Pyridine

[110-86-1]  · C5H5N  · Pyridine  · (MW 79.11)

(weak base useful as acid scavenging solvent or catalyst, especially for condensation,1 dehalogenation,2 halogenation,3 and acylation4 reactions)

Physical Data: 5 bp 115.3 °C; mp -41.6 °C; forms azeotropic mixture with water, bp 93.6 °C (41.3 wt % H2O); steam volatile; d 0.9830 g cm-3 at 20 °C; pKa 5.22 (in H2O at 20 °C).

Solubility: miscible water, alcohol, ether, petroleum ether, and numerous other organic solvents.

Form Supplied in: colorless liquid; widely available.

Analysis of Reagent Purity: titration, GLC.

Purification: distillation.

Handling, Storage, and Precautions: flammable solvent with flash point 20 °C; hygroscopic; LD50 rat (oral) 891 mg kg-1;5 minimum detectable odor 0.012 ppm;5 incompatible with acids, acid chlorides, oxidizing agents, and chloroformates.6

Use as a Base in Condensation Reactions.

Pyridine can be used as a base in cyclocondensation reactions. When the reaction of 2-acylphenoxyacetic acids in acetic anhydride is carried out in the presence of pyridine, formation of benzofuran-2-carboxylic acids is preferred. When weaker bases such as sodium acetate or sodium formate are used for the reaction, mixtures of benzofurans and benzofuran-2-carboxylic acids are produced, with the benzofuran derivatives as the major products.7 For example, 2-acetyl-4-nitrophenoxyacetic acid (1) gives 65% 3-methyl-5-nitrobenzofuran-2-carboxylic acid (2) and 25% 3-methyl-5-nitrobenzofuran (3) when treated with Acetic Anhydride in pyridine. The same reaction in the presence of sodium acetate instead of pyridine gives a reversal of products with (2) as the minor product (33%) and (3) as the major product (60%) (eq 1).

Pyridine has been used effectively as a catalyst in the Knoevenagel condensation reaction.8 Depending upon the nature of the base employed, the product selectivity can be altered. Different stereochemistry has been observed for aromatic heterocyclic bases such as pyridine and aliphatic tertiary amines such as Triethylamine. Reaction of hexanal (4) with Malonic Acid (5) in the presence of pyridine as the base gives the a,b-unsaturated acid (6) as the major product (91:9 a,b:b,g). When bases such as triethylamine are used in the reaction, a higher overall yield is obtained (76%); however, the corresponding b,g-unsaturated acid (7) is the predominant product1 (2:98 a,b:b,g) (eq 2). One factor that appears important in determining the product ratio is the steric hindrance of the base. Pyridine, without the steric hindrance, shows a definite preference for the a,b-unsaturated carboxylic acid.

Condensation of furfural (8) with malonic acid (5) in the presence of pyridine affords an excellent yield of furylacrylic acid (9) (eq 3).9 Similarly, condensation of m-nitrobenzaldehyde with malonic acid proceeds in the presence of pyridine as catalyst.10

Yield improvements in the Knoevenagel condensation reaction have been obtained when the reaction is carried out in the presence of Titanium(IV) Chloride and pyridine in either tetrahydrofuran or dioxane solvent.11 For example, the condensation of Acetaldehyde (10) with Diethyl Malonate, (11) affords an 86% yield of product (12), as compared to a 25% yield without the promoter (eq 4).8,12

Condensation of carboxylic acids with amines in pyridine in the presence of a phosphorous(III) acid/iodine complex is an effective method for the synthesis of amides (eq 5).13 Pyridine acts as a base and a solvent in this reaction.

Organoaluminum compounds such as Diisobutylaluminum Phenoxide with pyridine are good reagents for the regioselective aldol condensation of methyl ketones.14 This system works effectively with pyridine acting as a base to inhibit undesirable proton transfer reactions (eq 6). Commonly used methods such as formation of the silyl enolate are not practicable here since they do not undergo regioselective attack on the methyl side of the ketone. Cross-aldol condensation reactions can also be carried out regiospecifically in the presence of a tertiary amine such as pyridine or 2,6-Lutidine.15

Oxidation Reactions.

An extensive amount of research has been carried out on the Gif system, and related systems, for the selective oxidation of saturated hydrocarbons. Pyridine is commonly used as a solvent in these reactions which involve a metal-catalyzed oxidation using Hydrogen Peroxide in a pyridine-acetic acid solvent system (eq 7). Copper, zinc, and iron are commonly used in the reactions.16-19 Conversions are typically in the range of 10-25%; however, the selectivities are nearly quantitative.

Oxidation reactions of alcohols by Lead(IV) Acetate can be accelerated in the presence of pyridine. A kinetic study of this reaction has been carried out by Banerji using benzyl alcohol (13) as substrate (eq 8).20

Oxidation of alcohols can also be effectively carried out using Chlorine in pyridine to give aldehydes and ketones. Secondary alcohols can be selectively oxidized in the presence of primary alcohols.21 For example, treatment of 5b-cholestane-3b,19-diol (14) with chlorine and pyridine affords selective oxidation to 19-hydroxy-: 5b-cholestan-3-one (15) in almost quantitative yield (eq 9).

Aqueous pyridine is a very effective solvent for the oxidation of sulfides to sulfoxides with Phenyliodine(III) Dichloride. High yields of the sulfoxides are typically obtained without contamination by sulfones (eq 10).22

Halogenation Reactions.

Treatment of enones with Iodine and pyridine in carbon tetrachloride results in direct iodination. Good yields of 2-iodo enones are obtained when a solution of iodine (1.2-1.4 equiv) dissolved in a 1:1 (v/v) mixture of pyridine/carbon tetrachloride is added to cycloalkenones (eq 11).23

Pyridine is employed as a base in the conversion of tetrahydrofurfuryl alcohol (16) to the corresponding bromide (17). A fair yield of the bromide is obtained (eq 12).24 Addition of pyridine greatly increases the yield of product.3

In the bromination of 1-methylaminoanthraquinone (18), a good yield of 1-methylamino-4-bromoanthraquinone (19) is obtained using pyridine as acid scavenger and solvent (eq 13).25

Pyridine and 2,6-lutidine are useful as acid scavengers in the chlorination of a,b-unsaturated ketones and esters. For the ketones, the pyridine bases typically favor the Markovnikov isomer; however, for esters, pyridine shows little effect on the Markovnikov (alkoxy adjacent to carbonyl)/anti-Markovnikov isomer ratios (eq 14).26

Dehalogenation Reactions.

Dehalogenation of a-halo ketones can be effected by a number of reagents including pyridine and Tin(II) Chloride (eqs 15 and 16).2 In the absence of the pyridine, the yield of acetophenone (20) drops to 75% and the yield of cyclohexanone (21) to 10%. Sulfur compounds such as sodium sulfite and Sodium Sulfide, as well as benzene and aniline, are capable of dehalogenation in the presence of a promoter such as tin(II) chloride. An advantage of this reaction is that both aliphatic and aromatic a-halo ketones can be dehalogenated in good to excellent yields.

Dehydrochlorination of 2-(1-chloroethyl)thiophene (22) in the presence of pyridine gives 2-vinylthiophene (23) in 50-55% overall yield starting from thiophene (eq 17).27 Didehydrochlorination of 2,2-dichloro-4-alkylbutanolides affords 4-alkylidene-2-butenolides upon reflux in pyridine (eq 18).28

Epoxidations.

Taking advantage of its utility as a base, pyridine has been used for epoxidations in anhydrous organic systems with a-azo hydroperoxides as the epoxidizing reagents (eq 19).29 Sodium Hydroxide works equally well or better with some of the epoxidizing agents; however, with the hydroperoxide (24), sodium hydroxide is a poor catalyst. Sodium hydroxide-catalyzed dehydration of the azo hydroperoxide, which affords N-(4-bromophenyl)-N-benzyldiazene, is a competing side reaction.30

Coupling Reactions.

Dimerization of aromatic nitrile oxides can be catalyzed by pyridine, affording 3,6-diaryl-1,4,2,5-dioxadiazines in good yields (eq 20).31 Other nucleophiles such as 4-phenylpyridine, 4-methylpyridine, 4-Dimethylaminopyridine, and N-Methylimidazole are also suitable catalysts for the reaction.

Esterifications.

Pyridine is a widely used catalyst for acylation reactions. Acetylation reactions are effectively carried out in the presence of hexachlorocyclophosphazatriene and pyridine.32 Acetylation of phenols by Acetic Anhydride in carbon tetrachloride is also catalyzed by pyridine. In the absence of the pyridine catalyst, at 0 °C and 25 °C, no acylation of the phenols is observed (eq 21).4

Acylation of 6,7-dimethoxy-1-methyl-3,4-dihydroisoquinoline (25) with acetic anhydride in pyridine affords 2-acetyl-6,7-dimethoxy-1-methylene-1,2,3,4-tetrahydroisoquinoline (26) in 72-77% yield (eq 22).33

Treatment of o-hydroxyacetophenone (27) with Benzoyl Chloride in pyridine affords o-benzoyloxyacetophenone (28) in excellent yield (eq 23).34

Synthesis of Benzonitriles.

Arylthallium(III) salts with Copper(I) Cyanide or copper(II) cyanide afford fair to excellent yields of benzonitriles when heated at reflux in pyridine solvent (eq 24).35 The use of acetonitrile as solvent gives lower product yields.

Catalyst Poison.

Pyridine and Quinoline have been used in conjunction with Palladium on Barium Sulfate as a catalyst system for the reduction of alkynes to cis-alkenes.36

Related Reagents.

Borane-Pyridine; Chlorine-Pyridine; Copper(II) Sulfate-Pyridine; Di-t-butyl Chromate-Pyridine; Dimethyl Sulfoxide-Sulfur Trioxide/Pyridine; Sulfur Trioxide-Pyridine.


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Angela R. Sherman

Reilly Industries, Indianapolis, IN, USA



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