Terrahedron Vol. 51. No. 29. pp. 8023.

8032, 1995
Pergamon Copyright 0 1995 Elsevier Science Ltd
Printed in Great Britain. All tights reserved
004@4020/95 $9.50+0.00
0040-4020(95)004 17-3

Selective Oxidation of Primary Alcohols Mediated by Nitroxyl Radical in

Aqueous Solution. Kinetics and Mechanism.

Arjan E.J. de Nooy,* Arie C. Besemer

TN0 Nutrition and Food Research Institute, Department of Biochemistry, Utrechtseweg 48, 3700 AJ Zeist (The Netherlands)

Herman van Bekkum

Delft University of Technology, Laboratory of Qrganic Chemistry and Catalysis, Julianalaan 136, 2628 BL Delft (The
Netherlands)

Abstract: The kinetics of the TEMPO-mediated oxidation of methyl a-D-glucopyranoside to sodium

methyl a-D-glucopyranosiduronate were studied. An intermediate was found which was identified as
the hydrated aldehyde. This was oxidised in the same manner as the alcohol, with pseudo first order
rate constants ratio kOh,l,,&,,~C,E - 7. The reaction mechanism is discussed with emphasis on steric
factors and compared to literature data. Two different reaction pathways are postulated; under basic
reaction conditions via a cyclic transition state 3 and under acid reaction conditions through an acyclic
transition state 4.

INTRODUCTION

It has been well established now that stable organic nitroxyl radicals like 2,2,6,6-tetramethyl-l-
piperidinyloxy (TEMPO) can be applied as mediators for the oxidation of primary and secondary alcohols.‘~‘”
Several oxidants are able to oxidise the nitroxyl radical” to obtain the corresponding nitrosonium ion, which
is the actual oxidant.’ Conditions are generally very mild, which makes this method applicable to a variety
of alcoholic substrates. However, there seems to be some inconsistency with respect to the product obtained
from primary alcohol oxidation. Depending on the reaction conditions and the substrate, aIdehyde’-* or
carboxylate We,” is obtained. Also the selectivity with respect to primary and secondary alcohols differs
substantially depending on the applied reaction conditions and the substrate. Some authors found a
pronounced preference for primary alcohol oxidation,4.“7.‘.“’ while others found only little selectivity.‘-3.5.8 In
this paper we address these ambiguities.
Previously, we investigated the TEMPO-mediated oxidation of various carbohydrates in water at pH
10-l 1 with hypobromite, formed by reaction of hypochlorite and bromide, as the regenerating oxidant.1”S’2

8023
8024 A. E. J. DE NOOY et al.

Under the applied conditions primary alcohols were oxidised more rapidly than secondary ones and only
the carboxylate was found as the reaction product. Thus starch was selectively oxidised at the 6position to
obtain a polyglucuronate with >95% selectivity at complete conversion of the primary alcohol groups.” Here
we report on the kinetics and mechanism of the oxidation of methyl a-D-glucopyranoside (MGP, 1).
Oxidation of this substrate proceeds with high regio-selectivity and no other product than methyl a-D-

glucopyranosiduronate (2) could be detected.” Attention was focused on the mechanism of carboxylate
formation. Furthermore, the reaction rate for various alcoholic substrates was investigated and the influence
of steric factors on the transition state is discussed and compared to literature data.

RESULTS AND DISCUSSION

We reported earlier that the oxidation of MGP with TEMPO/hypochlorite/bromide was first order with
respect to MGP, TEMPO and NaBr.” Typical conversion-time curves for the oxidation of different
concentrations MGP are shown in Fig. 1. After about 30% oxidation the formation of acid was first order
with respect to the substrate (Fig. 2). This delay depended on several factors. Firstly, an induction period
can be expected due to formation of an aldehyde intermediate (see below). Secondly, there has to be a build
up of nitrosonium ion. Thirdly, it was found that hypochlorite delays the formation of acid as monitored with

0 20 40 60 80 0 20 40 00

time (min) time (min)

Figure 1. Typical plots for the oxidation of different Figure 2. Plots of In(@fGP],-[Acid]3 vs time. MGP$(A),
concentrations MGP as measured with pH-stat. Conditions: 10(B) and 20(C) mmol. Data from Fig. 1.
substrate (5-20 mmol) in 520 ml water, 0.4 g NaBr, 0.02 g
TEMPO, 30 ml 15% HOCI, pH 10, 1.5”C.
 Selective oxidation of primary alcohols 8025

a pH-stat, probably due to influence of the equilibria HOCI/OCI- and HOBr/OBr-. From experiments with
MGP under standard conditions (see experimental section) with 15, 30, 60 or 120 mmol hypochlorite, it
appeared that the [OCI-] had no influence on the observed reaction rate. The fact that the concentration of
primary oxidant had no influence on the reaction rate implies that the regeneration of the nitrosonium ion,
which is thought to proceed according to reactions 1,2 and 4,‘” is more rapid than the oxidation of the
substrate (reaction 3).

(H)OCI + Br- + (H)OBr + Cl- (1)

(H)OBr + 2TEMPO’ + H,O + 2TEMPO’ + 20H. + (H)Br (2)
TEMPO+ + OH- + RCH,OH - TEMPOH + RCHO + H,O (3)
TEMPO+ + OH- + TEMPOH - ZTEMPO’ + H,O (4)

Hence the amount of oxidant (nitrosonium ion) can be considered as being constant during the reaction after
circa 30% oxidation. Since the formation of acid was first order with respect to the substrate (Fig. 2), any
intermediate reacts either much more slowly or much more rapidly than the primary alcohol. This was
followed with high-performance anion-exchange chromatography (HPAEC, Fig. 3). The intermediate was

1.5.

UC

d
I I : I I I I I I I I II I I I
0 5 10 15
Min
Figure 3. HPAEK plots of reaction products during the oxidation of MGP (10 mmol). A-h pertains to the amount of hypochlorite
added; O-14 ml 15% hypcchlorite in steps of 2 ml. MGP (1): retention time is 1.7 min, hydrated aIdehyde: retention time is 4.2

min and methyl a-D-glucopyranosiduronate (2): retention time is 12.1 min.

8026 A. E. J. DE NOOY et al.

identified as the hydrated methyl a-D-&co-hexodialdo-I ,Spyranoside by ‘H NMR (doublet H6 at 5.3 ppm
in D,O). No free aldehyde could be detected with ‘H NMR. This is in agreement with methyl B-D-g&cto-

hexodialdo-1 ,Spyranoside in aqueous solution, obtained from oxidation of methyl D-D-galactopyranoside

with D-galactose oxidase, which is also completely hydrated.14 The intermediate could be reduced with
sodium borohydride to obtain the starting compound, which is further evidence for the fact that it is an
aldehyde. Another way of determining the amount of aldehyde formed was by adding known amounts of
hypochlorite and following the amount of acid formed with pH-stat (Fig. 4). These results agree well with
the results obtained from HPAEC.

0 5 10 16

(H)OCI (ml)
Figure 4. Amount of alcohol, aldehyde and acid present during the
oxidation as followed by pH-stat (-) and HPAEC (“).

Attempts to stop the oxidation at the aldehyde stage at another pH did not succeed. In the range pH 8.511 S,
the maximum concentration aldehyde was about 10%. Apparently, its oxidation is substantially more rapid
than the oxidation of the alcohol, which gives the following consecutive first order reaction scheme:

[Ale] k, [Ald] + Hz0 + [AldH,O] L [Acid], with k,>k, (5)

Here k, and k, are both first order rate constants with respect to the substrate and it is assumed that the
hydration of the aldehyde is very rapid, so that this reaction has no influence on the observed reaction rate.
For a consecutive first order reaction system with k,>k,, the following rate equations may be written:

[Ale], = [Alc],,exp(-k,t) (6)

Wdl, = [Alcl,{k,i(k,-k,)}{exp(-k,t)-exp(-kzt)} (7)
and as an approximation:

[Acid], - [Alc],{l-exp(-k,t)} (8)

From the results of HPAEC and the pH-stat experiments it follows that the ratio k&-7 for the oxidation
 Selective oxidation of primary alcohols 8027

of MGP. By applying the simplified equation 8 for the calculation of k, from the pH-stat experiments an
error in the order of several percents is introduced which has no influence on the qualitative interpretation
of the results.
Initially, it was expected that the aldehyde intermediate was oxidised by hypobromite to obtain the
acid. However, from the oxidation of butanal with and without TEMPO, it appeared that the oxidation with
TEMPO added was much more rapid (Table 1, entries 1 and 2). In organic solvents without water or with
only a low concentration of water the reaction stops at the aldehyde stage, which indicates that water is
necessary for the TEMPO-mediated oxidation of the aldehyde. It is thus concluded that the hydrated
aldehyde intermediate is oxidised in the same way as the alcohol. This is supported by the fact that the ratio
kZ/k, for the oxidation of MGP was not pH dependent in the range pH 8.5-11.5. At pH 8.5 and 11.5, the
observed reaction rate was much lower than at pH 10. At pH 8.5 the rate limiting step might be the
abstraction of a proton in the complex formed between the alcohol and TEMPO’ (see below). We found that
at pH 11.5, [(H)OCl] becomes rate limiting. Probably reaction 1 is then retarded, as was also found by other
authorsI At this pH, the delay period is also substantially lengthened. From Table 1 it can be seen that
is smaller than 7 (entries 1 and 3). This is attributed
k bs,b”lanal/kobsn-b”t”~, to the fact that butanal is only
according to equation 8 will also
hydrated for about 32% in water.” The error in the calculation of &b~n.bu,ano,
be substantial in this case.
From an Eyring plot (Fig. 5) in the range of 1.5-23°C for MGP the activation parameters were
calculated. Although the entropy of activation (-93 JK-‘mol.‘, 1.5”C) term is highly negative, the reaction
is rapid due to a relatively low enthalpy of activation (58 kJmo1.‘). The negative entropy of activation
indicates an organised bimolecular transition state.

-10

-13
3.30 3.40 3.50 3.00 9.70

1000 I/T

Figure 5. Eyring plot for the oxidation of MGP in the range 1523°C.

The mechanism of the actual oxidation (reaction 3) is still not clear. Semmelhack et al.” proposed a
concerted mechanism with a cyclic transition state 3, which would be much more sterically confining than
the acyclic transition state 4, proposed by Ma and Bobbit. These authors found only few steric effects in
8028 A. E. J. DE NOOY et al.

the TEMPO-mediated oxidation of alcohols. It can be expected however, that the observed regio-selectivity
for MGP is due to sterical hindrance caused by the four methyl groups in TEMPO. To investigate the
influence of steric factors, several substrates were oxidised (Table 1). We were especially interested in the
influence of the ring size because it was found that primary alcohols in pyranosides were oxidised more
selectively than those in furanosides.” To test this, the model substrates cyclohexanol and cyclopentanol
were oxidised (Table 1). Indeed it was found that the secondary alcohol on the five-membered ring was
oxidised four times as fast as the secondary alcohol on the six-membered ring. During the oxidation of
cyclohexanol and cyclopentanol, a small amount of acid was formed (0.25-0.75 mmol per 20 mmol substrate

Table 1. Rate constants for the oxidation of various substrates.*

Entry Substrate TEMPO k) lO”xk,,, (s-r)

1 butanal” 0.02 18

2 butanal’ 1.1

3 n-butanol” 0.02 12

4 n-butanol”,” <O.Ol

5 cyclohexanol” 0.02 0.52

6 cyclohexanolb 0.05

7 cyclopentanol” 0.02 2.1

8 cyclopentanol~ 0.05

9 3-methylcyclohexanolb (cisitrans mixture) 0.02 0.52

10 Z-methylcyclohexanolb (cis/trans mixture) 0.02 0.08

11 methyl a-D-glucopyranosidt? 0.02 7.8

12 methyl !3-D-glucopyranoside” 0.02 12

13 octyl a-D-glucopyranoside” 0.02 7.8

14 methyl a-D-galactopyranoside” 0.02 7.7

* Conditions: 20 mmol substrate in 520 ml water, 0.4 g NaBr, 30 ml 15% OCl-, pH 10, 1.5 “C. a Reaction followed by monitoring the

consumption of NaOH. b Reaction followed by the consumption of hypechlorite.

 Selective oxidation of primary alcohols 8029

conversion) which indicates overoxidation of the substrate. 3-Methylcyclohexanol (cis/trans mixture) was
oxidised with the same reaction rate as cyclohexanol, whereas the more hindered alcohol in 2-
methylcyclohexanol (cis/trans mixture) was oxidised more slowly. Note that the secondary alcohols tested
were oxidised faster with TEMPO added to the reaction mixture than with only hypobromite. However, this
difference becomes smaller with more sterically hindered secondary alcohols like 2-methylcyclohexanol.
Simple primary alcohols like n-butanol were oxidised rapidly and quantitatively to the corresponding
carboxylates. Without TEMPO added to the reaction mixture, no reaction was observed for eight hours. In
the oxidation of various pyranosides (entries 11-14) it appeared that the substituent on the anomeric centre
did not have much influence on the reaction rate. However, the anomeric configuration, in contrast to the
configuration at C-4, had a substantial influence on the reaction rate. The reasons remain to be clarified.
Obviously, under the applied conditions, primary alcohols are oxidised more rapidly than secondary
ones. With primary/secondary polyol substrates, the selectivity for the primary hydroxyl depends on the
sterical demand of the secondary alcohol. For example, in contrast to several pyranosides, the acyclic
substrates 1,3-butanediol and mannitol could not be oxidised selectively. The reaction was followed with
HPLC, and even in the initial stage of the reaction, more than one product peak was found. In general, the
observed regio-selectivity for different substrates under the applied conditions depends on the accessibility
of the alcohol, which would favour the more sterically confining transition state 3. A study of the literature
on nitroxyl-mediated oxidation of alcohols reveals that this sterically directed selectivity only occurs under
basic reaction conditions,4,6.7.9.“’ while under acid reaction conditions’-3,sX8 this selectivity disappears and
secondary alcohols may be oxidised more rapidly. This leads us to propose two different reaction pathways.
The one under basic conditions based on the cyclic transition state 3 and the one under acid conditions based
on the acyclic transition state 4:

Basic conditions

-l-l+
//
4%+1 + ‘)eb,
0
HO

Acid conditions

Scheme 1
8030 A. E. J. DE NOOY et al.

In addition to the difference in selectivity obtained, a second indication for two different reaction pathways
stems from the work by Yamaguchi et al.‘” They found that a R-oxygen in the alcohol inhibits the oxidation.
A probable explanation of this was given by Ma and Bobbitt: who reasoned that a complex formed between
the positive nitrogen and the &oxygen might be responsible for this decreased reactivity. They found, for
example, that ethylene glycol was completely unreactive under their conditions. Under our conditions this
substrate was rapidly oxidised. Since both Yamaguchi et nf. and Ma and Bobbitt worked under acid
conditions,‘!’ such a complex is conceivable, while in 3 such a complexation is less probable due to the
negative oxygen. Another perhaps more probable B-oxygen interaction is shown in formula 5. The hydrogen
bond is expected to lower the positive charge on the nitrogen, which would be the driving force in this
reaction pathway. Thus the reaction leading towards the products would be less favourable. Besides the
observed difference in selectivity, another general difference is that the oxidation under basic conditions is
more rapid than under acid conditions. The latter is usually performed with stoichiometric amounts of
radical, while the former oxidation is mainly performed with catalytic amounts (for the influence of the
TEMPO concentration on the reaction rate, see ref. 12). Obviously, base will facilitate the proton abstraction
step present in both mechanisms, which also is thought to be the rate-limiting step in both pathways.

EXPERIMENTAL SECTION

All chemicals used were commercially available and used without further purification, except for octyl a-D-

glucopyranoside, which was synthesised according to a previously reported method.‘” ‘H, 13C NMR and
HPAEC were performed as described previously.” The structures of all oxidised pyranosides were confirmed
with ‘H and “C NMR and reported elsewhere,‘* except for sodium methyl a-D-galactopyranosiduronate: ‘H
NMR (D,O) 6 4.82 (Hl, d, 5,,,=3.0 Hz); “C NMR (D,O) 6 56.8, 69.4, 71.2, 72.3, 72.9, 100.9, 177.3 and
sodium octyl a-D-glucopyranosiduronate: ‘H NMR (D,O) 6 4.87 (Hl, d, J,.,=3.9 Hz); “C NMR (D,O) 6
15.0, 23.6, 26.9, 29.9, 30.0, 30.2, 32.6, 70.1, 72.7, 73.5, 73.6, 74.5, 99.6, 178.2.
General procedures: All kinetic data were average values of at least three experiments. Oxidation of
secondary alcohols was followed by measuring the amount of hypochlorite consumed. Aliquots were taken
and added to an acidified 1M Kl solution, which was subsequently titrated against 0.1 M sodium
 Selective oxidation of primary alcohols 803 I

thiosulphate. Oxidation of primary alcohols was followed with pH-stat. Formation of uranic acid during the
oxidation of the carbohydrates was followed with a calorimetric method*’ and HPAEC.
General oxidation procedure: The substrate (20 mmol) was dissolved in water (520 ml) and NaBr (0.4 g,
3.9 mmol) and TEMPO (0.02 g, 0.13 mmol) were added. The solution was cooled in an ice-bath and a
solution of hypochlorite (30 ml, ca 60 mmol) was brought to pH 10 and also cooled. The reaction was
started at time=0 by adding the hypochlorite solution at once to the other solution. The temperature was
1.5+1 “C during the reaction and the pH was maintained at 10 by adding OSM NaOH with a pH-stat. When
the reaction was finished, excess hypochlorite was quenched by adding ethanol (5 ml) and the pH was
brought to 7-8 by adding 4M HCl.

ACKNOWLEDGMENTS

This work was carried out within the National Programme on Oxidation of Carbohydrates with financial
support of the Dutch Ministry of Agriculture, Nature Management and Fisheries. We thank Mr. Kees
Verbeek for assistance in the HPAEC analysis.

REFERENCES

1. Golubev, V. A.; Rozantsev, E. G.; Neiman, M. B. Izv. Akad. NaukSSSR, Ser. Khim. 1965, 1927-1936.
2. Cella, J. A.; Kelley, J. A.; Kenehan, E. F. J. Org. Chem. 1975, 40, 1860-1862.
3. Golubev, V. A.; Borislavskii, V. N.; Aleksandrov, A. L. IN. Akad. Nauk SSSR, Ser. Khim. 1977,2025-
2034.
4. Semmelhack, M. F.; Chou, C. S.; Cartes, D. A. J. Am. Chem. Sot. 1983, 105, 4492-4494.
5. Miyazawa, T.; Endo, T.; Shiihashi, S.; Okawara, M. J. Org. Chem. 1985, 50, 1332-1334.
6. Anelli, P. L.; Biffi, C.; Montanari, F.; Quici, S. J. Org. Chem. 1987, 52, 2559-2562.
7. Inokuchi, T.; Matsumoto, S.; Nishiyama, T.; Torii, S. J. Org. Chem. 1990, 55, 462-466.
8. Ma, Z.; Bobbitt, J. M. J. Org. Chem. 1991, 56, 6110-6114.
9. Davis, N. J.; Flitsch, S. L. Tetrahedron Lett. 1993, 34, 1181-1184.
10. de Nooy, A. E. J.; Besemer, A. C.; van Bekkum, H. Reef. Truv. Chim. Pays&s 1994,113, 165-166.
11. Bobbitt, J. M.; Flores, M. C. L. Heterocycles 1988, 27, 509-533.
12. de Nooy, A. E. J.; Besemer, A. C.; van Bekkum, H. Carbohydr. Res. 1995, 269, 89-98.
13. Straub, T. S. J. Chem. Educ. 1991, 68, 1048-1049.
14. Maradufu, A.; Perlin, A. S. Carbohydr. Rex 1974, 32, 127-136.
15. Kumar, K.; Margerum, D. W. Inorg. Chem. 1987, 26, 2706-2711.
16. Bell, R. P. Advan. Phys. Org. Chem. 1966, 4, l-29.
8032 A. E. J. DE NOOY et al.

17. Semmelhack, M. F.; Schmid, C. R.; CortQ, D. A. Tetrahedron Lett. 1986, 27, 1119-1122.
18. Yamaguchi, M.; Takata, T.; Endo, T. Tetrahedron Lett. 1988, 29, 5671-5672.
19. It should be noted that Yamaguchi et al.‘* added Na,CO, as acid scavenger. However, since this salt
is not soluble in CH,CI,, it is not expected to have influence on the reactions as shown in Scheme 1.
Probably only when acid is liberated, it will react with the heterogeneous acid scavenger.
20. Straathof, A. J. J.; van Bekkum, H.; Kieboom, A. P. G. Starch 1988, 40, 229-234.
21. Blumenkrantz, N.; Asboe-Hansen, G. Anal. Biochem. 1973, 54, 484-489.

(Received in UK I May 1995; revised 22 May 1995; accepted 26 May 1995)