PYRROLE AND PYRIDINE
Introduction:-
Pyrrole is a very important five membered heterocyclic compound. Its nucleus occurs in many
natural products such as alkaloids, chlorophyll haematin,
Pyrrole is a heterocyclic, aromatic, organic compound, a five-membered ring with the formula
C4H4NH. [1] It is a colorless volatile liquid that darkens readily upon exposure to air.
Substituted derivatives are also called pyrroles, e.g., N-methylpyrrole, C4H4NCH3.
Porphobilinogen, a trisubstituted pyrrole, is the biosynthetic precursor to many natural
products such as heme. [2]
Pyridyne in chemistry is the pyridine analogue of benzyne. [3] Pyridynes are the class of reactive
intermediates derived from pyridine. Two isomers exist, the 2,3-pyridine (2,3-
didehydropyridine) and the 3,4-pyridyne (3,4- didehydropyridine). The reaction of 3-bromo- 4-
chloropyridine with furan and lithium amalgam gives 1,4-epoxy-dihydroquinoline through the
2,3-pyridyne intermediate. The reaction of 4-bromopyridine with sodium in liquid ammonia
gives both 3-aminopyridine and 4-aminopyridine through the 3,4-pyridyne intermediate and an
E1cB-elimination reaction. [4]
History of PYRROLE and pyridine:-
Pyrrole was first detected by F. F. Runge in 1834, as a constituent of coal tar. [5] In 1857, it was
isolated from the pyrolysate of bone. Its name comes from the Greek pyrrhos (πυρρός,
“reddish, fiery”), from the reaction used to detect it-the red color that it imparts to wood when
moistened with hydrochloric acid. [6]
Pyridynes were first postulated by Levine and Leake in 1955.[7] In 1969 Zoltewicz and Nisi
trapped 3,4-pyridyne in a reaction of 3-bromopyridine with methylmercaptan and sodium
amide in ammonia. The methylthio and amino pyridines were found to be formed in the same
ratio.[8]
In 1972 Kramer and Berry inferred the formation of 3,4-pyridyne in gas-phase photolysis of
pyridine-3-diazonium-4-carboxylate via time-of-flight mass spectrometry. The dimer compound
diazabiphenylene was detected.[9] In 1988 Nam and Leroy reported the matrix isolation (13K,
Ar) of 3,4-pyridyne by photolysis of 3,4-pyridinedicarboxylic anhydride with the IR-spectrum
revealing an acetylenic bond in the same way as ortho-benzyne.
DISCUSSION
Classification of PYRROLE:-
From Bone Oil :- Bone oil is first treated with dilute alkalies to removes acidic substances and
then with acids to remove strong alkaline substances (pyrdine). It is then fractionally distilled.
The fraction distilling between 109-150° C is fused with potassium hydroxide to from solid
potassiopyrrole. This is subjected to stean distillation to obtained pure pyrrole.
It may be obtained synthetically by passing a mixture of acetylene and ammonia through a red
hot rule.
2) From ammonium mucate :- Pyrrole can be prepared by heating ammomum mucate with
glycerol at 473 K the ammonium mucate first dissociates into the free acid, which undergoes
dehydration and decarboxylation followed by cyclization of the product thus formed with
ammonia.
3). From furan :- Furan is a heterocyclic organic compound, consisting of a five-membered
aromatic ring with four carbon atoms and one oxygen atom. Chemical compounds containing
such rings are also referred to as furans.
Structure and bonding :- Furan has aromatic character because one of the lone pairs of
electrons on the oxygen atom is delocalized into the ring, creating a 4n + 2 aromatic system
(see Hückel’s rule). The aromaticity is modest relative to that for benzene and related
heterocycles thiophene and pyrrole. The resonance energies of benzene, pyrrole, thiophene,
and furan are, respectively, 152, 88, 121, and 67 kJ/mol (36, 21, 29, and 16 kcal/mol). Thus,
these heterocycles, especially furan, are far less aromatic than benzene, as is manifested in the
lability of these rings.[10] The molecule is flat but the C=C groups attached to oxygen retain
significant double bond character. The other lone pair of electrons of the oxygen atom extends
in the plane of the flat ring system.
Examination of the resonance contributors shows the increased electron density of the ring,
leading to increased rates of electrophilic substitution.[11]
Production :- Industrially, furan is manufactured by the palladium-catalyzed decarbonylation of
furfural, or by the copper-catalyzed oxidation of 1,3-butadiene:[12]
In the laboratory, furan can be obtained from furfural by oxidation to 2-furoic acid, followed by
decarboxylation.[13] It can also be prepared directly by thermal decomposition of pentose-
containing materials, and cellulosic solids, especially pine wood.
Preferred IUPAC name :- Furan[14]
Systematic IUPAC name :- 1,4-Epoxybuta-1,3-diene
1-Oxacyclopenta-2,4-diene
Other names :- Oxole
Oxa[5]annulene
1,4-Epoxy-1,3-butadiene
5-Oxacyclopenta-1,3-diene
5-Oxacyclo-1,3-pentadiene
Furfuran
Divinylene oxide
Properties:-
Chemical formula :-C4H4O
Molar mass:- 68.075 g·mol−1
Appearance :- Colorless, volatile liquid
Density:- 0.936 g/mL
Melting point:- −85.6 °C (−122.1 °F; 187.6 K)
Boiling point :- 31.3 °C (88.3 °F; 304.4 K)
Paal–Knorr synthesis :-
In organic chemistry, the Paal–Knorr Synthesis is a reaction used to synthesize substituted
furans, pyrroles, or thiophenes from 1,4-diketones. It is a synthetically valuable method for
obtaining substituted furans and pyrroles, which are common structural components of many
natural products. It was initially reported independently by German chemists Carl Paal and
Ludwig Knorr in 1884 as a method for the preparation of furans, and has been adapted for
pyrroles and thiophenes.[15][16] Although the Paal–Knorr synthesis has seen widespread use,
the mechanism wasn’t fully understood until it was elucidated by V. Amarnath et al. in the
1990s.[17][18]
The furan synthesis requires an acid catalyst:[19]
In the pyrrole synthesis a primary amine participates
And in that of thiophene for instance the compound phosphorus pentasulfide:
Synthetic applications :-
In 2000, B. M. Trost et al. reported a formal synthesis of the antibiotic roseophilin. Trost’s route
to the macrocyclic core of roseophilin, like others, relied on a Paal–Knorr Pyrrole synthesis to
obtain the fused pyrrole.[20] Heating the 1,4-diketone with ammonium acetate in methanol
with camphor sulfonic acid and 4 angstrom molecular sieves gave the pyrrole with no N-
substitution. This pyrrole was found to be unstable, and as such was treated with trimethylsilyl
ethoxy methoxy chloride (SEM-Cl) to protect the pyrrole prior to isolation.
In 1982, H. Hart et al. reported a synthesis of a macrocycle containing fused furan rings using a
Paal–Knorr furan synthesis.[21] Refluxing para-toluene sulfonic acid in benzene was found to
dehydrate the 1,4-diketones to their respective furans to achieve the challenging macrocyclic
fused furans.
Physical of pyrrole :- It is a colourless liquid, b.p. 129°C with an odour like chloroform. It is
sparingly soluble in water but miscible with most organic solvents and turn brown on standing
in air. Its high boiling point due to H₂ bond.
Chemical properties of pyrrole:
1).Basic Character :- Pyrrole reacts with dilute hydrochloric acid to give a crystalline
Hydrochloride.
2. Acidic Character :- Pyrrole is not only a weak base but also a very weak acid. This is Shown by
its reactions with potassium hydroxide and Grignard reagents.
3. Electrophilic Substitution Reactions :- Pyrrole undergoes electrophilic substitution reactions
at C-2 Because three resonance forms can be written for the Intermediate obtained from attack
at C-2, whereas only two Such forms are possible for substitution at C-3.
Consequently the C-2 intermediate is more stable and the Product with a substituent at C-2
predominates. Substitution at C-3 occurs only when both the 2-positions (that is, α and α’) are
Blocked.
Attack at 2-Position:
Attack at 3-Position:
a. Nitration. :- Pyrrole can be nitrated by a cold solution of nitric acid in acetic anhydride
to give 2-nitropyrrole.
b. Halogenation :-
C).Sulphonation:- Pyrrole may be sulphonated with sulphur trioxide in pyridine at about
100°C to yield 2-pyrrolesulfonic acid.
d).Friedel-Craft Acylation:- Pyrrole may be acetylated with acetic anhydride at 250°C to give 2-
acetylpyrrole. Notice that no catalyst is required in this reaction.
4. Oxidation :- Pyrrole is oxidized by chromium trioxide in acetic acid to give the imide of maleic
acid.
5. Reduction :- Mild reduction of pyrrole with zinc and acetic acid yields 3-pyrroline (2,5-
dihydropyrrole). Catalytic reduction completely hydrogenates the ring system and produces
pyrrolidine.
6. Ring Expansion Reaction :- When treated with sodium methoxide and Methylene iodide,
pyrrole undergoes ring expansion forming pyridine.
7. Ring Opening Reaction :- When treated with hot ethanolic hydroxylamine, pyrrole
undergoes ring opening forming the dioxime of succindialdehyde
8. Reimer-Tiemann Formylation :- Pyrrole reacts with chloroform in the presence of alkali to
yield pyrrole-2- aldehyde (2-formylpyrrole) and 3-chloropyridine.
9. Diazo Coupling :- Pyrrole couples with benzenediazonium chloride in a weakly acidic solution
to give 2-phenylazopyrrole.
10. Kolbe-Schmitt Carboxylation :- Pyrrole reacts with aqueous potassium carbonate at 100°C
to give pyrrole- 2-carboxylic acid.
Structure of pyrrole:-
1. Formation of sigma Bond: All carbon atoms and one nitrogen atom in pyrrole are in sp 2
hybridised state. Carbon has three sp¹ hybrid orbitals, each containing an unpaired
electron and unhybridised orbital with an odd electron. Nitrogen has three sp² orbitals
each containing an odd electron and an unhybridised p orbital perpendicular to the
plane of the hybrid sp² orbitals. Both carbon and nitrogen form C-H, C -C, C-N, C-H and N
– Ho-bonds through overlapping of their sp² hybrid orbitals.
2. Formation of π bonds: Also each carbon atom and the nitrogen atom nitrogen atom
possess an unhybridized p atom orbital and these are perpendicular to the plane of the
Sigma bonds. The p orbital on carbons contain one electron each and the p orbital on
nitrogen contains two’electros (the lone pair). The lateral-overlap of these p orbitals
produces a π molecular orbital containing six electrons. This arrangement is frequently
Preferred to as an aromatic sextet. Pyrrole shows aromatic Properties or aromaticity
because the resulting molecular orbital satisfied. The Huckel’s rule [n = 1 in (4n+2)] e
electrons]
A common short-hand representation of pyrrole is a pentagon, a five-membered cyclic
compound with a ring of electrons inside. The ring- represents the delocalized molecular
orbital.
3. Resonance Structure: According to the resonance theory, pyrrole is considered to the
hybrid of the following resonance stnictures.
Measurement of bond length by X-ray and analysis confirms the resonance hybrid character of
the pyrrole molecule. In particular, the C-N bond (1.38A), which is shorter than a normal C-N
single bond (1.48-Å), seems to possess significant double bond character. Since pyrrole contains
an aromatic ring, it has a rich electron density. This enables pyrrole to participate in
electrophilic substitution reactions.
Classification of pyridine :-
1. Isolation of Pyridine from coal tar : Only 1% of there is found in light oil fraction of coal
tar. Light oil is treated with dil. H₂SO₄ in a container having lead coating to obtain
pyridine form it. Pyridine and other alkaline substance get. Dissolved forming soluble
sulphate pridine base is released on treating acidic layer with caustic soda after
separation. These are purified by rectification. These basis are used as solvent to
denature alcohol and to purity anthracence. To obtain pure pyridine from mixture of
pyridine bases the mixture is subjected from mixture of pyridine bases the mixture is
subjected from mixture of pyridine basis the mixture is subjected to fractional
distillation again and again.
2. From acetylene: Pyridine can he prepared by passing a mixture of acetylene and
hydrogen cyanide through a red hot tube.
3. From pentamethylene diamine hydrochloride: It is heating undergoes cyclization to
forin piperidine and oxidation with cone. H2SO4 at 573 K or by catalytic
dehydrogenation with Pd-C gives pyridine.
4. From pyrrole: It may be prepared by heating pyrrole with methylene iodide and, sodium
methoxide at 200°C.
5. By Dehydrogenation of Piperidine: The dehydrogenation of piperidine with
concentrated sulfuric acid at high temperature yields pyridine: In The place of
concentrated sulfuric acid, even nitrobenzene at 260°C can be used.
6. By commercial method: The reaction of 2 atom acetylene with 1 ammonia and 1
formaldehyde dimenthylacetal in the presence of aluminium oxide at 500°C yield
pyridine.
7. From ẞ Picoline: In this reaction, B- picoline is converted to pyridine. This reaction is a
two step process
Step1: The step involves oxidation of ẞ-picoline with potassium. Dichoromate and sulfuric
acid to give nicotine acid or pyridine 3-carboxylic aicd.
Step2: Nicotinic acid on decarboxylation with calcium oxide yields pyridine.
Physical properties :-
Crystal structure of pyridine
Pyridine is diamagnetic. Its critical parameters are: pressure 5.63 MPa, temperature 619 K and
volume 248 cm3·mol−1.[22] In the temperature range 340–426 °C its vapor pressure p can be
described with the Antoine equation
where T is temperature, A = 4.16272,
B = 1371.358 K and C = −58.496 K.[23]
Structure :- Pyridine ring forms a C5N hexagon. Slight variations of the C−C and C−N distances
as well as the bond angles are observed.
Chemical Properties: The main chemical reactions of pyridine are described below:
1. Basic Character: Pyridine behave as a Lewis base (pKa= 5.2). It reacts with acid to form
fairly stable salts.
It is because Ip of e on N-atom is in molecular plane whereas aromatic sexet is formed in
the plane. So, the nitrogeneous Ip is readily available for the formation of a new N-H bond
after grabbing a proton, which leads to its basic nature
Electrophilic substitutions :- Owing to the decreased electron density in the aromatic
system, electrophilic substitutions are suppressed in pyridine and its derivatives. Friedel–
Crafts alkylation or acylation, usually fail for pyridine because they lead only to the addition
at the nitrogen atom. Substitutions usually occur at the 3-position, which is the most
electron-rich carbon atom in the ring and is, therefore, more susceptible to an electrophilic
addition.
Direct nitration of pyridine is sluggish.[24][25] Pyridine derivatives wherein the nitrogen atom is
screened sterically and/or electronically can be obtained by nitration with nitronium
tetrafluoroborate (NO2BF4). In this way, 3-nitropyridine can be obtained via the synthesis of
2,6-dibromopyridine followed by nitration and debromination.[26][27]
Sulfonation of pyridine is even more difficult than nitration. However, pyridine-3-sulfonic acid
can be obtained. Reaction with the SO3 group also facilitates addition of sulfur to the nitrogen
atom, especially in the presence of a mercury(II) sulfate catalyst.[28][29]
In contrast to the sluggish nitrations and sulfonations, the bromination and chlorination of
pyridine proceed well.[30]
Nucleophilic substitutions :- In contrast to benzene ring, pyridine efficiently supports several
nucleophilic substitutions. The reason for this is relatively lower electron density of the carbon
atoms of the ring. These reactions include substitutions with elimination of a hydride ion and
elimination-additions with formation of an intermediate aryne configuration, and usually
proceed at the 2- or 4-position.[31][32]
Many nucleophilic substitutions occur more easily not with bare pyridine but with pyridine
modified with bromine, chlorine, fluorine, or sulfonic acid fragments that then become a
leaving group. So fluorine is the best leaving group for the substitution with organolithium
compounds. The nucleophilic attack compounds may be alkoxides, thiolates, amines, and
ammonia (at elevated pressures).[33]
In general, the hydride ion is a poor leaving group and occurs only in a few heterocyclic
reactions. They include the Chichibabin reaction, which yields pyridine derivatives aminated at
the 2-position. Here, sodium amide is used as the nucleophile yielding 2-aminopyridine. The
hydride ion released in this reaction combines with a proton of an available amino group,
forming a hydrogen molecule.[34][35]
Analogous to benzene, nucleophilic substitutions to pyridine can result in the formation of
pyridyne intermediates as heteroaryne. For this purpose, pyridine derivatives can be eliminated
with good leaving groups using strong bases such as sodium and potassium tert-butoxide. The
subsequent addition of a nucleophile to the triple bond has low selectivity, and the result is a
mixture of the two possible adducts.[36]
Radical reactions :- Pyridine supports a series of radical reactions, which is used in its
dimerization to bipyridines. Radical dimerization of pyridine with elemental sodium or Raney
nickel selectively yields 4,4’-bipyridine,[37] or 2,2’-bipyridine,[38] which are important
precursor reagents in the chemical industry. One of the name reactions involving free radicals is
the Minisci reaction. It can produce 2-tert-butylpyridine upon reacting pyridine with pivalic
acid, silver nitrate and ammonium in sulfuric acid with a yield of 97%.[39]
Reactions on the nitrogen atom :-
Additions of various Lewis acids to pyridine
Lewis acids easily add to the nitrogen atom of pyridine, forming pyridinium salts. The reaction
with alkyl halides leads to alkylation of the nitrogen atom. This creates a positive charge in the
ring that increases the reactivity of pyridine to both oxidation and reduction. The Zincke
reaction is used for the selective introduction of radicals in pyridinium compounds (it has no
relation to the chemical element zinc).
Uses of Pyridine :-
(1) As a mild base in organic reactions. (e.g., acylation, dehydrohalogenation, etc.)
(2) As a solvent
(3) As a catalyst in a number of organic reactions (e.g., Knoevenagel reaction)
(4) As a denaturant for ethanol.
(5) As a raw material in the preparation of sulphapyridine, a sulpha drug.
Structure of pyridine:-
Formation of Sigma bonds: In pyridine all rings atoms – five carbons + one nitrogen atom are
sp² hybridized giving rise to a planar shape to the ring. Two of the shape sp² orbitals on each
atom overlap with each other to form the C-C bonds and C-No bonds as well. Third sp² orbital
on each carbon atom overlaps with an s orbital from hydrogen to form the C-Ho bonds and C-
NO bonds as well. The third sp² orbital on each carbon atom overlaps with an s orbital from
hydrogen to form the C-N σ bonds. The third sp² orbital on nitrogen is occupied by the nitrogen
lone pair electrons. Allo bonds in pyridine lie in one plane and all bond angles are 120”. The
different σ bonds are shown below.
Formation of pie bonds: In addition to the presence of three s * p ^ 2 hybrid orbitalscach ring
atom in pyridine possesses anunhybridized p orbital containing one un-used electron. These
electrons areperpendicular to the plane containing thebonds. The lateral overlap of the
p.orbitalsproduces a delocalized a bonds.Thiscompletes the aromatic sextet. One half ofthis
molecular orbital lies above and theother half below the plane. Of sigma bonds. It isbecause of
this pyridine shows aromaticproperties as the resulting molecularorbitals satisfies the Huckel’s
rule (4n + 2)
A common shorthand representation of pyridine is a hexagon a six-membered cyclic compound
with a ring inside like benzene.
Resonance structure: According to the resonance theory, pyridine is considered to be hybrid of
the following canonical structures.
Measurement of bond lengths by X-ray analysis confirms the hybrid nature of the pyridine
molecule. C-C and C-N bond lengths of 1.39 Å and 1.37 Å. These bond lengths are intermediate
between those corresponding to a single and a’double bond.
Comparison of basicity of Pyridine, Piperidine and Pyrrole :- Comparison of base strength of
pyrrole, pyridine and piperidine can be observe by pK, values as shown below and follows the
order. Pyrrole behaves both as a very weak base as well as a very weak acid. Piperidine is a very
strong base,
The basic strength of pyrrole, pyndine and piperidine can be easily explained on the basis of
availability of lone pair of electrons on the nitrogen atom for protonation.
The basicity of these heterocycles depends upon the availability of an unshared electron pair on
nitrogen. In pyrrole, the nitrogen lone pair is contributed towards n-electron cloud. As a result,
pyrrole is a very weak base. It is such a weak base that when treated with a strong base like.
potassium metal, it acts weak acid to form potassiopyrrole.
In pyridine, the lone pair of electrons is present in a sp²-orbital while in piperidine is present in
a sp-urbital. Since electrons in a sp²-orbital are more tightly held by the atomic nucleus than the
electrons in a sp³-orbital, therefore, the lone pair of electrons on nitrogen in piperidine is more
easily, available for protonation than that in pyridine. In other words, piperidine is a stronger
base than pyridine.
Reference:-
1. Loudon, Marc G. (2002). “Chemistry of Naphthalene and the Aromatic Heterocycles”.
Organic Chemistry (4th ed.). New York: Oxford University Press. Pp. 1135–1136. ISBN
978-0-19-511999-2.
2. Cox, Michael; Lehninger, Albert L.; Nelson, David R. (2000). Lehninger Principles of
Biochemistry. New York: Worth Publishers. ISBN 978-1-57259-153-0.
3. Handbook of Heterocyclic Chemistry, (2010) y, Alan R. Katritzky,Christopher A.
Ramsden,J. Joule,Viktor V. Zhdankin
4. Heterocyclic Chemistry, (2001) Malcolm Sainsbury
5. Runge, F. F. (1834). “Ueber einige Produkte der Steinkohlendestillation” [On some
products of coal distillation]. Annalen der Physik und Chemie. 31 (5): 65–78.
Bibcode:1834AnP…107…65R. doi:10.1002/andp.18341070502. See especially pages
67–68, where Runge names the compound Pyrrol (fire oil) or Rothöl (red oil).
6. Harreus, Albrecht Ludwig. “Pyrrole”. Ullmann’s Encyclopedia of Industrial Chemistry.
Weinheim: Wiley-VCH. Doi:10.1002/14356007.a22_453.
7. Levine, R.; Leake, W. W. (1955). “Rearrangement in the Reaction of 3-Bromopyridine
with Sodium Amide and Sodioacetophenone”. Science. 121 (3152): 780.
Bibcode:1955Sci…121..780L. doi:10.1126/science.121.3152.780. PMID 17773207.
8. Zoltewicz, John A.; Nisi, Carlo (1969). “Trapping of 3,4-Pyridyne by Thiomethoxide Ion in
Ammonia”. The Journal of Organic Chemistry. 34 (3): 765–766.
Doi:10.1021/jo01255a072.
9. Kramer, Jerry; Berry, R. Stephen (1972). “Gaseous 3,4-Pyridyne and the Formation of
Diazabiphenylene”. Journal of the American Chemical Society. 94 (24): 8336–8347.
Doi:10.1021/ja00779a010.
10. Smith, Michael B.; March, Jerry (2007), Advanced Organic Chemistry: Reactions,
Mechanisms, and Structure (6th ed.), New York: Wiley-Interscience, p. 62, ISBN 978-0-
471-72091-1
11. Bruice, Paula Y. (2007). Organic Chemistry (5th ed.). Upper Saddle River, NJ: Pearson
Prentice Hall. ISBN 978-0-13-196316-0.
12. Hoydonckx, H. E.; Van Rhijn, W. M.; Van Rhijn, W.; De Vos, D. E.; Jacobs, P. A. “Furfural
and Derivatives”. Ullmann’s Encyclopedia of Industrial Chemistry. Weinheim: Wiley-
VCH. Doi:10.1002/14356007.a12_119.pub2.
13. Wilson, W. C. (1941). “Furan”. Organic Syntheses.; Collective Volume, vol. 1, p. 274
14. Nomenclature of Organic Chemistry : IUPAC Recommendations and Preferred Names
2013 (Blue Book). Cambridge: The Royal Society of Chemistry. 2014. P. 392.
Doi:10.1039/9781849733069-FP001. ISBN 978-0-85404-182-4.
15. Paal, C. (1884), “Ueber die Derivate des Acetophenonacetessigesters und des
Acetonylacetessigesters”, Berichte der deutschen chemischen Gesellschaft, 17 (2):
2756–2767, doi:10.1002/cber.188401702228
16. Knorr, L. (1884), “Synthese von Furfuranderivaten aus dem Diacetbernsteinsäureester”,
Berichte der deutschen chemischen Gesellschaft, 17 (2): 2863–2870,
doi:10.1002/cber.188401702254
17. Amarnath, V.; Amarnath, K. (1995), “Intermediates in the Paal-Knorr Synthesis of
Furans”, The Journal of Organic Chemistry, 60 (2): 301–307, doi:10.1021/jo00107a006
18. Amarnath, V.; Anthony, D. C.; Amarnath, K.; Valentine, W. M.; Wetterau, L. A.; Graham,
D. G. (1991), “Intermediates in the Paal-Knorr synthesis of pyrroles”, The Journal of
Organic Chemistry, 56 (24): 6924–6931, doi:10.1021/jo00024a040
19. Thomas L. Gilchrist (1987). Heterocyclic Chemistry. Harlow: Longman Scientific. ISBN 0-
582-01421-2.
20. Trost, B. M.; Doherty, G. A. (2000), “An Asymmetric Synthesis of the Tricyclic Core and a
Formal Total Synthesis of Roseophilin via an Enyne Metathesis”, Journal of the American
Chemical Society, 122 (16): 3801–3810, doi:10.1021/ja9941781
21. Hart, H.; Takehira, Y. (1982), “Adducts derived from furan macrocycles and benzyne”,
The Journal of Organic Chemistry, 47 (22): 4370–4372, doi:10.1021/jo00143a049
22. Haynes, p. 6.80
23. McCullough, J. P.; Douslin, D. R.; Messerly, J. F.; Hossenlopp, I. A.; Kincheloe, T. C.;
Waddington, Guy (1957). “Pyridine: Experimental and Calculated Chemical
Thermodynamic Properties between 0 and 1500 K.; a Revised Vibrational Assignment”.
Journal of the American Chemical Society. 79 (16): 4289. Doi:10.1021/ja01573a014.
24. Bakke, Jan M.; Hegbom, Ingrid (1994). “Dinitrogen Pentoxide-Sulfur Dioxide, a New
nitrate ion system”. Acta Chemica Scandinavica. 48: 181–182.
Doi:10.3891/acta.chem.scand.48-0181.
25. Ono, Noboru; Murashima, Takashi; Nishi, Keiji; Nakamoto, Ken-Ichi; Kato, Atsushi;
Tamai, Ryuji; Uno, Hidemitsu (2002). “Preparation of Novel Heteroisoindoles from
nitropyridines and Nitropyridones”. Heterocycles. 58: 301. Doi:10.3987/COM-02-
S(M)22.
26. Duffy, Joseph L.; Laali, Kenneth K. (1991). “Aprotic Nitration (NO+2BF−4) of 2-Halo- and
2,6-Dihalopyridines and Transfer-Nitration Chemistry of Their N-Nitropyridinium
Cations”. The Journal of Organic Chemistry. 56 (9): 3006. Doi:10.1021/jo00009a015.
27. Joule, p. 126
28. Joule, pp. 125–14
29. Möller, Ernst Friedrich; Birkofer, Leonhard (1942). “Konstitutionsspezifität der
Nicotinsäure als Wuchsstoff bei Proteus vulgaris und Streptobacterium plantarum”
[Constitutional specificity of nicotinic acid as a growth factor in Proteus vulgaris and
Streptobacterium plantarum]. Berichte der Deutschen Chemischen Gesellschaft (A and B
Series). 75 (9): 1108. Doi:10.1002/cber.19420750912.
30. Shimizu, S.; Watanabe, N.; Kataoka, T.; Shoji, T.; Abe, N.; Morishita, S.; Ichimura, H.
“Pyridine and Pyridine Derivatives”. Ullmann’s Encyclopedia of Industrial Chemistry.
Weinheim: Wiley-VCH. Doi:10.1002/14356007.a22_399.
31. Joule, pp. 125–141
32. Davies, D. T. (1992). Aromatic Heterocyclic Chemistry. Oxford University Press. ISBN 0-
19-855660-8.
33. Joule, p. 133
34. Davies, D. T. (1992). Aromatic Heterocyclic Chemistry. Oxford University Press. ISBN 0-
19-855660-8.
35. Shreve, R. Norris; Riechers, E. H.; Rubenkoenig, Harry; Goodman, A. H. (1940).
“Amination in the Heterocyclic Series by Sodium amide”. Industrial & Engineering
Chemistry. 32 (2): 173. Doi:10.1021/ie50362a008.
36. Joule, pp. 125–141
37. Badger, G; Sasse, W (1963). The Action of Metal Catalysts on Pyridines. Advances in
Heterocyclic Chemistry. Vol. 2. Pp. 179–202. Doi:10.1016/S0065-2725(08)60749-7. ISBN
9780120206025. PMID 14279523.
38. Sasse, W. H. F. (1966). “2,2’-bipyridine” (PDF). Organic Syntheses. 46: 5–8.
Doi:10.1002/0471264180.os046.02. ISBN 0471264229. Archived from the original (PDF)
on 21 January 2012.
39. Joule, pp. 125–141
