid., 36 ( 1 979).
( 1976). vanaghi, and J. Sommer, Angew. c) G.A. Olah, Y.D. Vankar, and
16) G.A. Olah, "Friedel-Crafts Chem­ Chem., in press. A.P. Fung, ibid., 59 ( 1 979) .
istry," Wiley-lnterscience Publishers, 33) a) G.A. Olah and J. Welch,
New York, N.Y., 1973. Synthesis, 809 ( 1 976).
1 7) G.A. Olah, G. Messina, J. Bukala, b) G.A. Olah, J. Welch, G.K.S. About the Author
J.A. Olah, and G.D. Mateescu, Prakash, and T. L. Ho, ibid., 808
Abstracts, 1st North American ( 1 976) . George Olah is Professor of Chemistry
Chemical Conference, Mexico City, c) G.A. Olah and J. Welch, ibid., at the University of Southern California,
Mexico, Dec. 1 975, Paper PHSC l 53 . 4 1 9 ( 1 97 1) . Los Angeles, and Co-director of the
1 8) G.A. Olah and J. Kaspi, J. Org. d) G.A. Olah, J. Welch, and M. Hydrocarbon Research Institute. His work
Chem., 42, 3046 ( 1 977). Henninger, ibid., 308 ( 1 977) . was honored by such previous recognitions
19) a) J. Kaspi, D.D. Montgomery, and 34) G.A. Olah and J. Welch, J. Org. as the American Chemical Society A ward
G.A. Olah, ibid., 43, 3 147 ( 1 978) . Chem., 43, 2830 ( 1 978) . in Petroleum Chemistry, the Leo Hendrick
b) G.A. Olah and D. Meidar, 35) a) G.A. Olah, N. Yoneda, and D.G. Baekeland Award and the Morley Medal.
Nouveau J. Chim., 3, 269 ( 1 979) . Parker, J. Am. Chem. Soc., 99, He belongs to a number of scientific
c) J. Kaspi and G.A. Olah, J. Org. 483 ( 1 977) . societies and is a member of the National
Chem., 43, 3 142 ( 1 978). b) G.A. Olah and N. Yoneda, ibid., Academy of Sciences.
d) G .A. Olah, R. Malhotra, D. 99, 3 1 1 3 ( 1 977) . Professor Olah's research interests range
Meidar, J.A. Olah, and S.C. c) G.A. Olah and R. Ohnishi, J. from basic studies in hydrocarbon and
Narang, J. Catalysis, in press. Org. Chem., 43, 865 ( 1 978) .
a) G.A. Olah and J. Kaspi, Nouveau
petroleum chemistry to the study of new
20) d) G.A. Olah, D.G. Parker, and N. synthetic methods and reactions including
J. Chim., 2, 581 ( 1 978). Yoneda, Angew. Chem., Int. Ed. investigation of reaction mechanisms and
b) Idem, ibid., 2, 585 ( 1 978) . Engl., 17, 909 ( 1 978) . intermediates, most notably carbocations.
21) a) G.A. Olah, T. Keumi, and D. e) G.A. Olah, T. Keumi, and A. P. He pioneered, inter a/ia, the field of
M eidar, Synthesis, 929 ( 1 978) . Fung, Synthesis, in press. superacid chemistry, i.e., acid systems
b) G.A. Olah, G.F. Salem, S.C. 36) a) G.A. Olah, N. Yoneda, and D.G. millions of times stronger than sulfuric
Narang, and D. Meidar, ibid., in Parker, J. Am. Chem. Soc., 98, acid, allowing observation and even isola­
press. 225 1 ( 1 976) . tion of many previously considered un­
c) G.A. Olah, D. Meidar, and A.P. b) Idem, ibid., 98, 526 1 ( 1 976). stable species such as carbocations,
Fung, ibid., 270 ( 1 979). c) G.A. Olah, N. Yoneda, and R . halonium ions, and various other onium
d) G.A. Olah and D. Meidar, ibid., Ohnishi, ibid., 98, 734 1 ( 1 976). and carboxonium ions. A new field of
358 ( 1 978). 37) a) G .A . Olah and T . L . Ho, chemistry is rapidly evolving using both li­
e) Idem, ibid., 67 1 ( 1 978) . Synthesis, 609 ( 1976). quid and solid superacidic catalysts
22) a) H. Meerwein, Org. Syn., 46, 1 20 b) Idem, ibid., 6 I O ( 1 976) . developed in his studies.

48 Aldrichimica Acta, Vol. 12, No. 3, 1979

Aldrich offers these compounds cited 17,506-4 Nitrosonium tetrafluoroborate SOLVENT FOR
by Professor Olah: 25g $28.00; 50g $45.00
17,625-7 Acetyl fluoride 62g $72.25 19,773-4 Phenyltrimethylsilane LOW- AND HIGH­
17,5 12-9 Antimony pentafluoride 25g $ 15. 10; 100g $43. 10
17,8 10- 1 Sulfuryl chloride fluoride
TEMPERATURE 1 H-NMR
100g $54.00
14,074-0 Benzoyl fluoride 25g $ 14.05 !Og $32.50; 25g $65.00 DD D D i
JO0g $36.85 16,467-4 Triethyloxonium hexachloro- g D
C7,285-4 Chlorotrimethylsilane antimonate 25g $24.00
JO0g $5. 50; 500g $ 1 1.00 50g $38.00
ro
D
17,757-1 Dimethylbromonium hexa- 16,468-2 Triethyloxonium hexafluoro-
D
D D
fluoroantimonate
D
phosphate 25g $33. 00 DD DD
25g $45.00 50g $55.00 Decahydronaphthalene- d1 e,
17,759-8 Ethyl fluorosulfonate 17,623-0 Triethyloxonium tetrafluoro- m ixture of cis and trans
IO0g $28.00; 500g $93.20 borate, I M in CH2Cl2
21,713-1 1 g $35.00
17,5 10-2 Fluoroantimonic acid 19g $23.00; 38g $34.00
50g $55.00 16,465-8 Trimethyloxonium hexachloro-
17,760- 1 2-Fluoro-2-methylpropane antimonate ! Og $ 19.00
(tert-butyl fluoride) 25g $38.00
FLASH
76. l g $72.25 16,455-0 Triphenylcarbenium hexa- CHROMATOGRAPHY
18,422-5 Hydrogen fluoride-pyridine chloroantimonate COLUMN
(pyridinium polyhydrogen 25g $ 16.00; 50g $26.00
fluoride) 100g $ 18.00 16,456-9 Triphenylcarbenium hexa-
19,552-9 Iodotrimethylsilane 5g $8.25 fluorophosphate
25g $27.50; J O0g $88.00 25g $ 16.00; 50g $26.00
17,509-9 Magic Acid® ! Og $ 13.00 17,539-0 Triphenylcarbenium penta-
25g $26.00; JO0g $55.00 chlorostannate 25g $ 16.00
16,048-2 Magic Methyl® 25g $ 12. 00 50g $26.00
JO0g $40.00 16,457-7 Triphenylcarbenium tetra-

- - /'IT
16,469-0 Methyloxocarbenium hexa- fluoroborate 25g $ 16. 00
chloroantimonate !Og $ 19. 00 50g $26.00

Lab Notes, cont'd use of which then becomes part of the iden­

I
tification process. To check for correct
The agitating motion imparted to the identification, the student enters the
paddle greatly increases its mixing efficien­
ball-and-socket
Aldrich Catalog-Handbook number of the
joint
cy and virtually eliminates the vortex en­ compound, which is compared by the
countered with rotary stirring which often program with the correct answer.
results in the thermometer being left "high
and dry" in the center of the reaction flask. A listing of QUALO, the main program,
If a hollow rod is used on the paddle stirrer and LABTEC, a utility program for
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Teflon®
the reaction solution can be sparged with stopcock
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written in BASIC PLUS and run in 8K of enables rapid
Dr. David E. Remy memory on a PDP 1 1/ 45. A magnetic tape preparative
Research Chemist, CEMEL (9-track, 800bpi, 600ft) containing separations
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THERMOMETER
tion that the unknown is insoluble in water !=specially important
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Aldrichimica Acta, Vol. 12, No. 3, 1979 49

 Choosing and Using
Noble Metal Hydrogenation
Catalysts
Choosing and Using Noble Metal Hydrogenation Catalysts
Paul N. Rylander
Engelhard Minerals and Chemicals Corporation
Engelhard Industries Division Paul N. Rylander
Newark NJ 07105 Engelhard Minerals and Chemicals Corporation
Engelhard Industries Division
Newark, NJ 07105

tion environment and by the overall elec­

tronic and steric structure of the molecule.

"
All organic chemists are familiar with this
type of thinking. Most noble metals will � �
reduce most functions, but the activities
vary tremendously. Metals can be chosen
most easily by recourse to one of several ,ti;e, - �
books that list metals effective for hydro­

-Q-Q
genation of various functions.1 -4 A first­
choice guide is appended herewith.

Suitable metals are chosen from these

lists on two counts: they should be good for
what one wants to do,and poor for what
one does not want to do. For instance,
palladium is excellent for the hydrogena­
Choosing a Support
tion of aromatic nitro compounds and is More effective use of a metal is made if it
Catalytic hydrogenation a t its best can­ widely used for this purpose,but it would is supported. Hundreds of supports have
not be topped as a means of achieving con­ not be the preferred catalyst for the hydro­ been used, but for most purposes a good
trolled transformations of organic com­ genation of halonitroaromatics to chloro­ carbon or alumina support will be ade­
pounds. Yields are often very high and the anilines, as palladium is also an excellent quate for the majority of reactions.Indeed
products are obtained free of reagents by c a t a l y s t for dehydrohalogenation. these supports account for most catalyst
simply filtering off the catalyst. Ap­ Platinum is much better for halonitroaro­ usage. Sometimes in reactions of the type
propriate conditions and catalysts usually matics,having excellent activity for nitro­ A - B - C,a support such as calcium car­
can be chosen quickly, and satisfactory group reduction, but relatively poor activi­ bonate or barium sulfate may give slightly
results obtained with very little experimen­ ty for dehydrohalogenation. This reduc­ better yields of B, presumably because B is
tation. tion can also be done quantitatively by use less strongly adsorbed. Hydrogenation of
of a sulfided platinum-on-carbon catalyst;
It is the aim of this paper to explore some acetylenes to cis-olefins is an example.
the sulfur present completely prevents
of the factors that enter into the choice of dehalogenation.
catalysts and conditions and to set down Carbon seems more effective than
general guidelines to facilitate suitable alumina in promoting intermolecular re­
Sometimes a combination of properties
choices. Emphasis will be placed on noble­ ductions such as reductive alkylations and
metal catalysts. These catalysts can be ex­ renders a metal unsuitable. The point is il­
lustrated by hydrogenation of car-3-ene. the formation of dicyclohexylamines in the
ceedingly active and can reduce most func­ reduction of anilines.6 Alumina is a better
tions even at ambient conditions. This compound is reduced over platinum
to cis-carane in very high yield,but over support than carbon for the rhodium­
Choosing a Catalyst palladium the major product is trimethyl­ catalyzed hydrogenation of acetophenone
The main catalytic properties of a cycloheptane.The latter compound results to cyclohexylethanol; in various solvents
catalyst are determined by the major metal from three properties of palladium: it is ex­ the yields with alumina are 15-25% higher
present. In choosing a metal it is con­ cellent for double-bond migration, for than with carbon. 7
venient to treat the metal as if it were a hydrogenolysis of conjugated cyclopropyl
reagent with characteristic properties systems, and for olefin saturation. Plat­ Concentration of Metal on a Support
toward each type of function. This is done inum,on the other hand,is relatively active Metal concentration on commercial
with the realization that these charac­ only for olefin saturation, hence the ex­ hydrogenation catalysts varies from a frac­
teristic properties are modified by the reac- cellent yield of carane. 5 tion of a percent to 30% or more. High
©1979 by Aldrich Chemical Company, Inc. Aldrichimica Acta, Vol. 12, No. 3, 1979 53
 metal concentrations decrease the volume the rate of hydrogen transport to the system. Deliberate deactivation of the
of catalyst to be handled, low metal con­ catalyst surface, as it often is, the catalyst catalyst may be in order. Solvents tend to
centrations increase the activity on a can be said to be operating in a "hydrogen­ increase hydrogen availability by lowering
weight of metal basis. Some change in poor" condition. That is, the reduction the surface tension and viscosity of the
selectivity may also occur as concentration would go faster if more hydrogen were system. However, solvents have more com­
changes, as will be discussed later. In available at the catalyst sites. On the other plex effects as well, as will be discussed. On
general, unless there are special demands, hand, when the rate is controlled largely by the other hand, if B is favored by a condi­
5% metal-on-support is a convenient the intrinsic rate of the chemical reaction, tion of low hydrogen availability, the
catalyst for most applications. the catalyst can be said to be operating in a reverse actions are taken.
"hydrogen-rich" mode. That is, the rate
Concentration of Catalyst in the System would not increase substantially if more
Commercial hydrogenations have been Two types of reactions that are favored
hydrogen were available at the catalyst. It by "hydrogen-poor" catalysts are the isom­
run with catalyst concentrations from a is easy to determine experimentally these
fraction of a percent of catalyst to equal erization of a double bond relative to its hy­
different modes of operation. drogenation and, in general, hydrogen­
weights of substrate and catalyst. In
general, for easily hydrogenated functions olysis relative to hydrogenation.
Reactions operating in a "hydrogen­
a 0.5 to 2% catalyst on support loading is poor" mode increase in rate when the agita­
probably more than enough; more resis­ tion is increased. Also, in reactions rate­
tant functions and sterically impeded func­ Solvents
limited by gas-liquid hydrogen transport, Solvents can have profound effects on
tions may require higher loadings for con­ the rate will not increase linearly with an in­
venient rates. It is much less frustrating to both rate and selectivity of hydrogenation. 8
crease in the amount of catalyst. Reactions Rates can be influenced markedly both by
use an unnecessarily large amount initially, operating in a "hydrogen-poor" mode
than too little: The amount of catalyst can an intrinsic property of the solvent and by
clearly are not using the catalyst efficiently, its contained impurities. The number of ac­
always be cut down once the reaction has a consequence of some importance in in­
been shown to go. Easily hydrogenated tive sites in a catalyst is usually only a small
dustrial operations. fraction of the catalyst present, and the
functions may produce marked exotherms
and due allowance should be made for this. Effect of Hydrogen Availability on Selec­ amount of total catalyst used, a small frac­
tivity tion of the amount of solvent. Very small
Temperature and Pressure The concept of "hydrogen-poor" and percentages of certain impurities can thus
Temperature and pressure ranges over "hydrogen-rich" catalysts can be used to exert large influences on the rate. On the
which successful hydrogenations can be predict the direction of change that chang­ other hand, gross amounts of impurities
carried out are often very large, fortunate­ ing pressure, temperature, metal concen­ can easily be tolerated if they happen not to
ly. In general, activity increases with in­ tration, catalyst loading and agitation will affect the catalyst adversely. The best
creasing temperature and pressure, but ob­ have on the selectivity of a reaction. Con­ method for ascertaining suitability of a
vious and not-so-obvious exceptions exist. sider that hydrogenation of a substrate A particular batch of solvent is by actual test.
In practice the conditions are often set by can afford products B and C either by the In general, impurities apart, more polar
the equipment available, and lack of activi­ parallel reactions A - B andC or the series solvents tend to give faster rates than less
ty is compensated for by use of more reaction A - B - C. If the rate equations polar ones.
catalyst and by patience. leading to B and to C contain hydrogen
terms raised to different powers then the Selectivity of hydrogenation sometimes
Agitation two reactions will be affected differently by
Heterogeneous liquid-phase hydrogen­ can be drastically altered by the solvent
changes in hydrogen availability at the and, fortunately, in ways that are largely
ations are three-phase systems. For a reac­ catalyst surface.
tion to proceed, hydrogen must leave the predictable. Solvent is often a most impor­
Whether this condition exists can be tant variable, but it is one whose potential
gas phase, cross a gas-liquid interface,
easily determined experimentally. For in­ for selectivity control is often overlooked.
cross a liquid-solid interface, and be ad­
stance, in going from a reaction with poor Some idea of the extent of influence by sol­
sorbed on the catalyst surface. There are
agitation to one with good agitation the vent is illustrated in the following examples
surprisingly high resistances to these pro­
ratio of B to C increases, then the assump­ concerning stereochemistry. From these
cesses and the rates of many hydro­
tion can be made that B is favored by a data and others not presented here, some
genations, especially over the very active
"hydrogen-rich" catalyst. Under this cir­ working generalities for choice of solvent
noble metal catalysts, are controlled large­
ly by these and other diffusional resis­ cumstance the product B is favored by a will be given.
tances. Vigorous agitation is important to higher hydrogen pressure, a lower oper­
achieve maximal activity of the catalyst. ating temperature (in that it decreases the Stereochemistry: Solvents offer an im­
rate of reaction relative to the rate of mass portant means of influencing stereo­
Hydrogen Availability transport), a lower concentration of metal chemistry, as illustrated by the following
When the rate is limited in large part by on the support, and less catalyst in the abstracted data:9

- +
CHP

Solvent Dielectric Constant Relative Amounts in Product

Hexane 1 .9 39 61
DMF 36.7 94 6

54 Aldrichimica Acta, Vol. 12, No. 3, 1979

 In this case the influence of solvent was Stereochemistry of ketone hydrogena­ temperatures (-20°C) and/ or inhibitors
thought to arise from competition for tion also can be profoundly altered by sol­ such as Pb or Cd may be used, if needed, to
catalyst sites by solvent and the hydroxy­ vent and catalyst. For example, hydro­ maximize the yield.
methyl function, which anchors the olefin genation of 5a-cholestan-3-one over plati­
in an orientation such that hydrogen adds num in t-butyl alcohol gives mainly the Acetylene - Paraffin
from the same side of the molecule. Only e quatorial alcohol 5a-cholestan-3,8-ol,
e xtremes are shown here and the correla­ whereas the axial alcohol 5a-cholestan-3a­
-C=C- - -CHzCHr
Pd
tion between dielectric constant of the sol­ ol is obtained in high yield over rhodium in
vent and stereochemistry holds for a vari­ i sopropyl alcohol-hydrogen chloride. 1 1
ety of solvents. From these data the gener­ The latter system, rhodium i n isopropyl
ality was derived that to the extent this type a l c o h o l - h y d r og e n chloride or i n Palladium gives excellent results. Plat­
of anchoring (haptophilic effect) is tetrahydrofuran-hydrogen chloride, has inum is better, if isomerization of the in­
operative, the extremes of stereospec­ been claimed to be one of the best means of termediate olefin prior to its saturation is
ificity are likely to be found at the extremes producing axial alcohols from unhindered likely to affect selectivity.
of the dielectric constant of the solvent. ketones by hydrogenation. 1 2 Propargyl Alcohols - Allylie Alcohols
Augustine !O found it necessary, in mak­
ing a correlation between dielectric con­ -CHP==CT H- - -CH2CH=CHTH-
Pd

stant and stereospecificity, to group

solvents as protic and aprotic. When this is 0H OH
done the extremes of stereospecificity are
again f ound at the extremes of dielectric Hydrogenolysis of the allylic function is
constant, but the direction of change is op­ usually not a troublesome side reaction and
posite in the two groups. The extremes of palladium gives excellent results. Acet­
the two series are shown in the data below. ylenic glycols are more difficult. Rho­
dium, especially in the presence of alkali,
HOOC� may be suitable if palladium fails.
Acids - Alcohols

Catalyst Solvent cis/trans

Platinum black t-BuOH 3.5
Rhodium black i-PrOH-HCI 11
The reduction is difficult and requires
high pressures. Ruthenium has been used
at pressures of 15,000 psig. Rhenium hept­
lJseful Working Generalities Regarding
oxide has given good results at 4,000 psig.
Solvents
1) The extremes of selectivity of any kind Acid Chlorides - Aldehydes
will be found at the extremes of the
dielectric constants of the solvents used,
RC0CI - RCH0
Pd
with the following provisos:
a) protic and aprotic solvents may have
to be considered separately as noted
D ielectric Percent
Solvent Constant cis-/3-Decalone above Palladium is the preferred catalyst. Re­
MeOH 33.6 41 b) the species actually undergoing duction goes easily but the problem is to
t-BuOH 1 0.9 91 hydrogenation must not change, as prevent reduction to the alcohol. Inhibitors
DMF 38.0 79 for example, a neutral species being are often used. Excellent yields have been
n-Hexane 1 .9 48 changed by solvent into either an obtained with one mole of added base or
anionic or cationic one. reduction at reduced pressures.
2) Hydrogenolysis relative to hydrogena­ Aliphatic A ldehydes - Alcohols
tion is favored by solvents of higher
The data illustrate also how easily one dielectric constant. The generality is ap­
plicable to a variety of competitive situ­
Ru
can be misled in deriving generalities about RCH0 - RCHPH
solvents from limited experiments. If, for ations, and presumably holds because
instance, only methanol and hexane had the transition state in the hydrogen­
been compared, the conclusion would have olysis reaction always has the greatest Ruthenium is excellent. Water acts as
been reached that large differences in charge separation. cocatalyst. Maximal yields are obtained at
d ielectric constant cause only small high pressures and low temperatures
changes in stereospecificity, whereas a GUIDE TO CATALYST (which minimize noncatalytic conden­
comparison of methanol and dimethyl­ SELECTION sations).
formamide would suggest that relatively Acetylenes -cis-Olefins
small differences in dielectric constant Aromatic Aldehydes - Alcohols
cause large differences in stereoselectivity.
Perhaps the safest way of ascertaining -C=C- --+ -CH=CH-
Pd
whether a stereochemical (or other) sen­
sitivity to dielectric constant exists, with­
out extensive testing, is to compare two Palladium usually gives excellent results
solvents of widely differing dielectric con­ if the reduction is arrested at one mole of Palladium is excellent. If the yield of
stant with both solvents being either protic hydrogen absorption. Some trans olefin alcohol is less than quantitative, the prob­
or aprotic. Presumably the protic solvents may form even in the earliest stages of lem can be corrected usually by the use of
should require separate treatment only reduction, but the amount increases rapid­ nonpolar, nonacidic solvents with perhaps
with those substrates that would readily ly as absorption of one mole of hydrogen is a trace of base. Hydrogen absorption
hydrogen-bond. approached and exceeded. Subambient should be limited to one mole.

Aldrichimica Acta, Vol. 12, No. 3, 1979 55

 Aromatic Aldehydes - Hydrocarbons Aromatic Ketones - Saturated Carbinols

O8
the operating conditions available. Pal­
ladium and ruthenium require more vigor­
Oc H O � oC H3 CR � oCH R
ous operating conditions than rhodium or
Rh
OH
platinum.
Benzyl Compounds - Aromatic Hydro­
Palladium is excellent. Hydrogenolysis carbons Rhodium and ruthenium have given ex­
is promoted by traces of acids and by polar cellent yields. Hydrogenolysis decreases as
solvents. The reduction proceeds largely in pressure is increased. Acidic solvents
a stepwise fashion through the benzyl should be avoided although traces of acid
alcohol. have proved beneficial.
Unsaturated Aldehydes - Unsaturated Palladium is excellent for hydro­ Aliphatic Nitriles - Primary Amines
Alcohols genolysis of benzyl functions. The reaction
is accelerated by polar solvents and by
Re
RCH=CHCHO - RCH=CHCH20 H
acids. Ring saturation is nil.
Pt Dehydrohalogenation Palladium, platinum and rhodium have
been used in this reduction, but little
RX --+ R H + HX
Pd
The reduction is difficult. Rhenium primary amine will result unless the nitrile
(modified), ruthenium (modified), and is hindered or the reaction is carried out in
platinum (modified) have all been used suc­ Palladium is excellent and is widely a reactive solvent, such as ammonia, acid,
cessfully. The reaction depends critically used. The reaction is frequently carried out or acetic anhydride.
Aliphatic Nitriles - Secondary Amines
on the metal, catalyst preparation and the in the presence of a mole of base. In com­
presence of various modifiers. Most plex molecules the base chosen may make a
catalysts exhibit the reverse selectivity. Rh
difference in yields. Polyhalo compounds 2 RC N - (RCH2)2N H +
Anilines - Cyclohexylamines
N H3
can usually be dehalogenated in a stepwise
manner.
Epoxides - Alcohols
Rhodium is uniquely effective in this
reduction and gives high yields of second­
-HC-C H- Pd -CH CH- ary amines.It is also useful in making un­
0
'\ / --+ symmetrical secondary amines by nitrile
OH
21
Rhodium and ruthenium are excellent. reduction in the presence of an amine.
Aliphatic Nitriles - Tertiary Amines
They are active and give little dicyclohex­
ylamine. Slightly more coupling is ob­ Palladium is usually used. It mainly
opens the ring with inversion. Direction of
3 RCN - (RCHz}3N + 2 N H3
tained over carbon support than over Pt
alumina. Coupling may be decreased by the ring opening depends on the substrate
Pd
the presence of ammonia, increased pres­ and often on the pH. Deoxygenation is
sure, and decreased temperature. rarely a problem. High yields of tertiary amines are ob­
Anilines - Dicyclohexylamines Hydrazones - Hydrazines tained from low-molecular-weight nitriles
in nonreactive solvents over either palla­

F\ . RCH= N NH2 - RCH2N HNH2

Pt dium or platinum.
N H2 - Aromatic Nitriles - Benzylamines
Pd, Pt
�
Platinum is usually used in this reduc­
tion. Hydrogenolysis of the nitrogen­
nitrogen bond is rarely a problem.
Imines - Amines Using palladium, yields approach
theoretical if small amounts of an aliphatic
-CH2 N =C H- --+ -CH2N HC H2
Pt
Palladium and platinum give moderate secondary amine are present. Otherwise a
yields which increase with increasing tem­ mixture of benzyl and dibenzylamine
perature. Coupling is decreased by increas­ Platinum is widely used for this reaction results. The yield is also solvent dependent.
Aromatic Nitriles - Dibenzylamines
ing pressure. and for reductive alkylation, which gives
Anilines - Cyclohexanones

O
an imine intermediate. Palladium can be
OcN !!.. (OcH2)2N H
effectively used when there is little steric
N HR -! Oo + RNHz
hindrance around the bond.
H20 Ketones (aliphatic) - Alcohols
RCR Ru RCH R
Nearly quantitative yields of diben­
Palladium is quite effective, probably --+- zylamines are obtained over platinum, pre­
0 OH
II I
due to its excellence for double-bond ferably with one-half mole of water present
migration in partially hydrogenated rings to minimize catalyst inhibition.
Ruthenium is excellent. Water functions
and relative ineffectiveness for imine
as cocatalyst. Hydrogenolysis is nil, as is Aromatic Nitriles - Aldehydes
saturation. Yields increase with increasing
substitution on the nitrogen atom. ketal formation in lower alcohols.
Aromatic Ketones - Aromatic Alcohols
Aromatic (carbocyclic)- Cycloparaffin
F\
0-0
Rhodium, platinum, ruthenium and
W R � o�H R
�O �·OH
Palladium is excellent and yields ap­
proach 100%. Hydrogenolysis can be
Good yields of aldehydes can be ob­
tained over palladium in acidic media.
Conditions should be arranged so that
hydrolysis of the intermediate imine is
palladium are all used industrially. Choice prevented by use of nonacidic, nonpolar faster than its hydrogenation. Hydrogen
depends on other functions present and on solvents with traces of base if necessary. absorption should be limited.

56 Aldrichimica Acta, Vol. 12, No. 3, 1979

Nitroaromatic Compounds - Anilines Hydrogenolysis of Vinyl Compounds as nitrobenzenes or nitrosobenzenes may
be used directly in the reductive alkylation
'c=CHX 4 'cHCH3 + HX without prior conversion to anilines.
/ /
References:
I) P.N. Rylander, "Catalytic Hydrogenation
X Cl, Br, OR, OCOR, etc.

The reduction goes very easily over a The result is sensitive to structure.
H ydrogenolysis should precede hydrogen­
over Platinum Metals," Academic Press,
number of catalysts. Palladium is usually New York, N.Y., 1 967.
preferred for economic reasons and for ation. Platinum seems generally preferred 2) P.N. Rylander, "Catalytic Hydrogenation
minimal ring reduction. over palladium. in Organic Syntheses," Academic Press,
N itroaromatic Compounds - Aromatic Hydrogenolysis of Allylic Compounds New York, N.Y., 1 979.

0
Hydroxylamines
3) M . Freifelder, "Practical Catalytic Hydro­
C=CHCH2X .....+ CHCH 2CH3 + HX
'-
/ /
Pd '- genation," Wiley Interscience, New York,
N .Y., 1 97 1 .
DMSOF\_
N HOH
= Cl, 4) M . Freifelder, "Catalytic Hydrogenation in
NO2 -;;
X Br, OR, OCOR, etc.
�
The result is sensitive to the steric re­
Organic Synthesis, Procedures and Com­
quirements of the molecule. Palladium
mentary," Wiley Interscience, New York,
H igh yields of aromatic hydroxylamines seems generally more effective than
N.Y., 1 978.
can be obtained by hydrogenation over platinum. Hydrogenolysis should precede
5) W. Cocker, P.V.R. Shannon, and P .A.
platinum in lower alcohols containing 1- saturation.
Staniland, J. Chem. Soc. (C), 4 1 ( 1966).
2% of dimethyl sulfoxide. 6) P.N. Rylander, L. Hasbrouck, and I .
Oximes - Primary Amines Karpenko, Ann. N. Y. Acad. Sci., 2 14, JOO
N itroaromatic Compounds - Amino­
phenols Rh
( 1 973).
C=NOH - �CH N H�
,
/ + HzO 7) P . N . R ylander and L. Hasbrouck,
Engelhard Ind. Tech. Bull., 8, 148 ( 1 968).
Excellent yields have been obtained by 8) P .N. Rylander in "Catalysis in Organic Syn­
reduction over rhodium in alcoholic am­ theses, 1 978," W.H. Jones, Ed., Academic
monia. Yields may be sensitive to substrate
Press, New York, N.Y., 1 978.
Production of aminophenol depends on concentration due to hydrolysis of oxime
9) H .W. Thompson, E. McPherson, and B.L.
Lences, J. Org. Chem., 41, 2903 ( 1976).
s uccessful competition between hydro­ by water formed in the reduction.
IO) R.L. Augustine, Advan. Catalysis, 25, 63
genation of the intermediate hydroxyl­
Phenols - Cyclohexanones
amine and its acid-catalyzed rearrange­
( 1976).
ment. Platinum is the preferred metal. The
1 1) S. Nishimura, M. Katagiri, and Y.
Kunikata, Chem. I.e tt., 1 235 ( 1 975).
yield is sensitive to reaction variables.
1 2) S. Nishimura, M. Ishige, and M. Shiota,
Halonitroaromatics - Haloanilines ibid., 963 ( 1 977).
Palladium is excellent due to low activity About the Author
for ketone reduction and high double-bond
isomerization. Rhodium is perhaps better Dr. Rylander received the B.C h.E .
with polyhydric compounds. H igh yields degree from Johns Hopkins University in
The product can be obtained in excellent can be expected. 1942 and his Ph.D. from Indiana Universi­
yield over inhibited palladium or platinum, ty in 1948. After postdoctoral studies at the
Phenols - Cyclohexanols University of Rochester and at Harvard, he
or over platinum or rhodium (sulfided).

Q-oH :: OoH
joined Standard Oil Co. of lndiana in 195 1 .
Nitroolefins - Saturated Amines For the past 23 years, Dr. Rylander has
been associated with Engelhard Industries
where he has pursued research in the field
High yields are expected over rhodium of his main interest: application of catalysis
or ruthenium. Hydrogenolysis is minimiz­ to organic syntheses.
ed by neutral, nonpolar solvents, low tem­
perature, and high pressure. Dr. Rylander is the author of three
books and numerous papers on catalysis.
Phenols - Benzenes He has edited two other books and holds
Good yields of saturated amine can be quite a number of patents in the areas of
obtained over palladium in acidic media. hydrogenation, dehydrogenation, dehy­
In neutral media dimeric butane deriva­ dration, oxidation, alkylation and poly­
tives result. merization.

-
This reduction is easily achieved if the
N-Nitrosoamines - Hydrazines phenol is first converted to a suitable ether
derivative as by reaction with 2-ch!oro­ Also available from the Aldrich
'NNO benzoxazole or 5-chloro-1-phenyltetra­ bookshelf...
Pd
/ zole.
Over palladium, hydrogenolysis of the Reductive Alkylation Catalytic Hydrogenation
nitrogen-nitrogen bond can be kept to low in Organic Syntheses
levels. Excellent yields can be expected. ON H + ACOR' �
� by
Nitrosoaromatic Compounds - Anilines
0-NHCHRR + H2O Paul N. Rylander
Published in 1979 by Academic
Platinum is used usually, affording high Press
yields of alkylated product. Palladium is
The reaction proceeds easily and in ex­ effective with aldehydes or low-molecular­ Z10,430-2 $34.00
cellent yield over palladium. weight ketones. Precursors of anilines such

Aldrichimica Acta, Vol. 12, No. 3, 1979 57

 bla n k
P a g e i n te nt i a l ly
Aldrichimica Acta
Volume 12, Number 4, 1979 Volume 12 Number 4 1979

Selective Oxygenation with tert-Butyl Hydroperoxide. See page 63.

Tilorone, Its � and Chemical Immunology. See page 77.
chemists helpi ng chem, sts in research & industry

aldrlch chemlcal co_

Aldrichimica
Volume 12, Number 4, 1979
A publication of ALDRICH CHEMICAL COMPANY, INC.

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 described in C.F. Lane, Aldrichimica Acta, When used with a cooling bath in the usual
10, I 1 ( 1977). manner, collection efficiency of both high­
and low-boiling compounds is improved.
K.L. Smouse
Chemistry Department
University of Utah
Salt Lake City, Utah 84112
A. G. Anderson
Central Research & Development Dept.
oil bubblers E.J. du Pont de Nemours & Company
Oil bubblers are frequently used in the Experimental Station
chemistry laboratory to monitor the evolu­ Wilmington, Delaware 19898
tion of a gas produced in a reaction, the
Any interesting shortcut or laboratory hint
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means of closing off a reaction vessel from Send it to Aldrich (attn: Lab Notes) and if
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our glassblower to make a bubbler of the which is more rapid and easy. We reserve the right to retain all entries/or
following design which can simply be fitted consideration for future publication.
into the top of a condenser or addition Water and ethanol present in commer­
funnel equipped with a standard-taper cial chloroform or carbon tetrachloride
glass joint. The lower chamber is filled to can be eliminated simply by addition of
zeolite NaA (pellets) just prior to use. After
swirling for some minutes the amounts of
- Upper chamber large enough to water and ethanol are reduced to less than 5
hold any oil which may be pulled ppm and less than I ppm, respectively (as
up when pressure is reduced determined by 1 H FT-NMR). Generally,
- vent 50g zeolite pellets/ liter solvent is sufficient
for effective elimination of water and
- Oil (sufficient amount to ethanol. The zeolite can be recovered via
cover tip of tube)
filtration or after decantation of the sol­
:---...._ Attached here for strength vent. As known, zeolite can be reused after
- Standard-taper joint
drying in air at room temperature, at 1 20°
(2 hrs) and at 400° (4 hrs).
J.A. Peters
the proper level with an appropriate oil or Laboratory of Organic Chemistry
other liquid through the vent. When not in Delft University of Technology
use the bubbler can be stored by simply Julianalaan 136
hanging it on a convenient hook. If desired, 2628 BL Delft
the bubbler could be fitted with a sidearm The Netherlands
and stopcock for introduction of a gas. Professor Richard Bertrand's letter
Robert F. Boswell from the University of Michigan in Dear­
Research Chemist During preparative VPC collection, born is typical of dozens of letters I have
A. H. Robins Company many high-boiling compounds often form received recently:
Research Laboratories troublesome aerosols instead of completely "I am not sure how long you have been
1211 Sherwood Ave. condensing in the collector. Aerosol offering the Fieser Molecular Models for
Richmond, Virginia 23220 (smoke) formation can be greatly reduced sale through your catalog, but I wish to
Editors note: by decreasing the rate of cooling of the gas­ thank you for doing so. They are about the
For the convenience of our customers, eous compound as it leaves the collector best models available for classroom use
Aldrich offers the bubbler shown below. port. Accordingly, a thin strip of aluminum and are a bargain at that.
approximately 2.5-3cm long is cut with "There is one other device Prof. Fieser
scissors from an aluminum can or the back­ came up with that I cannot find anywhere,
ing of a used, washed TLC plate. The width
of the strip should equal the inside and that is the "Fieser Triangle." This is a
diameter of the collector tube. The strip is template which can be used to draw
inserted into the collector as shown. The organic chemical structures. The scale of
strip, being heated by the effluent gases at the drawings is just right for manuscript
one end, provides a shallower cooling copy and classwork or examination copy. I
gradient for the compound to be collected. would like to suggest you consider offering
them for sale through your catalog. As with

<D�====
To collector Side View the models, making available the Triangle
End View ..,._ port would be of great service to the chemical
community."
t We now offer the Fieser Triangle.
Zl0,432-9 'f24/40 $35.00
Aluminum
strip Zl0,377-2 Fieser Triangle $4.00
Also available from Aldrich 1s the It was no bother at all, just a pleasure to
bubbler shown below whose use has been be able to help.
62 Aldrichimica Acta, Vol. 12, No. 4, 1979
 Metal-Catalyzed, Highly Selective
Oxygenations of Olefins and Acetylenes
with tert-Butyl Hydroperoxide.
Practical Considerations and Mechanisms.
Metal-Catalyzed Highly Selective Oxygenations of Olefins and Acetylenes with tert-Butyl
Hydroperoxide.
Practical Considerations and Mechanisms K. Barry Sharpless
K. Barry Sharpless Thomas R. Verhoeven
Department of Chemistry
and Thomas R. Verhoeven
Stanford University
Department of Chemistry
Stanford California 94305 Stanford University
Stanford, California 94305

Scheme II. Oxygen Atom Sources

I . Introduction When one considers the combined
features of economics, selectivity, and safe­
The purpose of this review is to call ty, TBHP emerges as one of the best
attention to recent advances in the use of sources of oxygen atoms for a variety of �H,
tert-butyl hydroperoxide (TBHP) in organic oxygenations. Some of the factors CH,,C-0-,c>:-H
CH, \�)
organic synthesis. The emphasis here will which make TBHP ( 1) superior to better
be on the nonradical, metal-catalyzed oxy­ known sources of oxygen atoms such as 1 2
genations shown in Scheme I. hydrogen peroxide (2) and peracetic acid
( 3) are worth discussing. Perhaps the key
advantage of TBHP is its selectivity. In
contrast to hydrogen peroxide and 3
peracetic acid, TBHP is unreactive toward
most organic compounds in the absence of Peracetic acid is on every count less stable
catalysts. TBHP is less sensitive to con­ than TBHP. The 40% solution of peracetic
tamination by metals than either peracetic acid in acetic acid sold by FMC can only be
acid or H 202, and on this basis is safer to shipped by truck, and even then only in
handle. In dilute organic solution TBHP minidrums or smaller containers, whereas
has high thermal stability (its half-life is 36 solutions which are (by weight) 70% TBHP
days at 1 1 5° C as a 0.2M solution in and 30% H 20 may be shipped in tank car
benzene). 1 Hydrogen peroxide is, in princi­ quantities. This does not mean there are no
ple, also very stable thermally, but it is hazards associated with using TBHP
more sensitive to decomposition catalyzed (potentially hazardous situations to be
by trace metallic impurities than is TBHP. 2 avoided in handling TBHP will be discuss-
Scheme I.

OH TBHP OH
v•s catalyst
Professor K. Barry Sharpless
R� ► R¼ (eq. 1 )
Dr. Thomas R. Verhoeven

TBHP R�
Mo+6 catalyst
► 0
(eq. 2)

TBHP R�OH
Os•a catalyst ► (eq. 3)
OH

OH
TBHP
Se•• catalyst ► RAf (eq. 4)

OH
TBHP
Se•4 catalyst ► R� (e q. 5)

© 1979 by Aldrich Chemical Company, Inc. Aldrichimica Acta, Vol. 12, No. 4, 1979 63
 VO(acac)z catalyst'
ed later). What it does mean is that
TBHP
peracetic acid is more dangerous in almost
PhH, reflux ►
every situation than is TBHP. High­ �OH
strength hydrogen peroxide solutions also (eq. 6)
tend to be less stable than TBHP solutions 8, 93%
4
of comparable peroxide content.
VO(acac)z catalyst•
After six years of working on metal­
catalyzed reactions of TBHP (somtimes as TBHP
much as five moles in one reaction) we have PhH, reflux ► (eq. 7)
not yet had a single explosion. On the other
hand, we have had a few small explosions 5 84% (mixture of diastereomers)
while working with small amounts of
VO(acac)z catalyst'
hydrogen peroxide and also with peracetic
TBHP
acid. The above mentioned explosions only

Hi;& PhH, reflux

JXJ
occurred when some metal-catalyzed
process was being attempted. In our opin­
► H
(eq. 8)
ion, these explosions were due to OH OH
accelerated decomposition of H 2 O2 or of 6 95%
peracetic acid catalyzed by the metal.
Mo(CO) 6 catalyst'
We have made safety comparisons of TBHP
TBHP with the two most common perox­ PhH, reflux ► (eq . 9)
idic oxidants, H 2 O2 and peracids, because
it is our experience that most chemists 7 90%
Alcohols (Scheme I, eq. l ) catalyzed epoxidations of olefinic alcohols
regard these latter reagents as less
dangerous than tert-butyl hydroperoxide
From reports by Sheng and Zajacek9 proceed readily at, or below, room
temperature. 1 2 b (2) We originally used
( TBHP). The origin of this phobia toward
organic peroxides (e.g., TBHP) almost cer­ and by List and Kuhnen 10 one could see
tainly is derived from two factors, the more that simple allylic alcohols were especially aqueous bisulfite (HSO3 -) to reduce excess
important being that common organic reactive toward epoxidation by TBHP in TBHP. We have found that the use of
ethers (diethyl ether, tetrahydrofuran and, the presence of vanadium catalysts. We bisulfite makes it difficult, and often im­
especially, diisopropyl ether) form decided to have a look at more complex possible, to distill the products without ex­
dangerously explosive hydroperoxides by allylic alcohols in order to determine the tensive polymerization occurring. These
autoxidation upon exposure to the at­ regioselectivity and/ or stereoselectivity problems became especially severe when
mosphere. Chemists are justifiably afraid available with these systems. The results large-scale (>I mole) distillations were
of ether hydroperoxides, and tend to were unexpectedly dramatic in that the attempted (after bisulfite work-up) with
associate tert-butyl hydroperoxide with selectivities were much greater than those simple epoxides as well as with epoxy
discovered by Henbest 1 1 for the epoxida­ alcohols and even allylic alcohol products.
The use of aqueous sulfite (e.g., N a2SO3,
this deadly class of compounds. Thus, any
tion of olefinic alcohols by carboxylic
pH of aqueous solution is ca. 9)17 or
substance whose name includes the word
peracids. As shown in equations 6 through
9, geraniol (4), linalool (5), 4,8-hydroxy­ dimethyl sulfide (with or without a
peroxide is regarded as very dangerous to
catalytic amount of acetic acid)18 provide
work with. Some peroxides are indeed ex­
cholesterol (6) and 3-cyclohexen-1-ol (7) all
preferable alternatives 19 for reduction of
tremely unstable and can only be stored at
gave excellent yields of only one of the
excess TBHP.
low temperature; but the range of stability
possible isomeric epoxy alcohols. 1 2" Both
allylic and homoallylic (e.g., 7) alcohols
is wide, and TBHP is one of the most stable
organic peroxides known. During the past five years these molyb­
showed the effects. In the case of vanadium denum- and vanadium-catalyzed epox­
The other important factor in the TBHP catalysis even a bishomoallylic alcohol [ l ­
hydroxy-(E)-4-nonene] exhibited a sub­ idations of olefinic alcohols have been
phobia is lack of familiarity. This is largely utilized often in complex synthetic se­
stantial (13.4 times) rate acceleration over
due to the fact that TBHP is a rather new quences. Space does not allow enumera­
an analogous olefin [(E)-5-decene). 12"
compound, being first prepared in 1938 by tion of all the applications. Consequently,
Milas. 3 This has led to the curious situation The different, and often superior, stereo­ only some of the more interesting examples
where chemists, who have long been com­ selectivity of these metal-catalyzed epoxi­ are presented here (eq. J O - eq. 3 I). The ex­
fortable with the idea of using peracids4 dations is also observed with acyclic amples are arranged in the order of allylic
(e.g., for epoxidation of olefins), have less olefinic alcohols (Table I). The examples in alcohols, then homoallylic alcohols, and
respect for the explosive possibilities with Table I are taken from our recent publica­ finally bishomoallylic alcohols.
peracids than they do with the tamer sub­ tion 1 3 in which we correct the errors in our
stance TBHP. All of this has begun to earlier work 14, 1 5 on this same subject. Allylic alcohols have been the substrates
most often epoxidized by these reagents
(e.g. , eqs. 10-26). Although molybdenum
change due to the discovery, almost
simultaneously (ca. 1965) in several in­
The experimental details for these epox­
dustrial laboratories, 5 -7 that propylene
idations are contained in our original catalysts are much (ca. 100 times) more
publications 1 2", 1 4 although two important reactive for epoxidation of isolated olefins,
could be epoxidized by TBHP in the
modifications of those procedures merit vanadium catalysts are usually preferred
presence of a molybdenum catalyst. This
process (Oxirane Process) is now yielding discussion: ( l ) Heating (reflux in benzene) for allylic alcohols. With vanadium
two billion pounds of propylene oxide each was employed for both the vanadium- and catalysts the rate acceleration for epoxida­
molybdenum-catalyzed epoxidations (eq. tion of allylic alcohols is so great (on the
6-9). Although heating is often necessary to
year. Our interest in metal-catalyzed reac­
order of 103 faster than the parent olefin)
achieve reasonable rates for the molyb­
tions of TBHP began in 1972 and was
that the absolute rates, and usually also the
denum-catalyzed process, most vanadium-
aroused by the remarkable effectiveness of
the industrial epoxidation process. 8 selectivities, surpass those realized with
� ,· �----
-·-,-- ----- �
•we usually add the va�adium and molybdenum molybdenum catalysis. 12 b
catalysts in these lower valent forms [i.e. , VO(acac),
II. Epoxidation Reasonable selectivities are also achiev­
ed with some homoallylic (e.g., eqs. 27-30)
and M o(CO)6]. However, these species are oxidized by

1. Selective Epoxidation of Olefinic

TBHP to the catalytically active V·5 and M o'" complex­
es. and bishomoallylic (eq. 31) alcohols. In

64 Aldrichimica Acta, Vol. 12, No. 4, 1979

 these cases peracids usually exhibit poor or
Table I. Stereochemistry of Epoxldatlon of Acyclic Allylic Alcohols." no selectivity. Kishi's use of NaOAc as a
Allyllc alcohol threo erythro buffer (eq. 3 1) to prevent premature
OH cyclization of the epoxy alcohols to the
OH H-
MT CH, H HH
tetrahydrofurans is a noteworthy modifi­
0
/y
CH, cationl9 which should prove useful in other
y+s, TBHP
9 cases where acid-sensitive epoxides are
MCPBA produced.
20 80
60 40
In spite of the remarkable selectivity ex­
H Q OH
- CH3
CH;} {
hibited in these new metal-catalyzed epox­
� c1-1;H·H
�
OH CH3 idations, they do have limitations. The
most common problem occurs with certain
y+s, TBHP 5
rigid cyclic allylic alcohols (eqs. 14-16). In
MCPBA
10 95
these cases there can be competition from a
45 55
OH
dehydrogenation process leading to the
a,,8-unsaturated ketone. 24,25 This side reac­
H H
0
'--'Y
OH
11
y+s, TBHP
)Mi�
CH3 CH, ;--{�
71
CH3 tion seems to intrude principally in six­
membered rings having an equatorial
hydroxyl group. However, eqs. 10, 12 and
MCPBA
29
64 36 13 reveal that even this structural feature
does not necessarily mean there will be
0 OH
N. H--��
H, H�
- :i
trouble. From existing results,24,25,4o the
factors leading to unsaturated ketone for­
mation are not altogether clear; however,
y+s, TBHP 71 this side reaction is likely if the face of the
12

MCPBA
29
95 5 molecule syn to the equatorial hydroxyl is
substantially hindered in the vicinity of the
°For the react ion conditions and for additional examples see ref. 1 3. olefinic linkage. Severe steric shielding of
the double bond can lead to unsaturated
(a) Allyllc Alcohols ketone formation even when the allylic
hydroxyl moiety has an axial orientation.8 5
(eq. 1 0)2° One of the more attractive features of

6
these metal-catalyzed epoxidations is that
they look appealing for the purpose of ac­
MCPBA 4 3
,B(syn) a(anti)

y+s, TBHP
complishing asymmetric epoxidations.
1 00 ~o The first successes in this area were achiev­
OCH,Ph ed independently by Yamada's group4 1 and
OH by our group.42 Yamada used a molyb­
OH denum catalyst with chiral ligands deriv­
TBHP ►
v+s
ed from ephedrine. We employed
OH vanadium catalysts bearing chiral hydrox­
1 5% amic acids as ligands. Since our initial
publication we have found43 more effective
(eq. 1 1 ) 21 (eq. 1 2 )22 chiral hydroxamate ligands. The best
excess asymmetric induction we ever achieved is
,.,OCH.Ph shown in eq. 32.
�OH
� Breslow and Maresca have reported that
V··oH these metal-catalyzed epoxidations can be
directed over a remarkably long distance
83%

using their template-directed strategies ( eq.

OTHP 33). 44
r'f--( Mo+6
TBHP ► TBHP ►
v+s
There has been recent interest in assign­
H� ing optimum 0-C-C=C dihedral angles
for epoxidation of allylic alcohols by both
(eq. 1 3)23
peroxy acids45. and by vanadium cata­
THP
(eq. 1 4) 24
� lysts. 25,40 The conclusions reached in ear­
46

HO),J,l._) od:t lier studies were based on epoxidation of

cyclohexenols and suggested optimum
dihedral angles of ca. 150° (peroxy-acid
93% (MCPBA, 90%)
: H
47% 39%
epoxidations)25, 4G.45 and ca. 90° (V•5 -cata­
lyzed epoxidations). 25 We feel that the dif­
ferent steric environments between equa­

· r:f
torial and axial positions in cyclohexenols

OH
►
<:f OH
+
OH
+
0
� (eq. 1 5) 25
as well as the rapid half-chair/ half-boat in­
terconversion could cloud the interpreta­
tion of epoxidation results based on such
models. We feel a careful consideration of
y+s, TBHP the stereoelectronic requirements of the
MCPBA epoxidation process might provide a more
18% 1% 74%
2% 0.5%
fruitful approach.
90%

Aldrichimica Acta, Vol. 12, No. 4, 1979 65

 if -
OH
► «d 6H
· ·d 6H
+

� (,q. 16)"
v+s
TBHP ►
(eq. 1 7)26
v+s, TBHP 83% 0.08% 1 5%
MCPBA 80% 9% 3%

lYn
H�
v+s
TBHP ►
v•s
TBHP ►
V+S
TBHP ►
(eq. 1 8)27 (eq. 1 9)28 (eq. 20)29

84%
70% 95%

v+s
V•S TBHP ►
TBHP ►
._ o .-H
�
(eq. 21 )3° '-;:: 1/
(eq. 23)3 1
�-�t HO H

_\J
l)o 50-60%
7:1 mixture of diastereomers, peraclds
60% attack only the isolated double bonds

OH
Mo+s
1/
:
· TBHP ►

+ A,:. •
(,q. 25)"

A
� ('r'
I
Ph Al;
MCPBA 1 1
y+s, TBHP 15 85
··\, -..!-·�95%

0 6
(b) Homoallylic Alcohols

MCPBA
►
0.2
+
O·n
99.8
,,, (eq. 26)25 OH

MCPBA
► �
erythro
1 .2
+
�
tnreo
1
(eq. 27)34

y+s, TBHP 97 3 V•5, TBHP 2 1

�
HO
v+s
TBHP ►
&J! COOCH,
V+S
TBHP ►

�78
v+s
TBHP ►
(eq. 28)35 � (oq. 29)• (eq. 30)37

'" �°'"· ��·---�

COOCH,
� + � .
OH HO
HOOH .
·o· . ..
erythro - erythro erythro - threo H
5 1 91%
50-60%

(c) Bishomoallyllc Alcohols

1 ) v•s
TBHP
NaOAc ► _n_ � 1 ) v+s, TBHP, NaOAc
2) Ac2O, pyridine ►
n�
Ar · ·l;'o�Ac IC._ (eq. 31)38 ,
2) HOAc
A,·· /;-o�oH � 39

75%
8 : 1 in favor of desired diastereomer ~5 : 1 in favor of this dlastereomer

66 Aldrichimica Acta, Vol. 12, No. 4, 1979

 Our detailed mechanistic picture for the
vanadium-catalyzed epoxidations is shown Ph
1% v•s, 2mol TBHP
y-OH PhCH3, -20 ° C, 4 days Ph�OH
in Scheme III. The exchange reactions
depicted are well precedented for similar 3% OH
► (eq. 32)43
Ph CY' Ph
vanadium(+5) alkoxide complexes. 47 The N/
N 'H I 90% (80% e.e.)
key intermediates are 13 and 14, both being cF,Ao Ph
neutral, roughly trigonal bipyramidal com­
plexes. The slow step in the catalytic cycle
is thought to be the oxygen-transfer step

a§P
(i.e., 13-14 in Scheme III). Of course,this
is also the step in which the stereoselectivity
is determined. A crucial variable associated Mo•6, TBHP
with the transformation of 13 to 14 is the tt
► (eq. 33)44
PhH, reflux
orientation of the olefinic linkage with c( H H
�
respect to the peroxide bond being broken n = 1, 60%
i-{CH,)n � /,
in the oxygen-atom-transfer process. It is -0--?
n = 2, no reaction
our opinion that all epoxidation processes
involving attack of olefins on peroxide
reagents will be subject to fairly rigid Scheme Ill. Possible Mechanism for the Vanadium-Catalyzed Epoxidations.

'
stereoelectronic requirements. (Surprising­
ly, this point has often been ignored even t-Bu
in the well studied epoxidations of olefins
t-Bu
q R/r
by organic peroxy acids.) In particular, 2�

R O...J 1
displacement on the peroxide bond should TBHP + ,e__

OR

� G.
allylic alcohol o-· -
_.,,,,,, -" --0
occur from the backside and along the axis �
: ;OR -0 1 ( )
of the 0-0 bond being broken. 48 Thus, in
13 the conformation of the allyloxy group
which best allows linear backside displace­
ment on the 0 1 -02 bond produces a boat­
O=V
bR \..l:;
13
like folding resulting in an 0-C-C C = --(T� P •
angle near 50° . The predicted confor­ al lylic alcohol l slow step
mations for the vanadium(+5)-catalyzed t-BuOH
epoxidation are illustrated in Scheme IV +
( 15 and 16). Thus, the stereoselectivities for 2{f-Bu

�,J�.
the vanadium-catalyzed epoxidations of H� OR
�Qi-Bu
alcohols 10 (R1 and R2 alkyl) and 12 (R1 _,.,
=

� ·o'JJ-
and R3= alkyl) are readily rationalized in
terms of the stereoelectronically predicted
conformations (either 15 or 16) of the
\,A
allyoxy moiety. 14
To adequately deal with allylic alcohols
9 and 11 however, the interactions between
substituents on the allylic alcohol and the
ligands on vanadium need to be considered Scheme IV. Predicted O-C-C=C Dihedral Angles
(these interactions are ignored in the
simplified analysis of Scheme IV). To the
extent that the coordinated epoxy alcohol
product 14 resembles the transition state, for v•s, TBHP epoxldatlons:
one can rationalize the stereoselectivity by ~50 °
analyzing the interactions for various sub­
stitution patterns in 14. When RI is a (t hreo

15, leads to threo product 16, leads to erythro product

14 (erythro) 14( threo)
product) it experiences a 1,3-diaxial-like for peroxy acid (MCPBA) epoxldatlons:
interaction with the L' ligand (L' is either 0 ~ 1 20 °
or OR). At present we have no way of
predicting the relative positions of the 0
and OR ligands in 14. When R 1 is {3
(erythro product) there is no obvious in­
teraction with the metal ligands. R3 ex­
periences a weak 1,3-diaxial-like inter­
action with the L ligand in 14 (L is either 0
or OR) in both the erythro and threo cases;
therefore its effect on the product ratios 1 7, leads to threo product 1 8, leads to erythro product
should be negligible. R2 and R4 are not in a
position to interact with the vanadium
Aldrichimica Acta, Vol. 12, No. 4, 1979 67
 0.2% 0s04
ligands. Thus, it appears that other things
1 0% Et4 NOH
being equal these interactions add up to a
slight disadvantage for the threo transition
1 .6mol TBHP(70% grade) ► (eq. 34) 61
R-'y.H

tert-butyl alcohol
state. This effect provides an appealing
rationale for the weak erythro selectivity
�
69%
with substrates 9 and 1 1 (Table I).

0.2% 0s04
The application of similar stereoelec­ c�
25% Et4 NOAc
(eq. 35) 62
tronic considerations to the peroxy-acid
epoxidations leads us to propose the orien­
1 .7mol TBHP(70% grade) ► c:.tt
tation of the reactants illustrated in acetone
OOEt H COOEt
Scheme V. The plane defined by the per­ 1 mol 106.3g ( 72%)
acid molecule is oriented (about 60° to
plane B) so that one of the nonbonding
pairs on oxygen (pair a) lies in plane B and
is nicely oriented to begin bonding with the
olefinic carbon; it may also be able to in­
teract favorably with the antibonding rr or­
bital of the olefin.The nonbonding pair b is
jY + CH,j'
I?
0
1% 0s04
THF/H20 ► Mr"· 80%
(eq. 36)6sb

olefins can be carried out efficiently by collected, and this leaves about 650ml of an
favorably oriented (in front of plane B) to operating in nonreactive solvents (e.g. , anhydrous," ca. 4.IM solution of TBHP (ca.
2.67moles) in dichloroethane.• [The precise TBHP
hydrogen-bond with an allylic hydroxyl benzene, dichloromethane, dichloro­ concentration can be very easily determined by
group. It should be noted that the selectivi­ ethane) under moderately anhydrous con­ iodometric titration; the exact details for these
ty effects seen in the peracid epoxidations ditions. The use of small amounts of titrations are given in Note 58a below. The TBHP con­
of allylic alcohols have previously been ex­ anhydrous disodium hydrogen phosphate centration can also be estimated (± 10%) by NMR in­

(Na2 HP04) powder as an additive in these

plained by hydrogen bonding to either tegration; a convenient equation for calculating the
oxygen-2 or oxygen-3 of the peracid,45 reactions further reduces the formation of
molarity of such solutions when using dichloroethane
as solvent is given in Note 58b below.] The anhydrous
never to oxygen-I as is suggested in byproducts. 52 Since this work has not been TBHP solution is allowed to cool and can be stored" or
Scheme V. However, if one invokes published yet5 1 the complete experimental used immediately.

Scheme V. Consideration of Stereo­

b) Molybdenum-catalyzed epoxidation: A 2-liter, 3-
details for the epoxidation of 1-decene are
electronic Effects In Peracid Epoxi•
necked round-bottomed flask is equipped with a

�atlons of Allylic Alcohols.

presented below. Monosubstituted olefins Teflon-coated magnetic stirring bar, a reflux con­
such as 1-decene are among the most dif­ denser, a 500-ml dropping funnel, and a nitrogen inlet.
ficult to epoxidize. Therefore, the con­ All glassware was dried in an oven, and the system
8 flushed with nitrogen. The flask is charged with I liter
ditions now given for 1-decene will epox­ of reagent-grade 1,2-dichloroethane, 146. 14g ( I .OOmol,
idize all simple di-, tri- and tetrasubstituted
olefins much more rapidly5 1 than the ca. IO
corrected for purity) of Aldrich 1 -decene (95% purity),
0.668g (0.0025mol, 0.25mol %) of Mo(CO)6 , and I .0g
hrs at reflux required for complete conver­ (0.007mol) of anhydrous disodium hydrogen
sion of 1-decene. With more reactive phosphate (Na2 HPO4 , AR grade, freshly ground into a
powder). The dropping funnel is charged with 490ml
olefins we recommend that the course of (ca. 2mol) of the previously prepared solution of
oxidation be followed so that it can be anhydrous TBHP in dichloroethane. The stirrer is
stopped soon after completion. The more started, and the reaction mixture is brought to a gentle
reflux. Dropwise addition of the TBHP solution is
reactive olefins also give rise to more reac­ started and then the source of heat is removed from the
tive epoxides, and there is no sense in reaction vessel. 60 The TBHP solution is added to the
heating such epoxides in the presence of stirred mixture at a rate which is sufficient to maintain
Mo•6 (a weak Lewis acid) any longer than reflux. The addition requires ~0.5hr. (With unreactive
necessary. olefins such as 1 -decene it may be necessary to reapply
the heat source before the addition is complete in order
backside displacement on the peroxide Epoxidation of 1-Decene (I-mole scale) to sustain reflux.) When the addition is complete heat is
bond,48 it is impossible to form a hydrogen a) General procedure for azeotropic d rying of reapplied and refluxing is continued until the olefin is
"Aqueous TBHP-70" (or the equivalent Aldrich completely consumed (monitor by GLC, TLC or other
bond between the allylic hydroxyl and 18,47 1 -3): "Aqueous TBHP-70" (500ml, 3.6 mo!) and appropriate method). In the present experiment with 1 -
either oxygen-2 or oxygen-3. A hydrogen 850ml of reagent-grade 1,2-dichloroethane " are com­ decene this required ca. I O hours a t reflux (GLC
bond to oxygen- I in Scheme V appears bined in a 2-liter separatory funnel, which is then revealed <1% olefin). I f for some reason olefin still
feasible for 0-C-C=C dihedral angles swirled (vigorous shaking can lead to emulsions) for remains, one can simply add more of the anhydrous
~ ~
ranging from 50° to 130° . The observed about one minute. Two phases form, and the upper,
aqueous layer (ca. 1 25ml) contains only about 2.7%
TBHP solution to the refluxing reaction mixture.
stereoselectivities in Table I seem best ac­ (0. !0mol) of the TBHP originally added. The lower The reaction vessel is then cooled in an ice bath and
commodated by a dihedral angle near 120° 300ml (ca. 0.24mol) of a freshly prepared 10% solution
(see 17 and 18 in Scheme IV). 49
organic layer ( 1 225ml, containing ca. 2.35mmol of
TBHP per ml and, therefore a total of 3.5mol of TB HP) of sodium sulfite (N a2 SO3 ) is added dropwise with stir­
ring. When addition is complete the ice bath is removed
2. Epox idation of Isolated Olefins
is drained into a 2-liter, one-necked, round-bottomed
flask. [Thus, by simple phase separation one obtains and stirring is continued for 3 hours at autogenous
this TBHP solution which is similar in water content to temperature. At this point the organic phase should
(Scheme I, eq. 2) solutions which we used"·"·" to prepare by adding give a negative peroxide test using acidified starch­
If one wishes to epoxidize an isolated commercial Lucidol-90 or Aldrich's 21,312-8 to the ap­ iodide test paper. so If the test is positive additional
olefin, peracids are the first reagents which propriate organic solvent (e.g.. CH2 Cl2, benzene or aqueous sulfite solution should be added and stirring
come to mind. Several years ago we CICH2 CH2 CI). We now recommend TBHP solutions continued until the test is negative. The aqueous and
prepared in this way for the SeO2 -calalyzed ox­ organic phases are separated, and the milky white
wondered whether the industrially impor­ idations"•" (CH2 Cl2 or CICH2 CH2 CI as solvent) and organic layer is washed twice with 250-ml portions of
tant Oxirane Process (TBHP and Mo•6 for the vanadium-catalyzed epoxidation of allylic water, once with 250ml of brine, dried (MgSO,) and
catalyst) could be adapted to laboratory­ concentrated to afford a colorless but somewhat cloudy
scale (e.g., l -5 mole) epoxidations. We im­
alcohols (benzene or CH2 Cl2 as solvent). However, for
the molybdenum-catalyzed epoxidations of isolated oil. Distillation of this oil afforded 1 37.4g (center cut,
olefins removal of even this last bit ( estimated to be ca. bp 52-4° C/ I mm) of 1 -decene oxide which was 98%
mediately encountered two problems. The pure by GLC analysis (therefore 86% yield).
5-7%) of water is important, and is easily accomplished
commercially available forms of TBHP as described below.] A few boiling stones are added and
contained varying amounts of water. the flask is fitted with a distillation head. Distillation Other isolated olefins which have been
Water is deleterious to the reaction, for it (ClCH2 CH 2CI/ H 2 O azeotrope, bp 72° C) commences a epoxidized following the above procedure
not only inhibits the epoxidations, but also few minutes after heat is applied with a steam bath. The in 85-95% distilled yield include cyclohex-
distillate is cloudy and separates in the collection vessel
gives rise to epoxide opening which pro­ into organic and aqueous layers. After ca. 450ml of sol­ •Warning: It is important not to allow the distillation to
duces diols as byproducts. 50,5 1 We have vent is removed the distillate becomes clear and proceed too long, for this would eventually produce
since found that the epoxidation of isolated homogeneous. A total of ca. 575ml of distillate" is high-strength TBHP solutions.

68 Aldrichimica Acta, Vol. 12, No. 4 , 1979

ene, methyl oleate, 1-methylcyclohexene, we noted that the Upjohn procedure failed transformation. Of equal importance, the
1-phenylcyclohexene, (E)-2-decene and in our hands with the tetrasubstituted reaction can now be carried out on a one­
methyl 1 0-undecenoate. Other solvents olefin shown in eq. 34. We also suggested mole scale at a reasonable cost; this should
(e.g., benzene,53 C H2Cl2 and CC14) also that it might not be very useful with allow the use of such a step early in a syn­
work well in this epoxidation procedure trisubstituted olefins. We now wish to thetic sequence.
(i.e., in both the azeotropic drying and retract and apologize for that inference,
epoxidation stages of the process). The use because enough examples are now known I V , AHylh: Oxidation of Olefins
of methylene chloride, due to the less to make it clear that the N-methylmor­ an<I ,ec;\cctyier1es (Scherne l , eqs. 4
favorable composition of its azeotrope pholine-N-oxide method is marvelously e:1 nt�j �)
with water, requires about twice the initial effective with many trisubstituted olefins
volume of solvent needed for the other (e.g., eq. 36). Selenium dioxide is the most reliable and
solvents mentioned above. Furthermore, There have been only two appli­ predictable reagent for direct insertion of
the epoxidation step takes longer in cations66,67 of our method so it has not real­ oxygen into an allylic carbon-hydrogen
methylene chloride due to its lower boiling bond. 68 A serious complication in this reac­
ly been adequately tested. At present it tion is the inevitable production of reduced
point. In fact, 1-decene cannot be epoxidiz­ would appear to have only two possible ad­ forms of selenium. The frequent difficulty
ed in CH2Cl2 , but more reactive olefins can vantages over the Upjohn procedure. Our
be epoxidized in excellent yield in 5-24 of removing colloidal selenium from the
procedure does work with some tetra­ products is well known. Another drawback
hours at reflux.5 I substituted olefins, and TBHP is about 20 of these oxidations is the formation of
In summary, we feel that even with times less expensive than N-methyl­ organoselenium by-products. We reasoned
isolated olefins these metal-catalyzed morpholine-N-oxide (NMO) even at fine that an oxidant which would rapidly and
epoxidations may sometimes have advan­ chemical prices (and TBHP is available at selectively reoxidize the reduced selenium
tages over the more traditional peracid much lower prices in bulk quantities). species to SeO2 would circumvent these
methods. This would seem especially true Another minor point is that we always use problems, and furthermore might enable
for larger-scale ( l -5mol) epoxidations 0.2% OsO4 catalyst, whereas the NMO the reaction to proceed with catalytic
where cost and safety become important procedure has been reported with from 0.2 amounts of SeO2• Indeed, we found that
considerations.
to 5% OsO4 catalyst. If the TBHP and TBHP is an excellent oxidant for this pur­
NMO routes gave comparable yields of
pose. 54 Allylic oxidation proceeds in
Ill. Vicinal Dihydroxylation of diol in a given case, considerations of cost CH 2Cl2 at room temperature with catalytic
would favor the TBHP process, especially
Olefins (Scheme l , eq. 3) on larger-than-mmole scales. (2-50%) amounts of SeO2 . Examples from
Our experience with vanadium- and our work54 (eqs. 37, 38, 40) and from other
molybdenum-catalyzed epoxidations en­ In summary, these two new catalytic laboratories (eqs. 39, 4 1 , 42) are shown
couraged us to think of TB HP as a possible methods (TBHP-based6I,62 and NMO­ below. The transformation shown in eq. 42
oxygen-atom source for other metal­ based65") have greatly increased the by Cook and Campos70• is interesting in
catalyzed oxidations of olefins. This has reliability of the olefin to cis-vicinal diol that the substrate contains both indole and
led to the discovery of very effective
procedures6 1-62 for the osmium-catalyzed 50% Se02 n-C,H,,
�n-C,H,,
�
(eq. 37)5 4
2mol TBHP
CH Cld750ml) ►
vicinal hydroxylation of olefins (eq. 3, OH
Scheme I), and for selenium-catalyzed 1 mol
2
25 ° C, ~ 2days 93.8g {60%)
allylic oxygenations of olefins54 and
acetylenes55 (eqs. 4 and 5, Scheme I).
50% Se0 2
These new TBHP-based osmium­
(eq. 38) 54
0.2mol TBHP
catalyzed procedures for cis-vicinal dihy­ C H2Cl 2 (75ml) ►
droxylation of olefins are much more 25 ° C, ~2 days
reliable than the earlier ClO3 - (Hof­ 0.1 mol 44%
mann63)- and H 2 O2 (MilasM)- based
osmium-catalyzed procedures for this 50% Se02

fr
2mol TBHP OH
transformation. The key to the success of
CH2 Cl2 ► �.H
the new methods appears to be the presence 25° C , ~15 min.
of a nucleophile (either Et;1N•·OH 6 1 or H
Et4N +· OAc62). It seems likely that the role
of the nucleophile is to increase the turn­ {eq. 39)69
over rate of the catalytic cycle by 50% 20%
facilitating removal of the glycol product
from the coordination sphere of the os­ 28% ?%
mium. Thus, it has been possible to
hydroxylate even some tetrasubstituted 25% ?%
olefins using the Et4NOH modification (eq.

�-
34). The Et4NOAc modification fails with
tetrasubstituted olefins, but, being much 2% Se0 2
less basic than the Et4NOH method, it can 0.3 6mol TBHP (90%)
be used with base-sensitive olefinic sub­ 1 0% salicylic acid ► {eq. 40)54
C H2Cl 2, 25 ° C, 27hr
strates (eq. 35). OH
Upjohn chemists have also recently 0.1 mol 48%5 4° {550/o54b)
reported a very effective new osmium­
COOCH3 COOCH,
catalyzed p rocedure for cis-vicinal 50% Se0 2 OH COOCH,
dihydroxylation of olefins.65" The oxidant 0.2mol TBHP (70%)
in their process is N-methylmorpholine-N­ CH2Cl 2, 10° C ► �• �
oxide. In the short time since its discovery 4.5hr
q. 41)" '
it has been used many times with great
OH
success (e.g., eq. 36). In comparing this
0.1 mol 38% 7%
method with our TBHP-based procedures

Aldrichimica Acta, Vol. 12, No. 4, 1979 69

 Cat. SeO2
piperidine moieties. Stoichiometric SeO2
TBHP
((5)) CO))
oxidation of the same substrate required
C H2 Cl2 , 25 °
more vigorous conditions, and gave only
H
►
14 days H
the product of complete dehydrogenation (eq. 42)70"
(i.e., piperidine ring - pyridine ring) . 70° fl �
In our first publication on this subject, 54 50%

C;1
we mentioned that cyclohexene was a poor OH

C)1
50% SeO 2
substrate for the SeO2 / TBHP allylic ox­
2mol TBHP
idation procedure. The allylic alcohol is a
CH2Cl 2, 25 ° C
minor product and the two major products ►
are the allylic tert-butyl ether and the allylic
1 5hr
(eq. 43)55
tert-butyl perether. We have since found OH
that this is a general problem when the mp 1 22-123 °
olefinic linkage is in a ring (i.e., endo­ 55%, only one dlastereomer
cyclic).71 Smaller-ring olefins (e.g., 5- and
50% SeO 2
6-membered) are worse than larger-ring
olefins (e.g., 8- and 12-membered), but
even in the case of cyclododecene the ether
and perether by-products are still ap­
parent. For cyclododecene the ratio of
}-=_/ 2 mol TBHP
C H2Cl 2, 25 ° C
28hr
► }-=_/ 55%
(eq. 44)55

50% SeO 2
allylic alcohol to by-products (i.e., allylic
2 mol TBHP
ether and perether) is 7:3; the ratio for H CI-H _JH

0- -- CH2Cl 2, 25 ° C U - -
cyclohexene is 1 :4. Thus, it is important
► +
(eq. 45) 55
30 h r
that one be wary of applying our procedure
to endocyclic olefins which are in small­ 11%
37%
and medium-sized rings, especially if the
C-H bond to be oxidized lies within the

c; -< 0-=-{
same ring. However, exocyclic olefins
3mol TBHP
0-= _/
work well (eq. 39) , and it also appears that
the reaction proceeds normally with en­ CICH2C H2CI ► +
docyclic olefins if the allylic C-H bond OH (eq. 46)55
which is oxidized lies outside the ring. 7 1
72hr, 25 C °
41% 37%
We have recently found that, unlike 72hr, 25 ° C then 8hr, 8O ° C 18% 52%
olefins, acetylenes show a strong tendency
to undergo a,a'-dioxygenation upon reac­
~120°
tion with the SeO2 / TBHP system (eq.
43).55 The oxidation of ten different +H + Oz ► (eq. 47)72
acetylenes allowed assignment of the
relative reactivity sequence as CH2 ==o CH >
CH3, thus allowing selective monooxy­
genation in the case of CH2 vs. CH 3 or of
CH vs. CH3 (eq. 45) . Alkynes bearing one �-,/o-f (oq. 48)"
+
methylene and one methine substituent af­
ford the enynone as the major product ( eq .
46) . overcome the selenophobia which current­ molybdenum-catalyzed epoxidation of
ly afflicts many synthetic organic chemists. propylene. However, they do sell some of it
Both the olefin54and the acetylene55 for use outside their plant. This material is
Se02/ TBHP a-oxygenation procedures almost pure TBHP except for 30% water
have been performed on a one-mole scale which is added as a stabilizer to permit
with no difficulty. One advantage of these shipment in tankcar and tanktruck quan­
procedures is that they can be run quite tities. Oxirane calls this material "Aqueous
concentrated (at least I M in olefin or I. Commercial Sources. There are two TBHP-70". 74 The vital statistics for the Ox­
acetylene), and hence are conveniently commercial routes to TBHP. The most im­ irane "Aqueous TBHP-70", Lucido}
scaled-up. However, the key advantage of portant is the autoxidation72 of isobutane TBHP-90 and pure TBHP are given in
the SeO1/TBHP/CH2 Cl2 system is that it is ( eq. 47) . The older route involves acid­ Table II . Please note that the data for pure
more reactive and also more selective than catalyzed alkylation72 of hydrogen perox­
ide with tert-butyl alcohol (eq . 48) . This
TBHP are given only for the sake of com­
any known" stoichiometric SeO2 oxida­ parison with the commercial grades. Pure
tion procedures. With the exception of the latter route leads to coproduction of di­
tert-butyl peroxide (DTBP) . LucidoI offers
TBHP is not commercially available nor
endocyclic olefins mentioned above, it is should it, in our opinion, ever be prepared
clearly the method of choice for obtaining two grades of TBHP: ( 1) Lucidol-TBHP- and used except on a very small scale. The
synthetically useful yields of unrearranged 70 contains (by wt.) 70% TBHP, ~ 19% 70% TBHP is available from Aldrich and
allylic alcohols from a greatly broadened DTBP, and 1 1 % of TBA and water;73 (2) can be shipped by UPS making it an ideal
spectrum of olefins. The positional selec­ Lucidol-TBHP-90 contains 90% TBHP, form in which to receive TBHP for
tivity, which has been the chief attraction ~6% TBA, ~4% H 2 O, and <1% DTBP. laboratory-scale operations.
of Se02 oxidations, is retained . The milder
conditions avoid the rearrangements and The 90% grade ofTB HP is also available 2. Purification. Of the three75 commer­
dehydrations which can occur under the from Aldrich, but it must now be sent by cial grades of TBHP only the two shown in
standard stoichiometric conditions. Final­ truck according to a recent ruling of the Table II are suitable for use in the metal­
ly, the dramatic reduction in the amount of DOT. catalyzed oxidations described here . Since
colored, malodorous organoselenium by­ Oxirane Corporation produc�s TBHP the 90% grade is inherently more expen­
products formed, and the elimination of by the autoxidation route. Almost all of sive, and is made even more so because it
precipitated selenium metal should help to this TBHP is used on-site for the must travel by truck, we have adapted to

70 Aldrichimica Acta, Vol. 12, No. 4, 1979

using the 70% grade (70% TBHP/ 30% procedure for removing most of the water regarded as too dangerous to work with,
H20) for all our needs. This approach is ac­ from the 70% TBHP means that the less especially on a preparative scale. In the
tually much more attractive than one might convenient (more expensive and less past, perhaps the main reason for distilling
at first think. stable) 90% commercial grade of TBHP is TBHP was the desire to obtain anhydrous
no longer really essential. Recall that 90% material for further reactions (e.g. , to form
The aqueous 70% TBHP is ideal for TBHP was the grade we used to recom­ tert-butyl peresters from the corresponding
direct use in the osmium-catalyzed vicinal mend for the vanadium- and selenium­ acid chlorides78). Our new azeotropic
dihydroxylation of olefins (eq. 3, Scheme catalyzed oxidations (eqs. I, 4 and 5, procedure for generating anhydrous
I). 1 , This process requires the presence of
6 62
Scheme I). We have also found that the solutions of pure TBHP in aprotic organic
water and there is absolutely no virtue in
TBHP solutions one gets by the simple solvents should in many cases obviate the
using drier grades of TBHP. In fact,
phase-separation procedure have nearly need to distill pure TBHP.
anhydrous solutions of TBHP do not work
the same reactivity as solutions generated
by dissolving commercial 90% TBHP in
for this application. Since much of this review is concerned
The vanadium- and selenium-catalyzed the same solvent.76 This is as it should be with removing water from TBHP, one
since both methods yield TBHP solutions might naturally wonder about the effec­
oxidations (eq. 1,4 and 5, Scheme I) were
which contain similar (based on TBHP tiveness of molecular sieves for this pur­
all initially developed 2, ,54, using the
content) amounts of water (i.e., 4-5% H2 O
1 14 55
pose.For this reason we quote the follow­
commercial 90% grade (~4-5% H2 O) of
ing account of a small accident which oc­
TBHP. The vanadium-catalyzed processes for Lucido! TBHP-90 and 6-7% H2 O for
curred at Shell Development Company in
are definitely slowed by the presence of the TBHP solutions we prepare by phase Houston: "We had been routinely drying
water, but the 90% grade is dry enough to separation). 90% TBHP (typically containing 6% H2 O,
give reasonable rates and good yields. 3. Dangers. We have so far emphasized 3% TBA and 1% Di-t-butyl peroxide) on a
However, the rates and sometimes the
the relative safety of working with TBHP small scale using 4A molecular sieves. A
yields can be increased if one prepares
as compared to working with other perox­ technician inadvertently used Linde 13X
anhydrous solutions of TBHP in organic
idic substances. Now we must point out mo! sieves.After pouring one or two liters
solvents. The selenium-catalyzed processes
that TBHP, like almost all substances hav­ on the packed bed the technician was suf­
show a more complicated dependence on
ing 0-0 bonds, has to be regarded with ficiently alarmed at the unusual exother­
the water content of the TB HP. When us­
respect. However, provided one avoids cer­ mic reaction taking place that he quickly
ing 50% SeO catalyst the reactions are closed the fume hood. Within one or two
2
tain situations, this state of respect need
rather insensitive to water content. Thus, minutes the hydroperoxide ignited.The en­
not degenerate into a state of fear.
Sum and Weiler were able to use 70% suing fire was contained within the fume
TBHP directly for oxidation of methyl There are three main situations to avoid.
hood.We surmise that the heat of adsorp­
farnesoate (eq. 41),70 whereas we have
b
The first rule is never add a strong acid
(even just a drop) to high-strength TBHP tion of TBHP on 13X sieves (pore size
found that 90% TBHP was optimum when
solutions. The second rule is never add
~9A) was sufficient to raise the temper­
using only 2% SeO2 catalyst for oxidation ature to the autoignition point.Note that,
of the similar olefin, geranyl acetate (eq. transition metal salts known to be good
40).54 Both less water (anhydrous TBHP) autoxidation catalysts (e.g, Mn, Fe and Co in contrast, penetration of TBHP into the
are particularly bad) to high-strength
pores of a 4A sieve is not possible)."79
and more water (70% TBHP or phase­
separated TBHP in CH2 Cl2) resulted in TBHP solutions. Alkyl hydroperoxides are Perhaps this behavior is specific for the
substantially slower oxidations under sensitive to metal-catalyzed radical-chain 13X sieves, but at present we would not be
otherwise identical conditions.76 How­ a
decomposition. 8,7 2,77 Among other things too sanguine about pouring high-strength
ever, even in this case the phase-separated this produces a lot of oxygen gas. The third (e.g., 90%) TBHP over molecular sieves of
TBHP/ CH2 Cl2 solutions were adequate rule (which, if followed, will ameliorate any any kind.
for use. problems arising from violations of the One can remove some of the remaining
The only process in Scheme I which ac­ first two rules) is never work with pure (~6-7%) water from the organic solutions
TBHP and avoid using high-strength of TBHP (obtained from 70% TBHP by
tually requires anhydrous conditions for
solutions of it whenever possible. the phase-separation technique) by swirl­
good yields is the molybdenum-catalyzed
epoxidation of isolated olefins (eq. 2). For­ The literature contains a number of ex­ ing them with anhydrous MgSO4 • The
tunately, we have found that it is relatively amples of violations of this last rule.78 Most MgSO4 should be removed by filtration
easy to obtain anhydrous solutions of of these involve distillation of TBHP to through a plug of glasswool placed in the
TBHP in organic solvents, even when start­ purities of 98% or greater. These are per­ stem of a regular funnel; a sintered-glass
ing with the wettest grade of TBHP, name­ formed at reduced pressure and, if done funnel should not be used for it may be con­
ly "Aqueous TBHP-70" (70% TBHP/ 30% carefully in clean glassware, are probably taminated with metals. However, TBHP
H20, w/ w) by employing the phase­ quite safe. However, many people use solutions dried in this way are less effective
separation and azeotropic-distillation heating mantles for distillations and one (presumably because they are wetter) in the
techniques which are described above for wonders what would happen if the flask molybdenum-catalyzed epoxidations of
the epoxidation of 1-decene. broke or had a crack in it. But the real isolated olefins than are TBHP solutions
problem here is that one might produce dried by the azeotropic technique.5 1
Note that the easy phase-separation really pure (>99%) TBHP which has to be If one contemplates larger-scale (0.1
mole and greater) reactions of the type
Table II. Properties of Commercial Grades of TBHP shown in Scheme I, then the following ad­
Aqueous Lucidol Pure vice is of special importance. Whenever
Properties TBl-!P-70 TBHP-90 TBHP* possible add the TBHP slowly to the reac­
diluents ~ 6% TBA tion mixture under conditions where it is
~4% H20 being consumed as it is added. We have run
<1 % DTBP the molybdenum-catalyzed epoxidation of
bp( ° C/mm) 96n6o 1 33/760 isolated olefins (eq. 2, Scheme I) on a 2.5-
mp( ° C) -2.8 -10 4.2 mole scale; this involves at least 5 moles of
density (25 ° C) 0.935 0.90 0.8960 TBHP. However, the TBHP is added at a
ca. mmol TBHP/ml 7.2 9.0 9.94 rate which maintains a gentle reflux and
shipping UPS Truck only
*Not commercially available, only included in table for
therefore does not build up in the reaction
comparison with the two commercial grades.
mixture. The larger-scale reactions also
tend to need less catalyst. We have use.d as
Aldrichimica Acta, Vol. 12, No. 4, 1979 71
 little as 0. 1% Mo(CO)6 catalyst in the 2.5- circumstance would cause the concentra­ minute details needed to get this man­
mole scale epoxidations. A situation to be tion of the supernatant TBHP solution to uscript ready. Finally, we are indebted to
avoided at all costs is that where one places vary. TBHP containers should best be Drs. Orville L. Mageli, Edward S. Shanley,
large quantities of TBHP and the substrate stored in the dark or at least out of bright Chester S. Sheppard and Jeff White for
(olefin or acetylene) together and then adds light, and should be kept in an area free of reading and providing important criticisms
the catalyst. This can sometimes be done, accelerators, corrosives and other in­ of the manuscript, and to Prof. J ulius
but only after one has very carefully es­ herently hazardous materials. To avoid R ebek for many insightful discussions on
tablished that the substrate is so unreactive contamination while sampling always pour the mechanism of peracid epoxidations
that the reaction cannot get out of control. TBHP out of the container, never stick (see his student's Ph. D . thesis48d).
Finally, if you really must risk mixing sampling devices into the container, and
everything together at once it is always
References and Notes
never return unused TBHP to the con­ l) Technical bulletin on 70% TBHP/30% H,O (their
safer to be in a lower boiling solvent than a tainer. USP-800 grade) from Witco Chemical, a U.S.
higher boiling one.
Like all strong oxidants TBHP is an eye
Peroxygen Division.
2) The catalytic decomposition of H2O2 by a variety of
and skin irritant. It is especially bad in the
Dr. E.S. Shanley has pointed out that
transition metals is well known [see J .A. Connor
and E.A.V. Ebsworth, Adv. lnorg. Chem.
there is a common ambiguity in the use of eyes. Should it get in your eyes flush them Radiochem., 6, 359-360 ( 1964), and S.B. Brown, P.
the term "stability". We have used it in this immediately with copious amounts of Jones, and A. Suggett, Prog. lnorg. Chem., 13,
review to mean low decomposition rate water and contact a physician. Eye protec­ 159-204 ( 1970)].
tion and rubber gloves should be worn 3) N.A. Milas and S.A. Harris, J. Am. Chem. Soc.,
during storage. Another meaning of
"stability" is lack of potential for spon­ when handling these materials.
60, 2434 ( 1938).
4) a) N. Prileschajew, German Patent 230,723 (1908);
taneous change. TBHP is certainly not "Aqueous 70% TBHP" will burn b) N. Prileschajew, Ber., 42, 48 1 1 ( 1 909).
5) N. lndictorand W.F. Brill, J. Org. Chem., 30, 2074
stable in this latter sense. It is therefore im­ vigorously if ignited but will not explode
unless it is contained. This is one of the ad­
( 1965).
portant to be sure that most all peroxidic
vantages of shipping peroxides in plastic
6) J. Kollar, U.S. Patents 3,350,422 and 3,351,635
substances are reduced before engaging in ( 1967).
distillation of reaction mixtures in which containers. Should things get hot the con­ 7) M.N. Sheng and J.G. Zajacek, J. Org. Chem., 33,
TBHP was used as oxidant. The Na2 SO3 1 7 tainers melt down and prevent contain­
588 (1968).
and dimethyl sulfide18 procedures for ment. Should a fire arise copious amounts
8) For a very recent and excellent review on "Metal

reducing excess TBHP are reliable, and the of water, coolants and f oam extinguishers
Catalyzed Epoxidations of Olefins with
Hydroperoxides" by R.A. Sheldon, see Vol. IV. of
absence of TBH P can, and should, be es­ should be employed. "Aspects of Homogeneous Catalysis," C. Manfred,
tablished with acidified starch-iodide test
Ed., Monotipia Rossi-Santi-Milano, Italy, in
paper. 80 However, of greater concern is the
press.
VI . Condusion 9) M.N. Sheng and J.G. Zajacek, J. Org. Chem., 3S,
Because TBHP is a selective, inexpen­
possibility that the TBHP has become 1 839 ( 1 970).
10) F. List and L. Kuhnen, Erdoe/. Kohle, 20, 192
sive, and relatively safe oxidant, its
bound into the molecule in some more­
stable form. This is especially true in those
( 1 967).
applications in organic synthesis should I I) a) H.B. Henbest and R.A.L. Wilson, J. Chem.
reactions in Scheme I which involve mildly Soc., 1958 ( 1957); b) for a review on the
acidic conditions (viz., eqs. I , 2, 4 and 5). If continue to increase. Few reactions have
caught on as rapidly among synthetic
stereochemical aspects of the synthesis of epoxides,
see G. Berti, Top. Stereochem., 1, 93-25 1 ( 1973).
chemists as the vanadium-catalyzed epox­
the molecule contains a ketone or aldehyde
1 2) a) K.B. Sharpless and R.C. Michaelson, J. Am.
function in addition to the olefinic unit one
idation of olefinic alcohols (eq. I , Scheme Chem. Soc., 95, 6136 ( 1 973); b) epoxidations of
I). This gives some insight into the impor­
should be aware of the possibility of allylic alcohols proceed approximately ten times
tance of being able to stereoselectively in­
peroxyketal or peroxyacetal formation.8 1 faster with vanadium than with molybdenum
An NMR spectrum of the crude reaction
troduce new asymmetric centers into a
catalysts.
mixture should reveal contamination by
1 3) B.E. Rossiter, T.R. Verhoeven, and K.B.
molecule under the direct control of a Sharpless, Tetrahedron Lett., in press.
tert-butyl peroxyacetals or ketals.
preexisting chiral center. The fact that this
14) S. Tanaka, H. Yamamoto, H. Nozaki, K.B.
Above all, we prefer steam baths for particular reaction also exhibits good
Sharpless, R.C. Michaelson, and J.D. Cutting, J.
Am. Chem. Soc., 96, 5254 ( 1974).
heating TBHP reaction mixtures ( especial­ stereoselectivity on acyclic molecules, and
ly on a large scale). Oil baths are also accep­
I 5) Although this work was done in collaboration with
even over fair distances, makes it all the the Yamamoto/ Nozaki group, we wish to em­
table, but messy on a large scale, and more valuable. As synthetic chemists
phasize that the errors were exclusively due to our
heating mantles involve obvious dangers. become more familiar with TBHP, they
group and have nothing to do with that portion
(i.e., the juvenile hormone synthesis and the
We have used heating mantles f or heating may find that some of the other metal­
TBHP solutions, but are careful to use low
trisubstituted olefin synthesis)" of the publication
catalyzed oxygenations discussed here contributed by our Japanese colleagues.
power settings, and to see that the level of (Scheme I) are also useful f or the construc­ 16) A. Yasuda, S. Tanaka, H. Yamamoto, and H.
Nozaki, Bull. Chem. Soc. Jpn., 52, 1701 ( 1 979).
solvent in the flask is always above the top tion of complex molecules. 17) A.G. Davies, "Organic Peroxides," Butterworths,
of the mantle. London, 1961, pp 189-90. Peroxide chemists ap­
A lot more information about safety and Acknowledgement parently have known for a long time that sulfite
handling of TBHP as well as other perox­ We are grateful to Lucido!, Oxirane and
(SO3 ·2) is a much better reagent for reducing
ides is available in various bulletins from Witco Chemical Companies for having
hydroperoxides than is bisulfite (HSO3).

the companies which sell it (e.g. , Lucidol, 82

1 8) a) J.J. Pappas, W.P. Keaveney, E. Gaucher, and
provided us with generous samples of M. Berger, Tetrahedron Lett., 4273 ( 1 966);
Oxirane,83 and Witco 1 ). E.S. Shanley has various hydroperoxides and peroxides. We b) M.A.P. Dankleff, R. Curci, J.O. Edwards, and
written a chapter on "Organic Peroxides: H.-Y. Pyun, J. Am. Chem. Soc., 90, 3209 ( 1 968);
especially wish to thank Dr. Chester Shep­
Evaluation and Management of Hazards" pard of Lucido! for many helpful dis­
c) other reduction methods are available (see R.

in Swern's series on "Organic Peroxides". 84

Hiatt in "Organic Peroxides," Vol. II, D. Swem,
cussions over the past six years in which he Ed., Wiley, New York, N.Y., 197 1 , p 49).
4. Storage. The maximum recommend­ taught us a lot abo1.1t peroxide chemistry. 19) We still occasionally experience polymerization
ed storage temperature for TBHP is 38° C Most of our TBHP-related research
upon distillation especially with higher-boiling

( 1 00° F).82 It is stable essentially indefinite­ described here was carried out in the
epoxides. This may be due to the presence of small
amounts of the Mo•6 catalyst. The pot residues
ly at room temperature (25° C) and, thus, Chemistry Department of the Mass­ always give a weak spot test for molybdenum, but
does not need refrigeration. In fact, it is im­ achusetts Institute of Technology. This analyses of the residues for molybdenum indicate
that >95% of the molybdenum is removed by the
portant that the "aqueous 70% TBHP" not research was, and still is, supported by
be stored much below room temperature. grants from the National Science Founda­
extractions during the work-up.
20) D. Baldwin and J.R. Hanson, J. Chem. Soc.,
It is essentially saturated with water at tion and from the National Institutes of Perkin Trans. /, 1941 ( 1975).
25° C, and at lower temperatures an H ealth. We are also very grateful to Bryant 21) M.R. Demuth, P.E. Garrett, and J.D. White, J.
Am. Chem. Soc., 98, 634 (1976).
a queous phase separates which is visible on E. Rossiter, Doris J. Scheffel and Dr. Per 22) a) A. Murai, N. Iwasa, and T. Masamune, Chem.
the bottom of the storage container. This H .J. Carlsen for their help with many last- Lett., 235 (1977); b) A. Murai, N. Iwasa, M.

72 Aldrichimica Acta, Vol. 12, No. 4, 1 979

 Takeda, H. Sasamori, and T. Masamune, Bull. to the already known beneficial effect of basic ad­ 98, 1986 ( 1976).
Chem. Soc. Jpn., 50, 429 ( 1977); c) A. Murai, H. ditives on these reactions. See Ref. 6 for details. 62) K. Akashi, R.E. Palermo, and K.B. Sharpless, J.
Sasamori, and T. Masamune, ibid., 51, 234 ( 1978). 53) Most of our early development work on this Org. Chem., 43, 2063 ( 1978).
23) B.M. Trost, M.J. Bogdanowicz, W.J. Frazee, and problem was done using benzene as the solvent. 63) K.A. Hofmann, Ber., 45, 3329 ( 1 9 1 2).
T.N. Salzmann, J. Am. Chem. Soc., 100, 5 5 1 2 Benzene is an ideal solvent for these epoxidations, 64) N.A. Milas and S. Sussman, J. Am. Chem. Soc.,
( 1978). but for obvious reasons we decided to move away 58, 1 302 ( 1936).
24) K. Yamakawa, K. Nishitani, and T. Tominaga, from it. We have found that dichloroethane, with 65) a) V. VanRheenen, R.C. Kelly, and D.Y. Cha,
Tetrahedron Lett., 2829 ( 1 975). its similar boiling point and its similar ability to Tetrahedron Lei/., 1973 ( 1 976); b) S.D. Larsen
25) T. ltoh, K. Jitsukawa, K. Kaneda, and S. remove water azeotropically, is a good alternative and S.A. Monti, J. Am. Chem. Soc., 99, 8 0 1 5
Teranishi, J. Am. Chem. Soc., 101, 1 59 ( 1979). to benzene. H owever, it must be pointed out that ( 1 977).
26) S. Danishefsky, M. Hirama, K. Gombatz, T. benzene is the best solvent we have ever found for 66) S.G. Levine and B. Gopalakrishnan, Tetrahedron
Harayama, E. Berman, and P. Shuda, ibid., 100, these epoxidations. Anhydrous solutions of TB H P Leu., 699 ( 1979).
6536 ( 1 978). i n benzene are more stable than those i n dichloro­ 67) S. Current and K.B. Sharpless, ibid., 5075 ( 1978).
27) A. Murai, M. Ono, A. Abiko, and T. Masamune, ethane, and the Mo•6-catalyzed radical decomposi­ 68) N. Rabjohn, Org. React., 24, 26 1 ( 1 976).
ibid., 100, 775 1 ( 1978). tion of TBHP is more serious competition for the 69) H.E. Paaren, D.E. Hamer, H.K. Schnoes, and
28) T. Kato, M. Suzuki, M . Takahashi, and Y. desired epoxidation pathway 'in dichloroethane H . F. Deluca, Proc. Nat. A cad. Sci. U.S.A., 75,
K itahara, Chem. Lett., 465 ( 1977). than it is in benzene. However, given the toxicity 2080 ( 1978).
29) W.C. Still, J. Am. Chem. Soc., 101, 2493 ( 1 979). problem with benzene, dichloroethane is the best 70) a) 0. Campos and J. M . Cook, Tetrahedron Leu.,
30) J.-C. Depezay and A. Dureault, Tetrahedron Lett., alternative solvent we have found to date. l025 ( 1979); b) F.W. Sum and L. Weiler, J. Am.
2869 ( 1978). 54) a) M.A. Umbreit and K.B. Sharpless, J. Am. Chem. Soc., IOI, 4401 ( 1979).
3 1 ) R.K. Boeckman, Jr. and E.W. Thomas, J. Am. Chem. Soc., 99, 5526 ( 1 977); b) when the reaction 7 1 ) B. Chabaud and K.B. Sharpless, unpublished
Chem. Soc., 101, 987 ( 1979). was performed on a 1 -mol scale and followed by results.
32) J.J. Partridge, V. Toome, and M.R. Uskokovi�, BH 4 reduction (to reduce the a,P-unsaturated 72) R. Hiatt in "Organic Peroxides," Vol. I I , D.Swern,
ibid., 98, 3739 ( 1 976). aldehyde by-product), a 55% distilled yield was Ed., Wiley, New York, N.Y., 197 1 , pp 1 - 1 5 1 .
33) G. Stork, Y. Nakahara, Y. Nakahara, and W.J. realized: D.J. Scheffel and K.B. Sharpless, to be 73) This (Lucidol-TBHP-70) i s the one commercial
Greenlee, ibid., 100, 7775 ( 1 978). submitted to Org. Syn. grade of TBHP which should not be used for the
34) P.A. Bartlett and K. K. Jernstedt, ibid., 99, 4829 55) B. Chabaud and K.B. Sharpless, J. Org. Chem., 44 metal-catalyzed oxidations discussed in this
( 1 977). 4202 ( 1979). review. The problem is that it contains 19% di-tert­
35) K. Tsuzuki, Y. Nakajima, T. Watanabe, M . 56) This distillate (aqueous phase = 20ml, organic butyl peroxide (DTBP). DTBP will largely survive
Yanagiya, and T . M atsumoto, Tetrahedron Leu., phase = 555ml) contains ca. 0.9 mole of TBHP the reactions and then will present problems during
989 ( 1 978). which co-distills along with the dichloroethane and work-up and distillation. The presence of DTBP
36) M. Kobayashi, S. Kurozumi, T. Toru, and S. the water (90% of this TBHP is in the organic phase also greatly lowers the thermal stability ofTBHP.
Ishimoto, Chem. Lett., 1341 ( 1976). of the distillate). Co-distillation of TBH P also oc­ Lucidol-TBHP-70 should not be confused with
37) S. Masamune, Y. Hayase, W. Schilling, W.K. curs when benzene is used as the azeotropic sol­ Lucidol-TBHP-70X. The latter is equivalent to
Chan, and G.S. Bates, J. Am. Chem. Soc., 99, 6756 vent, but occurs only to a very slight extent when Oxirane's "Aqueous TBHP-70."
( 1 977). CH 2Cl2 is the azeotropic solvent. 74) This is equivalent to Aldrich's 1 8,471-3, Lucidol­
38) T. Nakata, G. Schmid, B. Vranesic, M. Okigawa, 57) We have no proof that these solutions are truly TBH P-70X, and Witco Chemical's USP-800.
T. Smith-Palmer, and Y. Kishi, ibid., 100, 2933 anhydrous. The important fact is that they are 75) Oxirane Aqueous TBHP-70, Lucidol-TBHP-90,
( 1 978). highly effective for the M 0•6-catalyzed epox­ and Lucidol-TBHP-70.
39) T. Fukuyama, B. Vranesic, D.P. Negri, and Y. idations of isolated olefins. 76) a) B. Chabaud, L.E. Khoo, B.E. Rossiter, D.J.
Kishi, Tetrahedron Lett., 2741 ( 1 978). 58) a) This procedure was adapted from that describ­ Scheffel, and K.B. Sharpless, unpuhlished results.
40) R.B. Dehne! and G.H. Whitham, J. Chem. Soc., ed in the October, 1971 technical bulletin available b) The TBH P solutions generated by phase
Perkin Trans. 1, 953 ( 1979). from the Oxirane Corporation. Place 2ml of glacial separation are slightly less reactive, presumably
4 1 ) S. Yamada, T. Mashiko, and S. Terashima, J. Am. acetic acid and 25ml of isopropanol in a 250ml because they contain a little more (ca. 1-3% more)
Chem. Soc., 99, 1988 ( 1 977). Erlenmeyer flask. Mix the contents and add 10ml water than the solutions made from commercial
42) R.C. M ichaelson, R.E. Palermo, and K.B. of a freshly prepared sodium iodide-isopropanol 90% TBHP.
Sharpless, ibid., 99, 1 990 ( 1 977). solution prepared by refluxing a mixture of 22g of 77) G. Sosnovsky and D.J. Rawlinson in "Organic
43) K. Oshima and K. B. Sharpless, unpublished Nal in 100ml of isopropanol, followed by cooling Peroxides." Vol. I I , D. Swern, Ed., Wiley, New
results. to room temperature and filtering. Add an ac­ York, N.Y., 197 1 , pp 1 53-268.
44) R. Breslow and L.M. Maresca, Tetrahedron Lett., curately measured sample of the TBHP solution 78) L.F. Fieser and M. Fieser, "Reagents for Organic
623 ( 1977). (containing no more than 2. 5mmoles of active ox­ Synthesis," Vol. I, Wiley, New York, N.Y., 1967,
45) P. Chamberlain, M . L. Roberts, and G . H . ygen) and gently reflux for 30 sec. After dilution pp 88-89.
Whitham, J. Chem. Soc. (B), 1 374 ( 1 970). with 1 00ml of distilled water, immediately titrate 79) Shell Development Company, private communica­
46) P. Chautemps and J.-L. Pierre, Tetrahedron, 32, the solution with 0. 1 N sodium thiosulfate (E.M., tion.
549 ( 1 976). 'Titrasol") to the disappearance of the yellow 80) TBH P reacts very slowly with starch-iodide test
47) P.J. White, M .J. Kaus, J.O. Edwards, and P.H. iodine color. Starch indicator solution may be used paper. Therefore, commercially available starch
R ieger, Chem. Commun., 429 ( 1 976). toward the end of the titration to enhance the end­ iodide test paper is acidified with a few drops of l -
48) N ucleophiles have long been thought to attack point. The concentration is calculated according to 3N hydrochloric acid solution. Then a few drops of
peroxidic reagents in this manner (i.e., S N 2 the equation: [S x N)/[2 x (ml of sample)] = the solution to be tested are placed on the wet,
process): a) J.O. Edwards in "Peroxide Reaction molarity of TBH P solution, where S = ml of acidified test paper.
Mechanisms," J.O. Edwards, Ed., Wiley, New thiosulfate for titration and N = normality of 8 1 ) We have observed peroxyketal and peroxyacetal
York, N.Y., 1962, pp 67- 106; b) A.O. Chong and thiosulfate. b) Molarity e, A/[(0. I0A) + (0. 18B)] formation with TBHP and ketones and aldehydes
K.B. Sharpless, J. Org. Chem., 42, 1 587 ( 1977). For where A integration of tert-butyl resonance ( ~ in CH 2Cl2 in the presence of catalytic amounts of
the particular case of peracid epoxidations, a 1 .25 6) and B = integration of dichloroethane SeO2 : I. Takagi, B. Chabaud, and K.B. Sharpless,
number of authors have favored this backside at­ resonance ( ~ 3. 70 6). unpublished results,
tack by the olefin along the axis of the 0- - 0 bond, 59) We have prepared, by this azeotropic technique, 82) A looseleaf folder entitled "Organic Peroxides" is
for example, see: c) T. Yonezawa, H. Kato, and 0. anhydrous solutions of TBHP in a variety of available from the Lucido! Division of the
Yamamoto, Bull. Chem. Soc. Jpn., 40, 307 ( 1967); organic solvents. We have stored these solutions Pennwalt Corporation. It contains numerous, very
d) S.F. Wolf, Ph.D. thesis, University of Califor­ for at least 6 months at room temperature with no useful bulletins on all aspects of the commercially
nia, Los A ngeles, 1977; e) R.D. Bach. C . L. Willis, significant loss of titer. However, such solutions available organic peroxides.
and J.M. Domagla, "Applications of M O Theory prepared from chlorinated solvents (e.g., CH 2Cl2, 83) A number of very informative technical data sheets
in Organic Chemistry," Vol. I I , I.G. Csizmadia, CICH 2CH 2CI, CHCl3 , and CCI,) all seem to very on TBHP are available from Oxirane Corporation.
Elsevier, 1 977; t) B. Plesnicar, M. Tasevski, and A . gradually release a gas (presumably oxygen); if the 84) E.S. Shanley in "Organic Peroxides," Vol. I I I , D.
Azman, J. A m . Chem. Soc., 100, 743 ( 1978); container is opened every few weeks, one notices a Swern, Ed ., Wiley, New York, N.Y., 1972, Chap.
g) E.J. Corey, H. Niwa, and .J .R. Falck, ibid. , IOI, hissing sound. This has never caused us any trou­ v_
1 586 ( 1 976). ble, but we would not recommend that large quan­ 85) Y. Kishi, private communication.

About the
49) We had originally preferred a dihedral angle near tities of such solutions be stored in sealed vessels
90° for these peracid epoxidations. We would like for long periods of time. In contrast to this
to thank Professor Satoru M asamune for pointing behavior, we have found that azeotropically dried Dr. Sharpless received a B.A. degree
out to us that the data (Table !) appears to betterfit solutions of TBHP in benzene, toluene, cyclohex­
a dihedral angle near 120° . Pierre had earlier ane, ethyl acetate and tert-butyl alcohol seem to be from Dartmouth College in 1963 and his
proposed 1 20° as a possible preferred dihedral completely stable (no out-gassing) when stored in Ph.D. from Stanford University in 1968.
angle. 46 sealed containers at room temperature. He was a professor at the Massachusetts
50) R. Hiatt, "Oxidation," Vol. 2, R.L. Augustine, Ed., 60) It is especially important to remove the heat source, Institute of Technology from 1970-1977
M arcel Dekker, New York, N.Y., 197 1 , Chap. 3. during TBHP addition, in large-scale epox­
and has been Professor of Chemistry at
51) B . E. Rossiter, R.C. M ichaelson, L.E. Khoo, and idations. The reaction is exothermic and renuxing
K. B. Sharpless, unpublished results. will be sustained by gradual addition of the TBHP Stanford University since 1977. He receiv­
52) We are at present uncertain of the reason(s) for the solution. I n small-scale epoxidations, especially ed an A.P. Sloan Fellowship and a Dreyfus
beneficial effect of anhydrous disodium hydrogen with less reactive olefins (e.g., 1-decene), it may be Teacher-Scholar Award in 1973.
phosphate. Dr. Jeff White of Oxirane has pointed necessary to maintain heating to sustain reflux.
out that the effect of Na2 HPO4 is probably related 6 1 ) K.B. Sharpless and K. Akashi, J. Am. Chem. Soc., His research interests include the
Aldrichimica Acta, Vol. 12, No. 4, 1979 73
 development of new homogeneous
catalysts for the oxidation of organic com­
NM R Shifi Reagents
pounds, utilization of inorganic reagents to
Position Available In response to numerous requests for a
effect new synthetic transformations in smaller unit size, we now offer these
organic chemistry, and the asymmetric ox­ Aldrich is seeking an experienced products in 100-mg quantities.
idation of organic compounds. M.S. or Ph.D. chemist with proven
Dr. Verhoeven obtained his Ph.D. from supervisory background and ex­
p erience in synthetic organic
the University of Wisconsin in 1979 and is
currently a postdoctoral fellow with Dr. chemistry to head its pilot plant
Sharpless at Stanford. operation in a new facility in
Milwaukee. The successful can­
didate's immediate responsibility
will include directing a staff of
Aldrich offers these compounds cited by chemists and coordinating a three­
Drs. Sharpless and Verhoeven: s hift operation. Allied duties involve
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remainder water 100g $4.50 scale-up of established procedures. 100mg $3.30; lg $ 13.95
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100g $26.60; 500g $ 106.50 pectations to Personnel, Aldrich
1 kg $ 176.00 Chemical Co., 940 West Saint Paul
Dl 80-7 1-Decene 1kg $7.70 Ave., Milwaukee, WI 53233. 1 7,649-4 Tris[3-trifluoromethylhydroxy­
20,809-4 Magnesium sulfate, anhydrous, methylene)-d-camphorato], europium(III)
tech. 500g $ 10.70 An Equal Opportunity Employer. derivative 100mg $4.40 ;lg $21.80
2kg $34.40 M/F/ H/ V Sg $72.60
M8, 163-2 Methyl sulfide ! kg $6.35
3kg $ 13.55
19,995-8 Molybdenum hexacarbonyl
50g $20.40; 250g $75.00
20, 103-0 Osmium tetroxide, 99.8%
l g $ 19.50
20,886-8 Osmium tetroxide, 2.5% w/ v
solution in tert-butyl alcohol
40ml $29.00
Now available.. .
10,59 1-0

2 1 ,336-5
Salicylic acid, 99+%
500g $5.80; 3kg $25.50
Selenium(IV) oxide, 99.8%
E I
20,0 I 0-7
I00g $ 18.90; 500g $72.00
Selenium(IV) oxide, 99.9+%
25g $ 19.85; 100g $65.00
E
Save time with this convenient 1 1 1 /2 x 20-cm
20,43 1-5 Selenium(IV) oxide, 99.999%
l Og $ 17.50; 50g $70.00 template made of sturdy plastic. Used
2 1 ,988-6 Sodium hydrogen phosphate, extensively by research chemists, twenty­
anhydrous, A.C.S. reagent four basic figures allow you to draw
250g $6.50; 1kg $2 1.50 accurately almost any kind of chemical
2 1 ,763-8 Sodium iodide, anhydrous structure. Bevelled edges prevent ink
100g $8.50; 500g $33.00 smears. Order yours today.
20,784-5 Sodium sulfite, anhydrous
500g $6.05
2 1,726-3 Sodium thiosulfate, anhydrous
21 0,377-2
250g $4.95; 1kg $ 15.50 $4.00 ea.
2 1,724-7 Sodium thiosulfate, pentahy­
drate, A.C.S. reagent
250g $4.25; 1kg $ 13.00
17,993-0 Starch, soluble, A.C.S. reagent
250g $4.95; 1kg $ 12.10
20,558-3 Tetraethylammonium acetate
tetrahydrate, 99%
25g $ 16.95; 100g $47.30
17,780-6 Tetraethylammonium hydrox­
ide, 20% solution in water
100g $8.00: 500g $30.00
2 1 ,287-3 Vanadyl acetylacetonate
250g $ 1 7 . 50; ! kg $55.00

14 Aldrichimica Acta. Vol. 12. Nn. 4, 1979

 Tilorone, Its Analogs, and
Developments in Chemical
Immunology *
Tilorone its Analogs and Developments in Chemical Immunology

Robert H. Levin Ph.D.

Research/Management Consultant
906 Oregan Trail Robert H. Levin, Ph.D.
Cincinnati Ohio 45215 Research/Management Consultant
906 Oregon Trail
Cincinnati, Ohio 45215

Starting with the demonstration of activ1ties related to the whole subject of

broad-spectrum oral antiviral activity, host defense.
further studies revealed that Tilorone is an In the laboratory the study of im­
inducer of interferon, a stimulator of the munoactive molecules is providing new in­
reticuloendothelial system and of cell­ sights into the complexities of the immune
mediated immunity, and, paradoxically, process, at the enzyme/ biochemical,
can also function as an immunosuppres­ molecular, cellular, tissue, organ, and
sant. whole-animal levels.
Today,after almost a decade of studies Advantageously, these studies can now
as reported in more than 250 international be conducted with pure chemical sub­
publications and countless meetings, new stances rather than with less well defined
and selective biochemical, pharmacologic, natural-product isolates. By comparison,
and immunologic effects of Tilorone are even today, after decades of study,
still being discovered. materials such as BCG, C-parvum and
ALG may give different results in different
The immune system is an enormously laboratories.
complicated mechanism, with hundreds of
Slightly more . than ten years ago an in interacting components that together Further,at the clinical level, it is general­
vivo screen for antiviral activity developed protect the body from infective micro­ ly agreed that these newly recognized sub­
by researchers R.F. Krueger and G.D. organisms and other foreign substances.It stances (Tilorone,Levamisole,thymic hor­
Mayer at the Cincinnati Research Center now appears to have some involvement in mone fractions, muramyl dipeptide
of Richardson-Merrell,showed that bis(3- almost every disease state. analogs, etc.) represent, collectively, ex­
dibu tylaminopropyl)-9-oxofluorene-2,7- citing leads to the treatment of disease by
dicarboxylate dihydrochloride (I) was The whole concept of immunology has
modulation of host defense mechanisms.
changed in the last ten years. In addition to
The elucidation of these biological ac­
the use of vaccines to stimulate the produc­
-Cc(]. tivities will certainly prove intellectually
�HJ,o,c co,(��j,�Bu2 tion of antibodies, now there is also a much satisfying,and must ultimately prove to be
0 broader approach - intervention in the in­ of great importance in human therapeutics.
(I) tricate chemistry of the immune processes
effective in protecting mice against lethal themselves. Tilorone: What Does It Do?
encephalomyocarditis. The new immunology has resulted in the
Intensive classical "molecular modifica­ Immunology has thus emerged as an en­ blurring of the boundaries of the classical
tion" of this compound resulted in the tirely new field with tremendous oppor­ scientific disciplines. Nevertheless, labora­
development of Tilorone (II) and its tunities for rapidly expanding basic tory studies with Tilorone may be listed
biomedical knowledge. We are beginning (somewhat arbitrarily) under the following
� ·2HCI to understand many of the chemical con­ areas and subjects:
Et,NCH,CH�OCH2CH2 NEt2 nections between abnormal immune A) Immu n o l o g y / i m m u n obiology / ­
processes and specific disease. Scientists of cellular immunology
(II)
0
diverse disciplines are using this informa­ B) Immunopharmacology and immuno-
analogs as a new class of orally active, tion to search for drugs that will correct the pathology
s m a l l - m o l ecule immunomodulating abnormal mechanisms,and thereby either C) Virology/ viral chemotherapy
agents. control or cure many diseases. Tilorone is a D) Interferon/ interferon induction
prime example of this new group of im­ E) Cancer
* A bibliography containing over 250 literature
references on Tilorone and analogs is available on re­ m un oacti ve compounds which can F) Enzyme and molecular biochemistry
quest. demonstrate a broad range of biological G) Microbiology and immunogenetics.
©1979 by Aldrich Chemical Company, Inc. Aldrichimica Acta, Vol. 12, No. 4, /979 77
 Table l
A. IMMUNOLOGY
Table I summarizes the effect of Tilo­
rone hydrochloride on antibody response. Effect of Tilorone Hydrochloride on Antibody Responses
Tilorone increases IgM and lgG antibody
production in the Jerne Plaque assay in 1. Increases IgM and IgG antibody production
mice and the IgE antibody production in 2. Increases IgE antibody titers
rats using the passive cutaneous 3. Increases HA antibody to S RBC
anaphylaxis ( PCA) model in rats. Tilorone 4. Enhances T-cell- and B-cell-dependent antibodies
enhances hemagglutination antibody (HA) 5. Acts as adjuvant for influenza vaccine
titer to sheep red blood cell (SRBC) in
mice. It also enhances thymus-dependent P.F. Hoffman, et al., Advances in Antimicrobial and Antineoplastic
( sheep red blood cells) as well as thymus­ Chemotherapy, 1, Urban and Schwarzenberg, Munich, 1972, p 2 1 7.
A.E. M unson, et al., Cancer Research, 32, 1 397 ( 1 972).
independent ( E-coli lipopolysaccharide) H. Megel, et al., Proc. Soc. Exp. Biol. Med., 145, 5 1 3 ( 1 974).
antibody production. Finally, Tilorone
Table 2
serves as an adjuvant for influenza vaccine
when given simultaneously at the same site
Effect of Tilorone on Cell-Mediated Immune Responses
with the vaccine, or when given at a
different site from the vaccine in guinea
pigs. 1. Prevents paralysis in EAE model
Table 2 summarizes Tilorone's effects on 2. Suppresses paw edema in adjuvant-arthritis
cell-mediated immune responses. Tilorone 3. Inhibits tuberculin skin reactions
prevents the paralysis associated with ex­ 4. Inhibits local GVH response
perimental allergic encephalomyelitis 5. Delays rejection of skin and heart transplants
( EAE) in Lewis rats. When administered to
H. Megel, et al., Proc. Soc. Exp. Biol. Med., 145, 5 1 3 ( 1 974).
rats, Tilorone completely inhibits the paw A. Wildstein, et al., Transplantation, 21, 1 29 ( 1976).
edema associated with adjuvant polyar­
thritis prophylactically, and it suppresses, tory animal test systems. that selectively suppresses T-lymphocyte
to a lesser degree, the inflammation when function, has been shown to delay
given therapeutically. Tilorone completely Table 3 presents comparative antiar­ significantly homograft rejection. How­
inhibits the tuberculin skin reaction in rats thritic profiles of Tilorone and other ever, a major problem in the clinical
and guinea pigs when administered at the representative antiarthritic compounds. In evaluation of ALG is associated with the
same time as the antigen, or after a tuber­ the complement-dependent Arthus screen need to establish specifications for the
culin skin reaction has been established. in which an inflammation of the rat paw is "biological preparation" which would
Tilorone completely inhibits the local induced, Tilorone and several other ana­ enable different investigators to work with
graft-versus-host reaction in the F1 hybrid logs markedly inhibited the paw edema. Of standardized material having reproducible
Lewis x Brown Norway recipient rat when the non-steroidal anti-inflammatory com­ biological end points.
administered to the donor parent Lewis rat pounds, only large doses of aspirin sup­
pressed the Arthus reaction. Phenylbuta­ Tilorone has also been reported to pre­
prior to the transfer of the spleen cells to vent the rejection of skin transplants in
the recipient. Lastly, Tilorone significantly zone and indomethacin suppressed the
response slightly, if at all. In addition, mice, heart transplants in rats, and kidney
delays the rejection of skin and heart transplants in dogs. As summarized in
transplants in rats and kidney transplants Tilorone was active in the classical anti­
inflammatory test. It inhibited the Table 4, Tilorone shares many of the
in dogs. reported attributes of ALG. It also has an­
carrageenan-induced abscess and carra­
In addition to the results summarized in geenan-induced paw edema in rats. This tiviral activity in various animal species.
Tables 1 and 2, Tilorone appears to have anti-inflammatory activity of Tilorone was Further, Tilorone would appear to have a
the paradoxical property of stimulating an­ also observed in adrenalectomized rats. potential advantage over ALG in that it is a
tibody production by way of the B­ well defined, synthetic organic substance,
lymphocyte, while simultaneously sup­ It is evident from these pharmacologic which is also orally active.
pressing T-lymphocyte function. The and immunologic studies that the biologic
reason for this paradoxical action was properties of Tilorone hydrochloride The antiviral activity of Tilorone has
clarified in part by Merrell scientists and meets new, more "rational" criteria for been demonstrated in mice, rats, rabbits,
others who showed that after an initial selecting a chemical compound for clinical and primates, as evidenced by an increased
lymphopenia and depletion of lympho­ trial in the treatment of rheumatoid number of survivors, increased length of
cytes from the T-lymphocyte areas in arthritis; more specifically, Tilorone has survival times, prevention of viremia.
spleen, lymph node and Peyer's patches, a been shown to inhibit an immunologically­ prevention of antibody response to live
rebound phenomenon took place in which induced inflammatory reaction and to virus, and attenuation of eye and skin
the T-lymphocytes in the peripheral blood selectively inhibit a variety of cell-mediated lesions. Activities are primarily observed
were replaced by B-lymphocytes. Further­ immune responses. with prophylactic regimens and can be ob­
more, there were significant increases in the The immunologic properties ofTilorone tained with oral, topical, or parenteral
numbers of B-cells in the spleen. Therefore, further suggest additional possible medical treatment, depending on the type of infec­
it was concluded that Tilorone selectively applications - in the prevention of homo­ tion. Viruses against which Tilorone or its
suppressed the T-cell and its function, and graft rejection and in the treatment of analogs were found to be effective in
increased the B-cell and its function, name­ laboratory animal experimentation in­
cancer. It is well documented that the ini­
ly, antibody production. Thus, from an im­ tial rejection phenomenon of transplants is clude: Semliki Forest (SF) virus, encepha­
munol ogic point of view, Tilorone a result of a cell-mediated immune pro­ lomyocarditis viruses, Venezuelan equine
represents a unique compound.
B. IMMUNOPHARMACOLOGY
cess, where the T-lymphocytes of the graft encephalomyelitis (VEE) virus, influenza
recipient recognize the antigenic deter­ viruses, herpes virus, vaccinia virus,
In the broad area of inflammation, minants on the graft itself as foreign and vesicular stomatitis (VS) virus, tick-borne
Tilorone again presents a paradox in that it cause its rejection. The use of general encephalitis (TBE) virus, foot-and mouth
shows broad-spectrum anti-inflammatory immunosuppressants, prednisolone, cyclo­ disease (FMD) virus, Friend leukemia
action using classical (pharmacologic) as phosphamide and the like, and more virus, scrapie virus, Spring-Summer me­
well as immune-mediated anti-inflamma- recently, antilymphocytic globulin (ALG), . ningoencephalitis virus, and flaviviruses.
78 Aldrichimica Acta, Vol. 12, No. 4, 1979
 Table 3

------------
Comparison of Tilorone's Actions With Representative Anti-arthritic Compounds
Adjuvant Arthritis
Compound Carrageenan Arthus Prophyl.R, Therap. R, TB Skin EAE PFC
(mg/kg) Paw Edema Paw Edema Paw Edema Paw Edema Reaction Antibody
Tilorone
25-100 p.o. t
Phenylbutazone
50-100 p.o.
Hydrocortisone
1 0-25 s.c.
Cyclophosphamide
5-25 p.o.
I Suppresses, t Slightly Suppresses, f Enhances, - No Effect

Composite table from H. Megel, et al., Proc. Soc. Exp. Biol. Med., 149, 39 ( 1975). M.E. Rosenthale, Anti-inflammatory Agents, l l,
123 ( 1974).

Although generally less active than Table 4

amantadine, Tilorone was more active
than this anti-influenza compound if the Effect of Tilorone and ALG on Cell-Mediated and Other Immune Responses
virus was given by aerosolization instead of
by nasal instillation. Immune Response Tilorone ALG
Tilorone was also an effective antiviral EAE
agent in many tissue culture systems. Adjuvant arthritis
Tuberculin skin reactions
D. INTERFERON GVH
Transplant rejection
Interferon was discovered in 1957 by Antibody responses Increases Increase or no effect
Isaacs and Lindermann. The concept of a Spleen and lymph node Transient T-cell depletion T-cell depletion
natural substance produced by cells and WBC Transient lymphopenia Lymphopenia
effective against a wide range of viruses ex­
cited the imagination of chemotherapists. I suppresses
I nterferon is formed by immune H. Megel, et al., personal data; editorial, Brit. Med. J., 1, 644 ( 1975).
stimulation involving sensitized lympho­ munopharmacological agents, poly-1:C scanty since few of these were isolated in
cytes. Gradually over the years, it has come and other natural and synthetic DS-RNA's sufficient quantity for systematic testing.
to be recognized that there is a family of in­ exert quite diverse and sometimes opposite
terferons. I nitially interferons were found effects on immune reactions, depending on An important discovery was reported in
to be species-specific. More recently, even 1 970 (from the Merrell National
dosage, time, and route ofadministration. Laboratories). It was found that a synthetic
within a single species, interferons are be­
ing differentiated. Tilorone has played a Immunostimulating substances like compound of relatively simple structure
role in this research, starting with its poly-I:C and other synthetic and natural possessed an in vivo broad-spectrum anti­
characterization as a small-molecule, oral­ DS-RNA's cause abnormalities in the viral activity in mice and was capable of in­
ly active inducer of interferon. lymphoid system of adult mice, concomi­ ducing the production of significant levels
tant thymic atrophy, and splenic hypo­ of serum interferon following oral or
INTERFERON INDUCERS plasia. parenteral administration to rodents.
Interferon is produced (induced) when One must remember that interferon­
the body's natural defenses are called upon In the search for effective and safe inter­
feron inducers many natural sources have inducing double-stranded polynucleotides
in response to various stimuli. The first in­ are totally devoid of activity when given
terferon inducers known were the viruses been found from which double-stranded
polyribonucleotides could be extracted, in orally. This synthetic compound, named
themselves. It was possible to show that most cases in a relatively low yield. In Tilorone, was extensively studied in many
viruses, when injected into animals, needed general, these natural products have laboratories, and its immunopotentiating
an intact genome to induce interferon. In behaved, in vivo and in vitro, like the syn­ activities, of which interferon induction is
this respect, the most active viruses are thetic polynucleotides described above. but one aspect, were soon recognized.
those whose replicative form is a double­ Two antiviral agents isolated very early,
stranded RNA (DS-RNA), or those like helenine and statolon, were later found to
reoviruses · whose nucleic acid is of the be identical with the DS-RNA from the
double-stranded type throughout their mycophages latently infecting the fungi It has become increasingly clear over the
replication. producing these agents. In most ex­ past few years that interferons are not
Such observations led the Merck group perimental systems the minimal effective wholly unique biological substances, but
to show that a synthetic homopolymer pair antiviral doses of the two natural inducers must be included among a group of so­
of polyriboinosinic and polyribocytidylic were of the same order of magnitude as called lymphokines or cytokines, all form­
acids (in short, poly-I:C) may be regarded those of poly-I:C. Data about many other ed concurrently. Literally dozens of these
as a model of inducers of the double­ interferon inducers and immunostim­ factors have been reported, and the nature
stranded RNA type. As with most im- ulating substances of natural origin are of the experimental process has made
Aldrichimica Acta, Vol. 12, No. 4, 1979 79
 replication of many of these results difficult On drug distribution studies, Tilorone is The effect of Tilorone on bacterial infec­
from laboratory to laboratory.Figure I il­ subcellularly concentrated in the nucleus. tions varies with the organism, route and
lustrates some of the more commonly The highest levels are found in the liver and timing of treatment, and other factors not
accepted factors such as interferon, migra­ spleen, and the brain receives an equal yet elucidated, thus, some Tilorone analogs
tion inhibition factor (MIF), transfer fac­ share of drug as compared to the spleen at increased the resistance of mice to S.
tor, cytotoxic factors, and mitogenic fac­ 16 hours (Gaur and Chandra, 1973; aureus providing the drug was injected 24
tors. Walker, 1972). hours before challenge. No protection was
afforded against D. pneumonia (Wampler,
. Although various interferon inducers
(e.g., pyran) are thrombocytopenic agents
E. CANCER 1972; Munson, 1972).
In common with other immuno­
modulators, Tilorone shows a wide spec­ both in vivo and in vitro, Tilorone may ac­ Tilorone Analogs Provide New
trum of activity against a variety of ex­ tually increase blood platelet levels. In Opportunities in the
perimental (and human) tumors including: vitro Tilorone exerts antiplatelet effect
A) the ascitic Walker 256 carcinosarcoma through a photoactivation process Laboratory
(R. Adamson, 1971) (Matyasova, et al., 1974). The opportunities for new research with
B) leukemia L 5178Y, Novikoffhepatoma Tilorone activates plant phenylalanine Tilorone analogs lie in two directions.One
(R. Adamson, 1971) ammonia lyase (Hadwiger, 1972). Ad­ is to sort out and further dissect the
C) Ehrlich carcinoma solid tumor, Friend ministration of Tilorone to rodents results paradoxical activities exhibited by
leukemia virus (Munson, 1972) in an increase in serum complement levels Tilorone in various biological systems. A
D) a syngeneic murine lymphoid leukemia (Raychaudhuri, 1977). second, and perhaps more attractive
MCAS-10 (Pearson, 1974) prospect, is to seek among these bis-basic
E) malignant hepatomas 3924A, 7777, Another interesting feature of Tilorone substituted polycyclic molecules, those
is the depression of the cytochrome P450 showing the greater specificities of
5123A, and 7794A (Rhoads, 1973)
F) an acute lymphocytic leukemia arising monooxygenase system (Leeson, I 976; biological action required for immuno­
in a BALB/ cX DBA/ 2F 1 mouse that is Renton, 1976). therapy.
morphologically and pathologically G . l\U C li O H I O i O C Y In limited studies reported to date, in the
similar to human acute lymphocytic ! M M l ; N OGJ:'\ ETICS areas of antiviral activity, immune­
leukemia and is generally resistant to regulation, inflammation, enzyme inhibi­
alkylating agents and somewhat less Tilorone and its analogs can stimulate tion, etc., Tilorone analogs have demon­
resistant to vincristine and pred­ phagocytic function in liver and spleen strated a range and spectrum of activities.
nisolone (Yancey, 1974) (Munson, 1972; Regelson, 1970). As with This fact is best illustrated by Table 5 which
G) In a Phase I study of Tilorone with other immunoregulators and/ or interferon summarizes the biological responses of
metastatic melanoma previously un­ inducers, the route of administration is eight of the analogs now being offered to
treated by chemotherapy, partial critical. Tilorone can abort foot-and­ the research community by Sigma-Aldrich
responses were obtained without mouth disease in mice when it is given in in comparison with Tilorone.It is evident,
marrow depression (G.L. Wampler, drinking water (Richmond, 1973), and is a and not unexpected, that no two com­
1973). potent stimulator of phagocytosis when pounds provide the identical spectrum of
H) When administered to C57BL mice given by mouth (Regelson, 1974). When biological responses.
with drinking water in a daily dose of Tilorone is given subcutaneously it is not as
about 50mg/ kg for a year, Tilorone effective in the same experiment. When we examine in greater detail, in
significantly retarded the appearance
of tumors induced by a single sub­ Figure I
cutaneous dose of 120µg methyl­ Lymphokine/Cytokine Formation by Immune Stimulation
cholanthrene (MC) dissolved in olive
oil. Several signs of chronic toxicity
were observed.No co-oncogenic effect
of Tilorone was f ound (Glaz, 1974).
I) Tilorone, given orally at weekly inter­
vals to rats, was effective against
Walker 256 carcinosarcoma and
Morris hepatoma 7777 and 3924A.
This inhibition did not relate to in­
terferon levels (Walker, 1974).
F. E NZ Y M E AND MOI.E< ' l :LAR
BIOCHEMISTRY

0
Tilorone is a specific inhibitor of DNA
polymerases from RNA tumor viruses
(Chandra, 1972). Product analysis of the
D N A - polymerase reaction (Friend
leukemia virus) in the absence and in the
presence of Tilorone ( I x J0-<1 M) showed .
that it specifically blocked the formation of
double-stranded DNA (Chandra, 1974). WHIM Phytohemagglullmn
Tilorone and its analogs appear to render
polynucleotides ineffective as template/ ­
primers by physically binding to them by Sensitized lymphocytes in the presence of specific antigen and phytohemagglutinin
intercalation (Smith, 1974). are known to undergo blast transformation and to release many biologically active
substances thought to be important in specific cellular immunity.
The mechanism of action for Tilorone's
stimulation of interferon is believed to be Reprinted with author's and publisher's permission from M. Ho, Resident and Staff Physician, October
inhibition of protein synthesis (Cahn, 1973, p 52.
1973).

80 Aldrichimica Acta, Vol. 12, No. 4, 1979

 Table 5
Summary of the Biological Responses of Tilorone Hydrochloride and Related Compounds0

Inter-
Acute LD51 feron Anth•iral lmmunolo1kal Anti-inflammatory Anticancer

Cell-mediated rf'llpOnH Pas-

sin

·-'
Tuberculin Humoral Ar-
adjuvant skin antibody carr11ttn thus
Cmlfk1.

_...,.
C-nd vac- Herpes arthritis rnponse MMIT mouse rat re■c
CRMI EMC SFV VEE VEE Flu mouse
cinia rabbit EAE rat �ulnea nl• in lion rat/ in
onl sc" oral S<
in vitro
Herpes VSV' moUH mouse mouse mouse monkey mouse oral top. oral top. rat pro.
'
ther: pro: therf vitro l1M l1C edema abscn, rat mouse vitro R.T.�

Tilorone 1520 111 + + + 0 + + + + + 0 + + I I I I I 0 I I I I I + +

9563 DA l>4000 684 0 + 0 + 0 + + 0 I 0 I 0 I 0 I + + +
I0,024 DA 1560 1 10 + + + 0 + + + 0 0 0 0 I 0 + + +
10,874 DA 1780 353 + + + + + + + 0 I + I I I 0 + + +
11,002 DA sooo 353 + + 0 0 0 + + + + 0 0 + 0 0 I I I I I + I I I I I + 0 +
1 1,Sll DA 1410 304 + + + 0 0 + + + 0 + 0 I 0 + +
1 1,567 DA 2700 IOOO + + 0 0 + + + + + 0 0 + 0 0 I I 0 I I + I I I + I + + 0
1 1,645 DA 2590 930 + + + 0 + + 0 I + I I 0 0 0 +
II.Sn DA 2930 820 + + + 0 + + + + + + 0 + + + I I 0 I I + I I I 0 I + +

•symbols: + - active, 0 - inactive, no entry - not tested, '"photoinactivation.

I - suppression, I - enhancement. "pro. - prophylactic, ther. - therapeutic treatment.
•sc - subcutaneous. top. - topical administration. •Reverse Transcriptase.

Table 6, the more precise activities of a of these compounds." phocytes that attack foreign tissues or
group of Tilorone analogs (selected as can­ foreign organisms directly. A third type of
didates for clinical trial), we find an even Fine Tuning the T-Lymphocyte T-cell functions as suppressor lympho­
greater range of quantitative d ifferences in
such biologic properties as interferon in­
System cytes, retarding the production of anti­
bodies. This function may be important in
duction, antiviral activity, anti-inflamma­ The immunoregulatory properties of regulating immunity.
tory action, and even LD50 values. Tilorone are probably related to its initial
In one series of studies mice were chal­
ability to deplete thymus-derived (T) lym­
lenged with allogeneic leukemia L l 2 10
phocytes. This is followed by an increase in
In a recent study of the enzymatic ac­ cells. Tilorone administered without an­
tivities of a group of Tilorone analogs B-cells, macrophages and probably new
tigen proved capable of creating "killer"
subpopulations of T-cells which cell
DiCloccio ( 1 978) commented that "al­ lymphocytes. However, Tilorone in this ex­
biologists can now characterize using more
though some or all of these compounds periment did not exert a truly adjuvant
sophisticated methodology.
have been shown to induce interferon, effect as it did not increase the response to
stimulate the immune system, and inhibit Some T-cells can function as helper T­ co ncomitant antigen. Thus, Tilorone
the DNA polymerase activity of several cells, so named because their presence resembled BCG and C-parvum in their ac­
RNA tumor viruses, none of these effects helps B-cells to produce antibodies. Other tion. H owever, in other tumor and viral
completely explains the antitumor action T-cells can become killer cells, i.e. , lym- systems, Tilorone and its analogs cause ad-
Table 6
Biologic Properties of Selected Tilorone Analogs

ACTIVITIES Tilorone RMI 11,002 DA RMI l l,567 DA RMI 1 1,877 DA RMI 9,563 DA
LD50, mg/ kg, p.o. 1 530 5000 2700 2930 >4000
s.c. Ill 353 1 000 820 684
Anti-inflammatory percent reduction
( 100 mg/ kg, rat, p.o.)
Carrageen paw 47 35 19 17 5 3 (s.c.)
Carrageen abscess 40 40 0 21 45 (s.c.)
Adjuvant arthritis 39 41 25 41
Arthus 90 49 43 42 92 (s.c.)
Complement (in vitro) 0 0 0 0 80
percent inhibition, J0-4M
Antiviral Activity
EMC (percent increase mean survival time, 1 37 1 23 145 1 29 1 16 (s.c.)
250 mg/ kg, p.o., -22 hr.)
Vaccinia (percent decrease tail lesion score, 89 28 66 79 26
250 mg/ kg, s.c.) ( !O0mg/ kg, s.c.)
SFV (percent survivors, 250 mg/ kg, 1 00 1 00 100 100 40
p.o., -24 hr.)
( JOOmg/kg, s.c.)
Interferon Induction
Reciprocal of interferon titer 6,400 (24) 3,200 ( 12) 25,600 (24) 6,400 ( 1 2) 800 (24)
(peak time hr.) 250 mg/ kg, p.o. (500mg/ kg, s.c.)

Aldrichimica Acta, Vol. 12, No. 4, 1979 81

 juvant effects in addition to selective
changes in the T-lymphocyte subpopula­ Thi s new polypropylene pro­
d u c t wi l l a b s o r b a l most a n y
tion.
liquid spill, i ncluding o i l , strong
Absorb
Tilorone is believed to augment cell­
acids and bases; also most l i q­
mediated immunity (CMI) in this ex­
u ids designated by the E. P.A. as
spills quickly. . .
perimental model by a direct effect upon T­
hazardous - without d isinte­
lymphocytes (Friedlander, 1974).

g rating or deterioratin g .
Finally, the current interest in Natural
S o rbent retains u p t o 1 2 ti m e s its
Killer (NK) cells and their enhancement by
own weight in liquid, picks up
interferon and interferon inducers, par­
cleanly and is easy to d ispose of.
ticularly Tilorone, again raises the question

I f n e c e s s a ry, a va l u a b l e a b ­
of mechanism of action. Here again a study

sorbed material c a n b e recover­

of Tilorone analogs could serve to help
clarify this point and perhaps accelerate the
opportunity of establishing a role in cancer ed by extractio n . Available i n
therapy for this exciting development. convenient sheet form.
Chemical Immunology has a bright future. 210,428-1
3M sorbent material
$17.00/bag of fifty 12" x 12" sheets
About the Author

$109.00/case of 8 bags
Dr. Levin earned a Bachelor's Degree in
1 937 from the University of Illinois and the
Ph.D. from the University of Wisconsin in $99.00/pkg. of two 24" x 100' rolls
1 94 1 . He spent the next 27 years with the
research staff of the Upjohn Company,
closely involved with steroid, cortical hor­
mone, and antibiotic developments. His
name appears on 26 publications and 90
U.S. patents.
In 1968 Dr. Levin was elected Corporate
Vice P resident for Research for
Richardson-Merrell, Inc. with line respon­
sibility for worldwide ethical phar­
maceutical research. In 1978 he retired
from Richardson-Merrell to establish his
Research/ Management consulting service
for government and industry.

Tilorone Analogs

21,364-0 21,807-3
Tllorone Analog R 11,645 DA 2 1,358-6 Tilorone Analog R 10,874 DA
lg 514.00 Tilorone Analog R 9,563 DA 100mg 510.00
100mg 510.00

2 1,808-1
2 1,362-4 Tilorone Analog R 10,556 DA
Tilorone Analog R 10,635 DA 100mg $6.00; lg $28.00
100mg 56.00; lg 528.00

2 1,368-3 21,804-9
Tilorone Analog R 10,233 DA Tilorone Analog R 11,567 DA
lg 514.00 100mg $6.00; lg $28.00

0 0

" C()C · " . ·,

\CH�2NCH,C 1/ -::::::-..CCH;N[CH,J,

r. ' � I I
'0
,,....... /;
-.__,.
1/
1 · 2 HC. ,1
· 1 .5 H1.0
21,363-2 2 1,367-5 21,805-7
Tilorone Analog R 1 1,513 DA Tilorone Analog R 10,024 DA Tilorone Analog R l l,877 DA
lg 514.00 lg 514.00 100mg $10.00

82 Aldrichimica Acta, Vol. 12, No. 4, 1979

 MilliPOR.e
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