Investigations on Pyrroles and Related Substances

Home , Pyrrole

INVESTIGATIONS ON PYRROLES AND RELATED SUBSTANCES

CONTAINING THE NITRILE GROUP

DISSERTATION

Presented in Partial Fulfillment of the Requirements for

The Degree of Doctor of Philosophy in the Graduate

School of The Ohio State University

Thomas Harvey Curry, B.S.

The Ohio State University

1953

Approved by:

Advisor i

Acknowledgement

The research for this dissertation was conducted at the Charles F. Kettering Foundation at Yellow Springs,

Ohio. The author is grateful for the Fellowship which made this dissertation possible. He particularly wishes to thank Dr. P. Rothernund under whose guidance this work was performed.

For their kind cooperation the author wishes to express his appreciation to Dr. Edward Mack, Jr., and the other members of the Department of Chemistry of The Ohio

State University.

A 07193 ii

Table of Contents

Page

Introduction 1

Historical 1

Nomenclature 3

Spectroscopic Properties of Pyrroles,

Dipyrryl-compounds, and Porphyrins 3

Synthetic Methods 6

Discussion 12

(3-Aminocrotonic acid ethyl ester 15

2.6-Dimethyl-4-chiorome thyl-1,4-dihydro-

3.5-dicarbethoxy pyridine 15

2.6-Dimethyl-4-cyanomethyl-1,4-dihydro-

5 .5-dicarbethoxy pyridine 18

Ring contraction to 2-methyl-4-cyanomethyl-

5-carbethoxy pyrrole 18

2-Methyl-4-cyanomethyl pyrrole 19

2-Methyl-4-cyanomethyl-5-carboxylic acid

pyrrole 22

2-Uethyl-4-cyanomethyl-5-bromo pyrrole 22

2-Methyl-4-cyanomethyl-5-formyl pyrrole 23

Resistance of 2-methyl-4-cyanomethyl-5-formyl pyrrole to oxidation 25

5,5'-Dimethy13,3 1 -dicyanomethyl dipyrryl-

methane 26 Efforts to condense 2-methyl-4-cyano-methyl

pyrrole with 2,4-dinethyl-3-carbethoxy

pyrrole

Preparation of new dipyrryl-compounds

Oxidation of - Cli substituted pyrroles with

lead tetraacetate

Sulfuryl chloride reactions

2.4-Dimethyl-o-chioromethyl-5-carbethoxy

pyrrole (chloromethylation)

2.4-D imethyl-3-c ya nonethyl-5-c arc e thoxy

pyrrole

2.4-Dir.iethyl-o-cyano-5-carbethoxy pyrrole

Miscellaneous experiments

Experimental

General Remarks on Physical Measurements

P-Aminocrotonic acid ethyl ester

2.6-Dimethyl-4-chloromethyl-l,4-dihydro-

3.5-dicarbethoxy pyridine

2.6-Dimethyl-4-cyan omethyl-1,4-dihydro-

3.5-dicarbethoxy pyridine

2-Methyl-4-cyanomethyl-5-carbethoxy pyrrole

2-Methyl-4-cyanomethyl pyrrole Eromination of 2-methyl-4-cyanomethyl

pyrrole

2-Chloro-3-cyanomethyl-5-carboxylic acid

- pyrrole

Conversion of 2-methyl-4-cyanonethyl

pyrrole into a substance having a

three banded spectrum

Attempted lead tetraacetate oxidation of

2-me thy1-4-c yan omethy1-5-carbethoxy

pyrrole

2 -Me thy 1 - 4- c y an ora e thyl -5 - c ar b o xy 1 i c

acid pyrrole

2-M e thyl-4-cyanom ethyl-5-f ormy1 pyr r ole

Attempted oxidation of 2-methyl-4-cyano

me thyl -5 -f ormy 1 pyrrole

5,5’-Dimethy1-3,3’-dicyanomethyl dipyrrylmethane

5,5'-Dimethyl-3,3 ’ -dicyanomethyl dipyrrylrnethene

hydrobromide

Attempted preparation of 3, 5,5'-trimethyl-

4-carbethoxy-3’-cyahomethyl dipyrryl

me thene hydrobromide 5.5 1 -Dime thyl-4-cyano-3 1 -cyanome thyl

dipyrrylme thane

5.5 f-Dimethyl-4,4’-dicyano dipyrrylmethene

Attempted preparation of 3 1,5,5'-Trimethyl-

- 4-cyano-4'-carbethoxy dipyrrylmethene

hydrobromide

2.4-Dimethyl-3-chloromethyl-5-carbethoxy

pyrrole 2,21,4,41-Tetramethyl-5,5’-dicarbethoxy

dipyrrylmethane

Condensation product of 2,4-dimethy1-3-

chioromethyl-5-carbethoxy pyrrole and

pyridine

2.4-Dimethyl-3-cyanomethyl-5-carbethoxy

pyrrole Attempted oxidation of 2,4-dimethyl-3-

cyanomethyl-5-carbethoxy pyrrole

to the corresponding 2-hydroxymethyl

compound

2-Chloromethyl-4-methyl-3-cyanomethyl-5-

carbethoxy pyrrole

4,4' -Dime thyl -3,3* -dicyanome thyl -5,5’-

diearbe thoxy dipyrrylme thane 2 .4-Dime thyl-3-cyano-5-carbe thoxy pyrrole

Attempted oxidation of 2,4-dimethyl-3-

cyano-5-carbethoxy pyrrole with lead

tetraacetate (Die'thylacetal of 4-methyl-3-cyano-2-

formy1-5-carbethoxy pyrrole) 2-Chioromethyl-4-methyl-3-cyano-5-

carbethoxy pyrrole

2.4-Dimethyl-3-propionyl-5-carbethoxy pyrrole

2.4-Dimethyl-3-propyl-5-caroethoxy pyrrole

2 .4-Dimethyl-5-butyl-5-carbethoxy pyrrole

2.4-Dimethyl-3-(y-ketobutyric acid)-5-

carbethoxy pyrrole

Summary

Bibliography

Au t ob i o graphy vii

List of Illustrations

Figure Page

I. 3,3’,5,5’-Tetramethyl-4,41-dicarbethoxy

dipyrrylmethene hydrobromide 4

II. Porphine 4

III. a,a1-Dipyrrylmethane 8

IV. P,P'-Dipyrrylme thane 8

V. a,p1-Dipyrrylmethane 8

VI. a,a'-Dipyrrylmethene hydrobromide 9 VII. 2,6-Dimethyl-4-chloromethyl-l,4-dihydro-

3.5-dicarbethoxy pyridine 17

VIII. 2,6-Dimethyl-4-cyanomethyl-1,4-dihydro-

3.5-dicarbethoxy pyridine 17

IX. 2-I.Iethyl-4-cyanomethyl-5-carbe thoxy

pyrrole 17

X. 2-I.Iethyl-4-cyanomethyl-5-carboxylic acid

pyrrole 21

XI. 2-I'ethyl-4-cyanomethyl pyrrole 21

XII. 2-I.?3thyl-4-cyanomethyl-5-bromo pyrrole 21

XIII. 2-Chloro-3-cyanomethyl-5-carboxylic acid

pyrrole 24

XIV. 2-Methyl-4-cyanomethyl-5-formyl pyrrole 24

XV. 5,5,-Dimethyl-3,5l-dicyanomethyl dipyrryl

me thane 24 vill

«*£, 5,5 ’-Dime thyl-3, 3 •-dicyanomethyl dipyrrylmethene hydrobromide 29

2.4-Dimethyl-3-carbethoxy pyrrole 29

2 .4-Dimethyl-3-carbethoxy-5-f“ormyl pyrrole 29

2-I.Iethyl-3-cyano pyrrole 30

5,5'-Dimethyl-4-cyano-3'-cyanomethyl dipyrrylmethane 30

2-I.!ethyl-3-cyano-5-formyl pyrrole 30

5,5'-Dimethyl-4,4'-dicyano dipyrrylmethene 31

3 1,5,5•-Trimethyl-4-cyano-4’-carbethoxy dipyrrylmethene hydrobromide 31

2 ,4-Dime thyl-5-carbethoxy pyrrole 31

2 .4-Dimethyl-3-chlorome thyl-5-carbethoxy pyrrole 37

2,2*,4,41-Tetramethyl-5,5’-dicarbethoxy dipyrrylmethane 37

2 ,4-Dimethyl-3-cyanomethyl-5-carbethoxy pyrrole 37

2-Chlcromethyl-4-methyl-3-cyanomethyl-5- carbethoxy pyrrole 40

4,41-Dimethyl-3,3•-dicyanomethyl-5,51- dicarbethoxy dipyrrylmethane 40

2.4-Dimethyl-3-aldoxime-5-carbethoxy pyrrole 40 ix

Figure Page

XXXI. 2,4-Dimethyl-3-cyano-5-carbethoxy pyrrole 41

XXXII. Diothylacetal of 4-methyl-3-cyano-2-

formyl-5-carbethoxy pyrrole 41

XXXIII. 2-Chloromethyl-4-methyl-3-cyano-6-

-carbe thoxy pyrrole 41

XXXIV. 2,4-Dimethyl-3-propionyl-5-carbethoxy pyrrole 43

XXXV. 2,4-Dimethyl-3-propyl-6-carbethoxy pyrrole 43

XXXVI. 2,4-Dimethyl-3-butyryl-5-carbethoxy

pyrrole 43

XXXVII. 2,4-Dimethyl-3-butyl-5-carbethoxy pyrrole 43

XXXVIII. 2,4-Dimethyl-3-(y-ketobutyric acid)-5-

carbethoxy pyrrole 43 / Introduction

Historical

Several investigators have attempted to prepare porphyrins containing the -CN, or nitrile, group because of its potential transformation into such functional groups as-the carboxyl, formyl or amino. These attempts were successful in two cases: Fischer and M&Ller (1) dehydrated the oxime of the corresponding 6-formyl substituted porphine with acetic anhydride and potassium acetate, and obtained 1,3,5,8,v-pchtamethyl-2,4-diethyl-

6-cyano-7-propionic acid methyl ester porphine. Fischer and Beer (2) used substantially the same procedure for the synthesis of

a. l,3,5,8-tetramethyl-2,4-diethyl-6-cyano-7- propionic acid methyl ester porphine,

b • 1,3,5,8-tetramethyl-4-cyano-6,7-dipropionic acid dimethyl ester porphine, and

c . 1,3,5,8-tetramethyl-2,4-dicyano-6,7-dipropionic acid dimethyl ester porphine.

In these cases the nitrile group was introduced after the porphyrin ring system was extant. Porphyrins contain ing nitrile groups, have never been synthesized from pyrroles with a nitrile group as substituent, in spite of a number of investigations undertaken by different authors in this field. 2

Substituted pyrroles, dipyrrylmethanes and dipyrryl me thenes containing -CN are, however, well known, since

the attempts at synthesis of nitrile substituted porphyrins necessarily involved the preparation of these

simpler compounds as starting materials.

Pisclier and Rothemund (3) attempted to synthesize

such a porphyrin from 3,5,3',5*-tetramethyl-4-cyano-4'- propionic acid dipyrrylmethene hydrobromide. The product, however, was 1,4,5,8-tetramethyl-2,3,6,7-tetraethyl

porphine, etioporphyrin II. Cleavage of the dipyrryl methene occurred, and only the nitrile-free pyrrole

rings formed porphyrin. It was assumed that the negative

result was related to the inertness of the a-methyl

groups; bromination of the dipyrrylmethene failed, and

2,4-dimethyl-3-cyano-5-carbethoxy pyrrole was slow to

react whereas 2,4-dimethyl-3,5-dicarbetlaoxy pyrrole brominates very readily.

Fischer and Wassenegger (4) condensed 3,5,3',5'-

tetra«ethyl-4-ethyl-4 *-(h>-cyano-6)-carboxyl) -vinyl dipyrryl methene with bis-(2-bromo-3-methyl-4-ethyl pyrrole)-

5-methene in a succinic anhydride melt and obtained only

etioporphyrin. Again cleavage occurred and only the

component without nitrile function was involved in

porphyrin formation. 3

Nomenclature

Fischer (5) reviewed the nomenclature for substituted

pyrroles and dipyrryl-compounds • The system for the

latter is illustrated in Figure I for 5,3',5,5'-tetramethyl-4,4*-dicarbethoxy dipyrrylmethene hydrobromide.

The nomenclature for porphyrins and other degradation

products of chlorophyll was reviewed by Rothemund (6).

Porphyrins contain 4 pyrrole nuclei linked by four methine bridges in a-positions. According to Fischer's

(7) system of nomenclature the pyrrole rings are assigned

Roman numerals I to IV; the methine bridge carbon atoms are

designated as a,p,Y and 6 starting between rings I and

II, and the p carbon atoms of the pyrrole rings are

numbered 1 to 8 beginning with ring I. Porphyrins are

substituted porphines and are named as such. Porphine,

Figure II, is the simplest porphyrin; the pyrrole nuclei

carry only hydrogen atoms. It was first synthesized by

Rothemund (8) ih 1935.

Spectroscopic Properties of Pyrroles. Dipyrryl-compounds.

and Porphyrins.

Spectroscopic properties of these compounds,

especially of porphyrins, are very characteristic and there

fore extremely helpful in synthetic work in this field. 4

H BC aOOC - C C - CH a H aC - C = C - COOC2HB

H aC - C. JZ ------C = s = s C L C - CHa H H HBr

5 , 3 1,5,5 * -Tetrame thyl-4 ,4 * -dicaroe thoxy dipyrrylmethene hydrobromide

Pig. I

Porphine

Pig. II 5 1. In the visible region of the spectrum substituted pyrroles and dipyrrylmethanes have no typical absorption spectra,

2. the spectra of dipyrrylmethenes and their salts exhibit one or several absorption bands, depending on the substance and the solvent used,

3. porphyrins have multi-banded spectra in neutral ether solution; usually three bands as hydrochlorides.

Ether is the accepted reference solvent for measuring absorption spectra in this field, since absorption bands in this solvent are usually very distinct. Occasionally the solubility of the dipyrrylmethenes, porphyrins and their salts requires the use of a solvent other than ether, such as glacial acetic acid, chloroform, or pyridine.

With regard to the measurements and recording of spectra the following is quoted from the article by

Rothemund (9).

"In direct visual measurement of sharp and broad symmetrical absorption bands the edges should be measured at points of estimated equal intensity in millimicrons and the maximum calculated as the arithmetical mean. For very narrow or for weak bands (shadows), measurement of the maximum alone is sufficient. Unsymmetrlcal bands are recorded by giving the lateral limits, with hyphenation, and the points of equal intensity. Measured values are always recorded directly; calculated values are placed in parentheses, e.g., 640.5..637.5a(634.5}«631i5..621«5. Absorption bands are numbered with Roman numerals, starting at the red end of the spectrum, and their estimated order of intensity (which does not necessarily correspond to the actual Absorption coefficients) is listed, the most intense band being given first. Essential differences in the intensities are indicated by semicolons, thus IV, V, III; I; VI, II. Distinct maxima within an absorption band are named by small letters (starting in the red region of the spectrum) and measured directly or (by measuring equal intensities) calculated. Their place in the order of intensity is marked as follows, e.g I (b,a). Recording of the end of the general absorption in the blue region (abbreviated E.A.) is desirable', since it gives an indication of the concentration of the solution used.11

Synthetic ‘Methods

Pyrroles containing nitrile groups have been

synthesized by at least four methods. The most used

method involves dehydration of the oximes of pyrrole

aldehydes by means of acetic anhydride and sodium acetate

Strain (10) prepared 2-methyl-3-cyan<£>yrrole by ring

synthesis using diacetonitrile and a,p-dichloroethyl

ether. Fischer and Neber (11) refluxed the corresponding

2-bromomethyl derivative with potassium cyanide in

aqueous alcoholic solution to give 2-cyanomethyl-4-

methyl-3,5-dicarbethoxy pyrrole. A unique method of

pyrrole synthesis was reported by Benary (12): 2,6-

dimethyl-4-cyanomethyl-l,4-dihydro-3,5-dicarbethoxy

pyridine underwent ring contraction on treatment with

ethanolic potassium hydroxide to form 2-methyl-4-cyano me thyl -5-car be thoxy pyrrole.

a .a*-Dipyrrylme thanes (also called dipyrr ome thanes)

are of three different structural types: a.a!,p.pf, or

a.p1-linked, as shorn in Figures III, IV, and V. From

the point of view of the chemistry of natural products such as porphyrins or chlorophyll the type represented by formula III is the most important one* In the course of this dissertation compounds of this type are considered almost exclusively. Several methods for their synthesis are known:

a* ‘Action of formaldehyde on a-(or p-) free pyrroles, usually in aqueous or alcoholic media. An acidic agent is required.

b. Acidic condensation of a-halomethyl substituted pyrrole with a- (or p-) free pyrroles.

c. Self condensation of an a-halomethyl pyrrole by prolonged heating in water or alcohol.

d. Fusion of a-alkoxymethyl pyrroles with a-

(or p-) free pyrroles in the presence of potassium hydrogen sulfate.

Of these methods a and c give symmetrical materials while b and d produce unsymmetrical products• Method a has been most widely used*

Dipyrrylmethenes (or dlpyrromethenes) are unsaturated compounds obtainable in the same three structural types given above for the dipyrrylmethanes. Only a.a1-linked compounds, Figure VI, are discussed here. 8

C C - - C----- C

5M c----- 5 M ^ N H H H

a ,a *-Dipyrrylme thane

Fig. Ill

H m\Jm -C- H c - - e N H H

P ,p ’ -Dipyrrylme thane

Fig. IV

C-----Cc - I H MM1 ,c! — ■C- H 11 - C C

a,p'-Dipyrrylmethane

Pig. V 9

- C ■■ 0 -

C: □ H H HBr

a,a1-Dipyrrylmethene

Hydrobranide

Pig. VI

They have been prepared from substituted pyrroles by one of the following methods!

a. The condensation of pyrrole a-aldehydes with a-free pyrroles.

Reaction is promoted by hydrohalogen acids, or perhalogen acids, especially perchloric acid. These agents form well crystallizing dipyrrylmethene salts.

This method is especially valuable for the preparation of unsymmetrical dipyrrylmethenes.

b. The condensation of a-free, a-carboxylated, or a-carbethaxy substituted pyrroles with concentrated formio acid, usually in the presence of mineral acid, especially hydrobromic acid. 10

Only products with symmetrical structure are thus obtained.

c. Reaction of a-free pyrroles with chloromethyl ether#

d. Oxidation of dipyrrylme thanes to dipyrrylmethenes by ferric*chloride, potassium permanganate, or sodium methylate in air.

In practice this method is little used. The same products are usually more accessible by one of the other procedures, particularly method a#

For the synthesis of porphyrins several methods are available. The dipyrrylmethene hydrobromides are usually used; in fact hydrogen bromide is required as promoter of the reaction.

a# Treatment of 5-bromo-5f-bromomethyl dipyrryl methenes with concentrated 3ulfuric acid or formic acid, or with acetic acid under pressure.

b. Refluxing of a.a'-free dipyrrylmethenes with formic acid.

c. Heating dipyrrylmethene 5,5*-dicarboxylic acids in acetic, phosphoric or formic acid*

d. Condensation of equimolar amounts of 5,5!- dimethyl- or 5,5t-dibromcmethyl dipyrrylmethenes with

5,51-dibranodipyrrylmethenes in an acid melt, e.g., of succinic or pyrotartaric acids# 11

e. Coupling a-free pyrroles with aldehydes.

f. Reaction of certain suitably substituted pyrroles.

Only one method (13) can be listed under section f ., namely, the oxidation of a number of 2-methyl-5-carbethoxy pyrroles to the corresponding 2-hydroxymethyl-5-carbethoxy compounds using molar quantities of lead tetraacetate in acetic acid.

Hydrolysis and decarboxylation of these esters yielded porphyrins. In this synthesis the reaction conditions of decarboxylation and porphyrin formation are relatively mild. The other methods mentioned require high heat, or pressure (or both) and often strongly acidic reagents, causing partial decomposition and low yields. 12

Discussion

The reactivity of the nitrile function in pyrroles

and related substances depends on its location with respect

to the pyrrole ring; becoming much less when the group is

attached directly to the pyrrole nucleus. Strain (10)

found that 2-methyl-3-cyano pyrrole was inert to

saponification, reduction (catalytic or with sodium and

alcohol) and to Stephen!s aldehyde synthesis. Fischer and

Rothemund (14) reacted 2,4-dimethyl-3-cyano-5-carbethoxy

pyrrole with sodium hydroxide. Here the ester was

hydrolyzed to give 2,4-dimethyl-3-cyano-5-carboxylic acid

pyrrole, which was then pyrolyzed to 2,4-dimethyl-3-

cyano pyrrole. The reactivity is greater for nitrile ii . . groups in side chains. Fischer and Muller (15) saponified

2.4-dimethyl-3-cyanoraethyl-5-carbethoxy pyrrole to give

2.4-dimethyl-3-acetic acid-5-carboxylic acid pyrrole;

however, Benary (12) obtained 2-methyl-4-cyanomethyl-5-

carboxylic acid pyrrole from 2-methyl-4-cyanomethyl-5- 0 carbethoxy pyrrole. On the other hand, Fischer and Muller

(16) converted the latter pyrrole ester to the 2-methyl-

4-acetic acid methyl ester pyrrole by prolonged treatment

under more vigorous reaction conditions•

From these differences in reactivity of the CN group

as substituent in pyrroles it was obvious that an extension

of these investigations was desirable. It would lead to 13 information concerning the relative stability of the CN group In the side chain. The extent of reactivity of the group could be determined and possibly applied to the synthetic methods given above for preparing porphyrins. It was realized from the beginning that the synthesis of porphyrin's with nitrile function might not be achieved in the light of the reported failures of preceding

Investigators.

Indeed no new cyano substituted porphyrin could be prepared from the starting materials chosen for this investigation. One of the pyrroles used was the 2-methyl-

4-cyanomethyl pyrrole which Senary (17) had prepared

In the very Interesting contraction of the pyridine ring to the pyrrole ring mentioned on page 6. The procedure gave poor yields and it became, therefore, necessary to reinvestigate the reactions involved thoroughly.

This need applied even to the starting material in

Benary's synthesis, p-aminocrotonic acid ethyl ester, which has been prepared by a number of methods, none of which was particularly satisfactory.

It was possible to work out modifications of the preparation of Benary's cyanomethyl pyrrole which gave good yields. This rendered it possible to synthesize not only several pyrroles with the -CHaCN group and desirable 14 other substltuents but also a corresponding compound with two pyrrole rings, namely, a dipyrrylmethene.

As the starting material for the investigations of the behavior of the -CN group attached to the pyrrole ring 2-methyl-3-cyano pyrrole and the corresponding aldehyde, both prepared by Strain (10), were used alone or in combination with Benary's pyrrole; the dipyrryl- compounds Pig. XX, and XXII were prepared. One, Fig. XXII, represents a dipyrrylmethene with both -C1J groups directly attached to the rings; the other one, Fig. XX, with one

-CN group and one -CHaCN group, is a dipyrrylmethane.

Another dipyrrylmethene, Fig. XXIII, was attempted from the aldehyde Fig. XXI, and the isomer of "Weiss" pyrrole,

Fig. XVII. Instead of the compound with one -CN group in the molecule, only the symmetrical dipyrrylmethene, Fig. I could be obtained.

Weiss pyrrole, Fig. XXIV, v/as used to synthesize a number of p 1-subs tituted pyrroles, Figs. XXXIV to XXXVIII.

Chiorome thylation experiments of Weiss pyrrole resulted in the chioromethylated derivative, Fig. XXV.

Some of the pyrroles which were available in the course of this work were subjected to other reactions such as the sulfuryl chloride reaction and the lead tetraacetate oxidation. The resulting products might have been suitable for porphyrin formation as indicated in the literature for 15 compounds without nitrile function. No porphyrin with

CN group was synthesized in the course of this dissertation.

B-Amlnocrotonlc acid ethyl ester.

This ester, the principal starting material for

Benary's synthesis, had been obtained by Collie (18) by passing dry ammonia gas into a solution of ethylacetoacetate in ether. Conrad and Epstein (19) recommended the addition of amnonium nitrate to the reaction mixture to increase the absorption of ammonia. Duisberg (20) had earlier prepared p-aminocrotonic acid ethyl ester by means of prolonged shaking of concentrated aqueous ammonia with ethylacetoacetate.

These methods were superseded in the course of the work for this dissertation by using concentrated aqueous ammonia and ether solution of ethyl acetoacetate. In addition to the convenience of using solutions only, the improved method gave higher yields of a very pure product.

Improved _prep_ara.tl^^of 2.5"dimethvl«4-chloromethyl-l .4- dlhjdr0-3.5-dicarbethoxy pyridine. Fig. VII.

Benary (21) made this compound with 5 g. of p-aminocrotonic acid ester in each run; it proved quite easy, however, to react 100 g. or mare of the ester at one time by using modem apparatus with efficient stirring, controlled rate of addition of reactants and good cooling.

Under these conditions, the order of addition was found 16 to be Immaterial, but 100% excess of o,p-dichloroethyl ether gave much better yields.

In Benary's investigation 10$ ammonium hydroxide was used to moderate the reaction temperature which otherwise causes decomposition of the product and to assist in driving the reaction by reacting with hydrogen chloride generated during the condensation. I found that the ammonia undergoes a side reaction with the a,p-diehioroethyl ether. This does not decrease the yield, but the products formed decrease the quality of the desired product. In addition the side reaction is itself exothermic. Distilled water proved to be just as satisfactory a diluent for the reaction, if one uses Benary's quantities of materials, and does not detract from the purity of the pyridine compound. One can even dispense with such a diluent if efficient stirring and effective external cooling are employed.

An attempt was made to substitute a,p-dibromoethyl ether for the dichloro-compound; however the desired

2,6-dimethyl-4-bromomethyl-l,4-dihydro-3,5-dicarbethoxy pyridine was not formed. 17

H CHaCl

HoC80aC — C C ■ COaCaH5

HaC -.! C - CHa “N H

2,6-Dimethy1-4-chioromethy1-1,4-dihydro ■ 3,5-dicarbethoxy pyridine

Pig. VII

H CHaCN HeCaOaC - - COaCaH0

H3C - !

2,6-Dimethyl-4-cyanomethyl-l,4-dihydro- 3,5-dicarbethoxy pyridine

Fig. VIII

NCHaC - C C - H

H„CaOaC - 0 CI. - CHa H

2-Me thyl-4-cyanomethyl- 5-carbethoxy pyrrole

Pig. IX 18

Improved preparation of 2,6-dimethyl-4-cyanomethyl-l.4- dlhydro-3.5-dlcarbethoxy pyridine. FIr . VIII.

In preparing the pyridine derivative, Pig. VIII, Benary

(17) heated the corresponding chloromethyl derivative,

Pig. VII, for 5 hours with KCN. He obtained not only the desired e'xchange of chlorine by - CN, but also a ring contraction to the pyrrole, Pig. IX, as side reaction. He converted the crude mixture of pyridine derivative and pyrrole derivative directly into the acid, Fig. X. Details for the experimental technique to obtain this acid were not reported, and it was therefore, necessary to reinvesti gate the conditions of this ring contraction. Prior to this study it could be shown (experimental part, page 52) that the pure cyanomethyl pyridine derivative was obtainable with reaction times as short as 30 minutes, instead of

5 hours.

The conditions for ring contraction, and improved prepara tion of 2-methyl-4-cyanomethyl-5-carbethoxv pyrrole. Pip:. IX.

For the ring contraction (Fig. VIII to Pig. IX) the critical factors were found to be the length of reflux time and the concentration of alkali. The pure cyancuiethyl pyridine derivative could not be converted quantitatively if the reflux time was shorter than approximately 10 minutes even at alkali concentrations of about 10/6. On the other 19 hand the use of low alkali concentrations for long times yielded only partial conversion into the pyrrole derivative.

In the latter case simultaneous hydrolysis of the ester group in the a-position of the pyrrole derivative was always observed under formation of the potassium salt of the carbolxylic acid, Pig. X.

It could also be shown that the overall yield of the ring contraction to form the pyrrole ester, Fig. IX, or the pyrrole carboxylic acid, Pig. X (as potassium salt) was greatly improved when the pyridine derivative, Fig. VIII, was isolated rather than to use it in the form of the crude mixture of the compounds represented by Fig. VIII and IX.

The yield was related to the degree of dryness of the ethanol used as solvent. It dropped from about 75$ with anhydrous alcohol to about 60$ with 95% ethanol. The kind of alcohol was also critical: Substitution of anhydrous methanol for ethanol resulted in other reaction products.

While it was possible to improve experimental procedure and yield in the ring contraction, the mechanism of this surprising reaction could not be elucidated in spite of the detailed investigation of the reaction products.

Hew method for preparing 2-methyl-4-cyahomethyl pyrrole.

FI*. XX.

A new method was developed which simultaneously hydrolyzes and decarboxylates the pyrrole ester to give 20 a purer product in improved yield as compared with that obtained with the original procedures.

The original reference (22) describes the decarboxy lation of the pyrrole carboxylic acid, Fig. X, by distilla tion from solid potassium hydroxide or from a mixture with sand, the*latter being preferred. In this connection no yield is given; therefore in order to evaluate the new procedure the decarboxylation with some sand was performed several times.

Table I

Comparison of the new method with that of Benary.

Product Yield Melting Range

Benary's Procedure:

Pig. X 65$ overall 45-52$ 70-85*

Pig. XI 70-80$

New method:

Fig. XI 70-85$ 85-88* 21 NCHgC - I C------IC - H HOOC - C 5 - CH»

2-Me thy1-4-cyanorae thyl- 5-carboxylic acid pyrrole

Fig. X

NCHa C - C C - H

H -.! C. .C - CHa *N H

2-Methyl-4-cyanomethyl pyrrole

Fig. XI

NCHSC - C Ci - H Br - C. - CHa ‘N H

2-M e thy 1 -4-c yan ome thy 1 • 5-brorao pyrrole

Fig. XII 22 Improved synthesis of £-methyl-A--£-V&iiQmeJ3iyl - 5-carboxy lie acid pyrrole. Fig. X.

At length a method was devised for obtaining tills compound In about 65$ yield. This and the quality of the product were found to be somewhat proportional to the purity of starting material. Prior to neutraliza tion of the potassium salt of the pyrrole carboxylic acid, it is essential that both the reaction mixture and the mineral acid used be thoroughly chilled. The carboxylic acid formed must be freed from residual acid without too much delay, or the product decomposes.

Synthesis of 2-methvl-4-cyanoinethyl-5-bromo pyrrole.

Fig. XXL,.

Bromination of a-methyl a'-free pyrroles has been one of the most used methods (23) for preparing brominated dipyrrylmethenes which are suitable for direct conversion to porphyrins. As a result it is one of those general reactions which is applied to all such new pyrroles. tr . . Fischer and Muller (24) report the synthesis of a compound analyzing for 2-methyl-4-cyanomethyl-5-bromo pyrrole.

After a new method for preparing 2-methyl-4-cyanomethyl pyrrole had been devised, it was desired to verify the formation of the correct compound by brominating the reaction product to the compound of Fischer and Muller.

Their directions led only to insoluble tars. By varying the concentration of reagents and the experimental 23 conditions somewhat, however, a product was obtained which analyzes for CyHyNgBr, the molecular formula for the reported substance. In contrast to this, the new material has a different color, different solubility characteristics and melts at 184-5° as compared with 167*.

Preparation ,o£ 2-tnethyl-4-cyanomethyl-5-formvl pyrrole.

Fig. XIV.

This new pyrrole was prepared by the L dams -Levine (25) modification of the Gattermann aldehyde synthesis. The original Gattermann method involved the use of anhydrous hydrogen cyanide; whereas in the modification zinc cyanide and anhydrous hydrogen chloride gas, which are much safer to handle, are used, and the zinc chloride formed causes the reaction to proceed. YJhen potassium cyanide was used instead of the zinc cyanide, no reaction occurred. Many of the older preparations of aldehydes by the

Gattermann method used a mixture of equal volumes of anhydrous ether and anhydrous chloroform. Fischer and

Zerweck (26) found that in general chloroform without the ether could be used; in some instances the yield was greater. In the preparation of 2-methyl-4-cyancanethyl-5- formyl pyrrole by the modified method, anhydrous chloroform is just as effective as anhydrous ethyl ether. 24

H - C C - CHaCN 1 HOOC - C Cl UN - H

2-Chloro-3-cyanomethyl- 5-carboxylic acid pyrrole

Pig. XIII

NCHaC - C C - H

OHC - C_ JZ - CHa *N‘ H

2-Methy1-4-cyanomethy1 ■ 5-formyl pyrrole

Fig. XIV

CN NC I H - C- ■C - CH« h 8c - C C C - H

H H aC - J3- -C- J LCH a H N‘ H H

5,51-Dimethy1-3,3 1-dicyanomethyl dipyrrylme thane

Pig. XV 25

Resistance of 2-methvl-4-cyanomethyl-5-formvl pyrrole to oxidation and Its failure to undergo the Cannizzaro reaction.

Since hydrogen in the alpha positions of pyrroles is easier substituted than hydrogen in the beta positions, the assumption that the Gattermann synthesis just reported yielded the a-aldehyde seemed amply justified. Yet it seemed desirable to confirm the structure of the pyrrole aldehyde by oxidizing it to the known 2-methyl-4- cyanomethyl-5-carboxylic acid pyrrole. This particular oxidation had obviously taken place during one preparation of the aldehyde, because the pyrrole carboxylic acid was isolated as one of the by-products of the reaction.

The oxidation of the formyl group to carboxyl with both potassium permanganate, and hydrogen peroxide was tried; only unreacted starting material could be isolated in these cases.

This pyrrole aldehyde likewise failed to undergo the Cannizzaro reaction which would be expected to yield the carboxylic acid as one of the two principal products.

Mixed melting point and elemental analyses definitely demonstrated that the compound obtained as product was identical with the initial reactant. This resistance of pyrrole aldehydes to alkali was not surprising, since

Fischer and Zerweck (26) had encountered the same inertness of the formyl group. 26 Synthes la or 5.5«-dimethyl_-5 .5 V-dlcxanomg.thympyrr^l- me thane. FI k *. 3C£*

2-Methyl-4-cyanomethyl pyrrole and 2-methyl-4- cyanomethyl-5-formyl pyrrole were condensed in methanol using hydrobromic acid. As this is cne of the standard methods for preparing dipyrrylmethenes, it was surprising to find that the reaction product was the corresponding dipyrrylmethane which had been previously prepared by

Senary (28) from 2-methyl-4-cyanomethyl pyrrole and formaldehyde. As far as could be determined this is the only reported instance of the formation of a dipyrrylmethane from the condensation of a pyrrole aldehyde and an a-free pyrrole.

During the reaction a small amount of the aipyrryl- methene was formed as indicated by the reddish brown color and by the spectrum of the solution. In order to explain, however, the formation of the dipyrrylmethane as main product it seems necessary to postulate elimination of formaldehyde from the pyrrole aldehyde, this formaldehyde then would cause the dipyrrylmethane formation in the normal manner* For the formation of the dipyrrylmethane, or dipyrrylmethene, the amount of water present in the reaction mixture is critical. Thus the same dipyrrylmethane was formed along with the desired dipyrrylme thene when 27

2-methyl-4-cyanomethyl pyrrole was reacted with the corresponding formyl pyrrole in 9 2 % formic acid. On the other hand, in 9 & % formic acid the dipyrrylmethene is the only product.

Efforts to condense 2-methvl-4-cvanomethvl pyrrole with

2 .4-dimethyl-5-carbethoxy pyrrole *

Even in the presence of the cyanomethyl substituted pyrrole with one free alpha position the aldehyde, Fig.

XVIII, underwent self-condensation. This tendency of the

2 .4-dimethyl-3-carbethoxy-5-foimyl pyrrole is well known

(27) .

Wher the 2-methyl-4-cyanomethyl-5-formyl pyrrole was reacted with 2,4-dimethyl-3-carbethoxy pyrrole, Fig. XVII, the symmetrical dipyrrylmethene from the latter again was the only product. Similar examples were found in the literature; for instance, only 3,31,5,51-tetramethyl-

4,4,-dicarbethoxy dipyrrylmethene was obtained from

2.4-dimethyl-3-ethyl-5-formyl pyrrole and 2,4-dimethyl-

3-carbethoxy pyrrole (28).

Preparation of new dipvrrvl-compounds.

When 2-methyl-3-cyano pyrrole was condensed with 2- me thyl-4-cyan ome thyl-5-f ormyl pyrrole, or when 2-methyl-

3-cyano-5-formyl pyrrole was reacted with 2-methyl-4- cyanomethyl pyrrole, only the unsyrametrical dipyrrylmethane,

Fig. XX, was obtained. 28 The following table shows the combinations of a-free

pyrrole and pyrrole aldehyde which were tried in order to

prepare new dipyrrylmethenes with nitrile function.

Table II

New dipyrrylmethenes

Illustra Reactant Melting tion a-Free pyrrole Pyrrole aldehyde point IIIIIIISII IKIlSIBStSBSSrSSSS :s:s:sss5siaiii8iai Pig. XVI 2-Me thyl-4-c vano- 2-Me thyl-4-cyano- hydrobromide methyl pyrrole methy1-5-f ormyl sintered pyrrole Pig. XXII 2-Methyl-3- 2-Me thy1-3-cya no- I’ree me thene cyano pyrrole 5-formyl pyrrole sintered

In each case dipyrrylmethene formation took place as evidenced by the color of the solution, absorption spectra, and solubility characteristics. The materials were recrystallized and their behavior at the melting point determination is included in the table. The elementary analyses of this group of dipyrrylmethenes presented difficulties as shown in the experimental part.

Oxidation of - CN substituted pyrroles with lead tetraacetate (13).

Siedel and Winkler prepared a number of 2-hydroxymethyl-5-carbethoxy pyrroles from the corresponding 2- methyl-5-carbethoxy pyrroles by oxidation with 1 mole lead tetraacetate per mole of pyrrole. These pyrrole esters could be hydrolyzed to the 2-hydroxymethyl-5-carboxylic acid pyrroles which were, in most cases, readily convertable 29

CN NC I I H • c CHa HaC - C C - H I •HBr |C - u .0* ■ C' JJ. CHa *N H H

5,5 '-Dimethyl-3,3' -dicyanome thyl dipyrrylmethene hydrobromide

Pig. XVI

HaC - C ■C - COaC aH 0

H - C. C - CH3 ■N H

2,4-Dimethyl-3-carbethoxy pyrrole

Fig. XVII

HaC - C C — COaCaH c

OHC - C!. J- CHa N' H

2 , 4-D ime thy 1 - 3 - c firb e thoxy- 5-formyl pyrrole

Pig. XVIII 30

- CN

H - c X3 - CH3 H nN H

2-Methyl-3-cyano pyrrole

Pig. XIX

NC - G - H HoC - C - H

H HaC - •C- -c - CHa J H

5 , 51 -D im e thyl-4-cyan o-3'-cyan one thyl dipyrrylraethane

Fig. XX

H - C G - CN

OHC - - CHa

2-Methyl-3-cyano-5-formyl pyrrole

Fig. XXI 31

NC - C i- H H - C* CN HaC - •Ci i j:CHa ■N- H H

5,5'-Dime thyl-4,4 '-dicyano dipyrrylme thene

Pis. XXII

NC - C C - H - COaC aH 0

HaC .! ! - CHa

IIBr

3 * ,5,5 '-Trimethyl-4-cyano-4 f-carbethoxy dipyrrylmethene hydrobromide

Fig. XXIII

HaC ------•c C -- H

HaC aOaC - CHa *rJ. H

2,4-Dimethyl-5-carbethoxy pyrrole

Pig. XXIV 32 to porphyrins in good yield. The following pyrroles with

- CN group were reacted with lead tetraacetate in analogous procedure to test them for the formation of new porphyrins containing the nitrile group:

a. 2-methyl-4-cyanomethyl-5-carbethoxy pyrrole,

available from the reinvestigation of Benary’s pyrrole

synthesis,

b. 2,4-dimethyl-3-cyano-5-carbethoxy pyrrole, readily

prepared by methods described in the literature, and c. 2,4-dimethyl-3-cyanomethyl-5-carbethoxy pyrrole,

prepared by a n e w method which is discussed hereafter.

In preparation for these experiments, Siedel and

Winkler’s synthesis of etioporphyrin I, 1,3,5,7-tetramethyl-

2,4,6,8-tetraethylporphyrin from 2,4-dimethyl- 3-obhy1-5- car be thoxy pyrrole was repeated. The reactions proceeded exactly as described in comparable yield.

When the above nitrile pyrroles were treated with lead tetraacetate, the desired reactions failed to take place; even increasing reaction time and temperature did not cause oxidation. Prom compound a. only unreacted starting material was isolated. Repeated experiments gave negative results. Prom one experiment with b. a few milligrams of material was isolated which, after crystallization from ethanol, analysed for CnHaoO^N*. 33 Obviously the oxidation with lead tetraacetate did not stop at the stage of the hydroxymethyl group; in spite of molar ratios used, it proceeded to form the aldehyde from a small portion of the pyrrole used. The solvent in the purification procedure was responsible for the acetal formation, and the diethyl acetal of 2-formyl-4- methyl-3-cyano-5-carbethoxy pyrrole, Fig. XXXII, resulted. It should be mentioned here that the formation of formyl pyrroles from a-methyl pyrroles by oxidation with lead tetraacetate has been reported as requiring two moles of the oxidant per mole of certain pyrroles (13).

Of the three pyrroles used 2 ,4-dimethyl-o-cya:.omethyl-

5-carbethoxy pyrrole (case c) would ceexn most likely to react because of its structural similarity to the 2,4- dimethyl-4-ethyl-5-carbethoxy pyrrole. Yet even with long reaction times the isolation of a definite pure reaction product could not be accomplished. It is Interesting to note that while Siedel and

Winkler were not able to prepare porphyrin from each of their 2-hydroxymethyl-5-carboxylic acid pyrroles (especially not from some of the p or p,p1-unsubstituted ones), they experienced no difficulty in the oxidation reaction with lead tetraacetate* 34

Sulfurvl chloride reactlong# In the hands of Fischer and his students chlorination

with sulfuryl chloride was a very fruitful reaction. Depending upon reaction conditions and ratio of reagents

the products included ring bound halogen or contained

it both in the nucleus and in the side chain. Reaction

occurred preferably in the a-position both in nuclear and

the side chain chlorination. This offered a general method

of converting a-methyl substituents to hydroxymethyl, formyl

or carboxylic acid groups.

As Fischer pointed out (29) it was often not possible

to isolate the intermediate halomethyl derivative. In

these cases the halogen compound was hydrolyzed, and the

corresponding hydroxy, or other derivative, was isolated. In general the method involves much tedious labor

in the isolation of the reaction products; since most

pyrroles are sensitive to acid, they have to be freed

carefully from all traces of the hydrogen chloride fornned

during the reaction.

With considerable difficulty Fischer and Rothemund

(30) prepared 2-hydroxymethyl-4-methyl-3-cyano-5-carbethoxy

pyrrole from the corresponding 2,4-dimethyl-5-cyano-5-

carbethoxy pyrrole. Several of the pyrroles prepared in

the present research were reacted with sulfuryl chloride

in an effort to obtain this hydroxymethyl type of product 35 which proved unobtainable by the lead tetraacetate roaction.

a. The results of the reaction varied: 2-methyl-4- cyanomethyl-5-carbethoxy pyrrole, Pig. IXj was unreactive with 1 to 6 moles of sulfuryl chloride. b. On the other hand 2,4-dimethyl-3-cyanomethyl-5- carbetho'xy pyrrole, Fig. XXVT.i , reacted with 1 mole of

SOaCla within a few seconds to yield c:loromethyl pyrrole derivative, Pig. XXVIII. Its analysis for carbon (53.6#) was in poor agreement with the theoretical value, 54.9#; however, the hydrogen and nitrogen analyses were satis factory. Proof of the structure shown in Fig. XXVIII was given by conversion to the known 4,4T-dimethyl-3,31- dicyanomethyl-5,51-dicaroethoxy dipyrrylmethane, Fig. XXIX, on hydrolysis (see page 78).

c. Chlorination of 2,4-dimethyl-3-cyano-5-carbethoxy pyrrole, Fig. XXXI, with 1 mole sulfuryl chloride resulted

In the corresponding 2-chloromethyl derivative, Fig. XXXIII, for which the carbon analysis was likewise poor; values of

49.7# and 50.8# were obtained (compared with an expected

53.0# carbon). Here again the analytical data for hydrogen, nitrogen and chlorine were acceptable.

It was hoped that these two chioromethyl homologues could be converted into the corresponding hydroxymethyl compounds, which were of interest in connection with forma tion of porphyrin by the method of Siedel and Winkler (13). 36

As stated above, 2-chloro-3-cyanome thyl -4-methyl -5- carbethoxy pyrrole gave only the corresponding symmetrical dipyrrylmethane. In the other case (c) no hydrolysis was attempted, due to the poor yield of the reaction.

d. 2-Methyl-4-cyanomethyl pyrrole, Pi:;. XI, reacted readily with sulfuryl chloride to form a subs Lance which analyzed for C7He0aNaCl and was soluble in alkali. It is most likely the 2-chloromethyl-3-cyanomethyl-5-carboxylic acid pyrrole, Fig. XIII. In another experiment with different ratio of chlorinating agent and pyrrole, Pig. XI, a transient material with a w 11 defined three-handed spectrum in acetic acid was observed. The disappearance of the pink color in the presence of ether was probably due to oxonium type salt formation between the ether oxygen and the pyrrole derivative. The experiment was repeated several times, but in these the colored substance failed to form.

Preparation of 2.4-dimethyl-3-chloromethyl-5-carbethoxy XXV v

The chlorcmethylation reaction is applicable in the furane series (31) , but Its use in the pyrrole series has has not been reported. In general, reaction of pyrroles containing unsubstituted a or p positions with formaldehyde and hydrochloric acid in water solution leads to dipyrrylme thanes. This is true, for example, for the 37

HaC - C----- C - CHaCl

H8Ca0*C - I I - CHa H

2,4-Dimethyl-3-chloromethyl- 5-carbethoxy pyrrole Fig. XXV

H HaC - C C------C------C-----C - CHa

H6CaOaC - C .0 C - CH-CHa H HaCHSC - CM ftC - COaCaH0 N H H

2,21,4 ,4 *-Tetramethyl-5,5'-dicarbethoxy d ipyrrylme thane

Fig. XXVI

HaC - C-----C - CHaCN

HeC*0aC - C J!j - CH® H

2 ,4-Dime thyl-3-cyanome thyl- 5-carbethoxy pyrrole

Fig. XXVII 38 formation of the symmetrical dipyrrylmethane, Pic* XXVI, from 2,4-dimethyl-5-carbetoxy pyrrole, Fig. XXIV. (32)

It was found that chloromethylation in the free R-position of the latter pyrrole could be accomplished by using paraformaldehyde, anhydrous hydrogen chloride gas and glacial ucetic acid (non aqueous solvent). The structure of the chloromethylation product (Fig. XXV) was established by conversion to the known 2,4-dimethyl-3-cyanomethyl-

5-carbethoxy pyrrole, Fig. XXVII, with potassium cyanide

(see below) and to 2,2',4,4f-tetramethyl-5,51-dicarbethoxy dipyrrylinethane, Fig. XXVI, mentioned above. This chioromethyl pyrrole, Fig. XXV, also formed an addition product with pyridine. Fischer and lie be r (33) reported a similar molecular compound between pyridine and 2- bromomethyl-4-methyl-3-propionic acid-5-carbethoxy pyrrole.

Since the investigation was limited to pyrroles with nitrile function, no effort was made to determine the applicability of this method of chloromethylation to pyrroles in general.

New synthesis of 2.4-dimethyl-3-cyanomethyl-5-carbethoxy pyrrole. Fig. XXVII.

This substance was previously prepared by Fischer and Neber (11) who dehydrated 2,4-dimethyl-3-acetaldoxime-

5-carbethoxy pyrrole with sodium acetate and acetic anhydride.

In the new procedure the chlorine atom of the chloro- v 39 methylated pyrrole, Fig. XXV, was replaced with the - CN group by dissolving the starting material in ether and shaking with an aqueous solution of potassium cyanide, as Fischer and Neber (11) had done with 2-bromomethyl-

4-methyl-3-propionic acid-5-carbethoxy pyrrcle. The usual method of refluxing the halogen substituted pyrrole with potassium cyanide in aqueous ethanol was not applicable here, since under these conditions the chloromethyl compound condensed with itself to form the symmetrical dipyrrylmethane, Fig. XXVI.

The identity of the cyanomethyl pyrrole was established by elemental analysis, because none of the compound prepared by the known procedure was available for comparison.

2. ._4-Dlme thyl— 3- cvano-5-carbethoxy pyrrole. Fig:. XXXI.

This pyrrole, like its cyanomethyl homologue, was desired as starting material for oxidation v/ith lead

tetraacetate and for reaction wit;, sulfuryl chloride.

Fischer, Weiss and Schubert (34) had previously prepared it in small quantities by dehydrating 2 ,4-dimethyl-3- aldoxime-5-carbethoxy pyrrole, Fig. XXX, with sodium acetate and acetic anhydride, Their method was extended without difficulty to the preparation of larger quantities of material.

Exchange of Br in 2,4-dimethyl-3-bromo-5-carbethoxy pyrrole against - CN by means of potassium cyanide was 40

H8C - C -C - CHaCH

HeCa0aC - C ,C - CHbCI ‘N' H

2-Chloromethyl-4-methyl-3-cyanamethyl* 5-carbethoxy pyrrole Pig. XXVIII

CN NC I I H,C - C ■C - CH. HaC -C - CHa H H„CaOaC - C > C ■0* COaCaH0 N H N' H H

4 ,41 -Dime thyl-3 ,3 ’ -dicyanomethyl-5 ,5 1 -dicarbethoxy dipyrrylmethane

Fig. XXIX

H5C - C C - CH = NOH I HoCa0aC - C. .0 - CHa N H

2,4-Dimethyl-3-aldoxime- 5-carbethoxy pyrrole Pig. XXX 41

HaC - C C - CN

h 8c 8o „c - C - CH,3 H

2,4-Dimethyl-3-cyano« 5-carbethoxy pyrrole

Pig. XXXI

HaC - C ----- C - CN

I I , 00aH„ HoC a0aC — C. — C N H x OC.H. H

Diethylacetal of 4-raethyl-3-cyano« 2-formyl-5-carbethoxy pyrrole

Pig. XXXII

H8C - C C - CN

HBCaOaC - ! C ^ ^ CI - CHaCl H

2-Chiorome thyl-4-methyl-3-cyano* 5-carbethoxy pyrrole

Pig. XXXIII 42

tried, although it was realized that the chances for such exchange were very unlikelyj indeed the experiment allowed only starting material to be recovered.

Miscellaneous experiments.

At one time in this research it was planned to prepare

a. 2,4-dimethyl-3-(«£-cyanoethyl)-5-carbethoxy pyrrole, and b. 2,4-dimethyl-3-(*^-cyanopropyl)-5-carbethoxy pyrrole, i .e. homologues of the 3-cyano and 3-cyanomethyl pyrroles previously mentioned, page 39 and 38. These substances were to be reacted with lead tetraacetate and aulfuryl chloride. This work was not completed, but a number of experiments were conducted in this direction. These are discussed below:

1. Attempt to prepare the propionamide of 2,4-dimethyl-

3-propionic acid-5-carbethoxy pyrrole, and to dehydrate it to the nitrile compound given under a.

Fischer and Rothemund (35) had prepared 2 ,4-aimethyl-

3-carboxylic acid amide-5-carbethoxy pyrrole by ring synthesis and then dehydrated it with acetic anhydride to

2,4-dimethyl-3-cyano-5-carbethoxy pyrrole. As starting material far the intended amide synthesis attempts were made according to standard procedures (36) to prepare the acid chloride of the 3-propionic acid pyrrole using thionyl chloride and the ammonium salt of the 3-propionic acid from (1) the propionic acid itself and (2) the 43

HgC - C C - X

H0CaOaC - <1 £ - CH8 N H

Substances derived from Weisa pyrrole, Pig. XXIV.

Pig. XXXIV,X a -COCHaCHa

Pig. XXXV,X = -CHaCHaCH0

Pig. XXXVI,X a -COCHaCHaCHa

Pig. XXXVII, X = -CHaCHaCHaCHa

Fig. XXXVIII, X = -C OCHaCHaC 00H

* 44

propionic acid methyl ester. None of these experiments

were successful; only starting material was recovered.

Another logical route to the desired 3-propionamide

and homologous 3-butyramide pyrroles was by the

Willgerodt reaction on 2,4-dimethyl-3-propionyl-5-

carbethbxy pyrrole, Fig. XXXIV, and 2,4-dimethyl-4-

butyryl-5-carbethoxy pyrrole, Fig. XXXVI.

Note: Turner (37) applied the Kindler modification of the

Willgerodt reaction to 2,4-dimethyl-3-acetyl-5-

carbethoxy pyrrole and obtained the thiomorpholide. These substances .v-ire readily prepared by Friedel-

Crafts reaction of the appropriate acid chlorides with

2.4-dimethyl-5-carbethoxy pyrrole, Fig. XXIV. The pyrroles thus obtained were treated with ammonium poly

sulfide In dioxane in sealed tubes in the usual way (38).

Only negative results were obtained.

2. Clemmensen reduction.

The method successfully used by Johnson (39) on

2.4-dimethyl-3-acetyl-5-carbethoxy pyrrole to give the

5-ethyl compound was applied without difficulty to reduce 2,4-dlmethyl-3-propionyl-5-carbethoxy pyrrole and 2,4-dimethyl-3-butyryl pyrrole to the 3-propyl and

3-butyl derivatives, Figs. XXXV and XXXVII.

3. Succinoylation of 2,4-dimethyl-5-carbethoxy pyrrole. In connection with a proposed synthesis of 2,4- I 45 dime thyl-3-(|£-cyanopropyl)-5-carbethoxy pyrrole, succinic

i anhydride was condensed with 2,4-dimethyl-5-carbethoxy pyrrole using carbon disulfide and aluminum chloride.

The desired compound, 2,4-dlmethyl-3-(Y-ketobutyric acid)- 5-carbethoxy pyrrole, Fig. XXXVIII, was obtained in fair yield. ‘This seems to be the first application of the succinoylation reaction in the pyrrole series. t

i 46 Experimental

Genera^ Remarks on Physical Measurements.

Melting Point Determinations

All melting point data were taken on a Kofler hot stage mounted on a Federal microscope stand at 100 diameters magnification.

Micro-analytical Determinations

All micro-analyses in this dissertation were perfomed by the author. Carbon and hydrogen were determined on a

Sargent Micro Combustion apparatus, while nitrogen was ascertained by the Dumas method. Halogen content was established by Carius procedure (40).

Spectroscopic Measurements

All spectral data were obtained with a Zeiss Universal

Spectrograph for Chemists. 47 Improved synthesis of B-amlnocrotonlc acid, ethyl ester.

In a one liter Erlenmeyer flask was placed 100 g. of ethyl acetoacetate, technical grade, and 250 ml. of concentrated ammonium hydroxide. After the very mild exothermic reaction had subsided, the flask was stoppered and placred in the refrigerator. After about 24 hours beautiful needles, 2-5 cm. in length, of (5-aminocrotonic acid ethyl ester extended throu^iout the reaction mixture.

These needles were removed from the mother liquor by suction filtration, washed with small portions of ice cold water and sucked and pressed as dry as possible.

Note: The filtration was carried out rapidly as the

moisture occluded in the crystals greatly lowered

the melting point.

The crude product was dissolved in ether. This solution was washed with small portions of distilled water, dried over anhydrous sodium sulfate, and vacuum distilled in a modified Claisen flask, / T h e outlet arm of the flask was converted into a short Vigreux c o l u m n ^ The yield of product distilling at 105-110* at 17 ram. Hg was 70-80 g. which was 70-80 per cent of theory.

Improved preparation of 2,6-dlmethyl-4-chloromethyl-l.4- dlhydrg-£.5-dlcarbethoxy pyridine. (A) Fig. VII. 48 a. A 500 ml. 3 neck flask was fitted with a

Hershberg stirrer and dropping funnel. The flask was mounted .in an ice bath since the reaction was exothermic.

In the flask was placed 100 g. of p-aminocrotonic acid

ethyl ester. To this was added dropwise with stirring

100 ml. 'of a,p-dichloroethyl ether (Eastman Kodak No.

1691) during a period of about 30 min. After the addition was complete, stirring was continued for another 15-20 min.

The viscous brown reaction mass was then filtered sharply under suction. The filter cake was v/ashed with several

50 ml. portions of ice cold ethyl ether, and air dried.

The yield of canary yellow colored crude product, melting

at about 125-130®, was 55-70 g. which is approximately

50-60$ of the theoretical amount.

Note: The impurities were quite soluble whereas the

desired product was almost insoluble in cold ether.

b. Reversed order of addition of reagents.

Several experiments were made in which the p-amino-

crotonlc acid ethyl ester was added to the a,p-dichloro-

ethyl ether. In none of these experiments was the yield

of collidine derivative appreciably different from that resulting from the procedure given in part a above.

o. Effect of varying the proportions of reagents.

(1) Use of theoretical proportions.

In a typical experiment ten g. (0.077 mole) of p-aminocrotonic acid ethyl ester was placed in a 150 ml. 49 Erlenraeyer flask. To this was added all at once 5.5 g.

(0.039 mole) of a,p-dichloroethyl ether. The mixture

turned opaque white. It was then covered immediately

with sixty ml. of 10# ammonium hydroxide solution.

Within a few minutes a vigorous exothermic reaction set

in. The* initial white color successively changed through

cream, yellow, and orange to yellow brown in a matter of

seconds. Simultaneously the reaction temperature rose

rapidly so that the ammonium hydroxide solution (upper

layer) boiled. On cooling the desired product precipitated

as a brownish semisolid mass. T;Is was suction filtered,

the filter cake washed with cold ether, and the product was air dried. The yield was 3 g. which is about 25#

of the theoretical amount. (2) Effect of fourfold the theoretical amount

of a,p-diehioroethyl ether.

Two experiments we.'e run, each Involving 10 g.

(0.077 mole) of p-aminocrotonic acid ethyl ester and

21.8 g. (0.153 mole) of a,p-dlchloroethyl ether. These

resulted in 6.3 g. (54#) and 6.1 g. (52#) of the expected

product.

d. Use of ammonium hydroxide as a diluent.

As shown by Benary (21) using the proportions given

in part a and using 10 per cent ammonium hydroxide as a

diluent the yield of the desired product was 50-60#. 50 e. Use of dilute hydrochloric acid as a diluent.

Eleven g. (0.077 mole) of a,p-dichloroethyl ether was added to 10.0 g. (0.077 mole) of p-aminocrotonic acid ethyl ester in a 150 ml. Erlenraeyer flask. The mixture was then covered with 60 ml. of 10/s aqueous hydrochToric acid solution. In this experiment the reaction was noticeably less exothermic and the dark color accompanying the use of dilute ammonium hydroxide was absent. The product was isolated in the usual way.

The yield of air dried canary yellow needles, m.p. 125-

130*, was 3.15 g., 27$ of theory.

f. Use of distilled water as diluent.

An experiment identical with that given in part e except that distilled water, rather than 10$ HC1, was used to cover the reaction mixture resulted in 6.6 g. of the desired product melting from 125 to 130#. In this experiment as in those in parts a and e above, the dark colors accompanying the use of ammonium hydroxide did not appear. The crude product remained yellow in color through out and on standing.

g. Study of the by-products from the preparation of 2,6-dimethyl-4-chloromethyl-l,4-dihydro-3,5-dicarbethoxy pyridine.

Into each of ten 100 ml. Erlenmeyer flasks was placed

10 g. (0.077 mole) of p-amino crotonic acid ethyl ester,

11.0 g. (0.077 mole) of a,p-dichloroethyl ether, and 60 ml. 51 of 10% ammonium hydroxide in the regular fashion. After

4 hours the muddy brown colored reaction mixtures were combined and suction filtered. The crude crystalline product and the aqueous filtrate were separately extracted with cold ether, and the extracts then combined. The ether was distilled off at atmospheric pressure from a Claisen flask. Water was added to the residue, and distillation was continued. A colorless mixture distilled at 96-8® at

735 mm. Hg. The non-aqueous layer (18.1 g.) was taken up in ether, dried over anhydrous sodium sulfat e and redis

tilled through a 12-lnch Vigreux column, at the reduced pressure given by a water aspirator. The main fraction

(about 16 g.) distilled at 64® at 24 mm. Hg (148® at

737 mm.) The refractive index was N^0 1.415.

h. Action of ammonium hydroxide on a,p-dichloroethyl ether.

To 25 g. of a,p-dichloroethyl ether in a 250 ml.

Erlenmeyer flask was added 100 ml. of 10J& ammonium hydroxide solution. A mild exothermic reaction took place, the temperature reaching a maximum of about 60®C . at the end of 15 min. During this time the mixture turned from cream, orange, and brown to brownish red in color. At near

60# the color change was quite rapid. After standing for two hours the mixture was brownish-black. The reaction mixture was extracted with 50 ml. of ethyl ether, then with 25 ml. more of ethyl ether to give a yellow brown 52 extract; a brown aqueous residue remained. The ether was removed at roor.: temperature under suction, and the residue distilled through a 12-inch Vigreux column, on a hot water bath. The main fraction distilled at 70® at 34 mm. Hg, it boiled between 143 and 150® at 737 mm.

Hg, and had a refractive index of N§° = 1.415.

Replacement of the chlorine atom in (A) by the^nltrile group to form 2 ,6-dlmethyl-4-cyanomethyl-l,4-dihydro-

3 75-dicarbethoxv pyridine. (B) Fig. VIII. modified fror, (17).

A 250 ml. round bottom flask was fitted with a reflux condenser. In this flask was placed 25 g. (0.083 mole) of crude 2,6-dimethyl-4-chloromethyl-1,4-dihydro-

3,5-dicarbethoxy pyridine, 25 g. (0.384 mole) of technical grade potassium cyanide and 55 ml. of 95/» ethanol. This mixture was refluxed in a fume hood for 30 min. during which time the color of the ethanolic solution changed from light yellow to dark yellow brown. The mixture was filtered hot. Together with about 25 ml. of fresh 95^ ethanol, the filter cake was returned to the reaction vessel, refluxed for about 10 min. and filtered hot again. The filter cake was washed with a small amount of ethanol. This wash liquor and the ethanolic filtrates were combined in a 1 liter beaker, and about 600 ml. of distilled water was added with vigorous stirring. After the mixture had cooled to room temperature, the light brown crystals were filtered off, washed with small portions of distilled water, and air 53 dried. Typically the yield of crude product, melting point 100-105* (lit. 106-7) was 20 g., 82$ of the theoretical quantity.

Ring contraction of 2.6-dimetbyl-4-cyanomethyl-

1 .4-dlhydro-5.5-dlcarbethoxy pyridine to form 2-methyl-

4-cyanomethyl-5-carbethoxy pyrrole. Fig. IX. Llpdlfjed from (17).

A mixture of 25 g. of 2,6-dimethyl-4-cyano-methyl-

1.4-dihydro-3,5-dicarbethoxy pyridine, 90 g. of anhydrous

ethanol, and 10 g. of pellet potassium hydroxide (C.P.) was refluxed for 10 minutes in a 250 ml. round bottom flask fitted with a reflux condenser. After cooling

slightly the now light yellow solution was poured with vigorous stirring into about 800 ml. of distilled water

in a two liter beaker. On cooling the pyrrole derivative

prepipitated as white needles. These were collected by

suction filtration, washed with distilled water, filtered

again, and air dried. The usual yield was about 12.5 g.

(75$ of the theoretical), melting at 147-150*.

Simultaneous hydrolysis and decarboxylation of 2 -methyl-

4-cyancmethyl-5 -carbe thoxy pyrrole resulting in 2-methyl-

4-cyanomethy 1 pyrrole. Fig. XL,

Into a 100 ml. flask fitted with a reflux condenser was plaeed 10 g. of 2-methyl-4-cyanomethyl-5-carbethoxy

pyrrole, 6 g. potassium hydroxide (pellets), 50 ml.

distilled water and about 4 g. 95$ ethanol. This mixture 54 was refluxed for 36 hours. Initially the solution was homogeneous; later two layers developed. The reaction mixture was chilled in the refrigerator, suction filtered, washed with a little distilled water, and air dried.

The yield of crude material melting at 85-86° was 5-6 g. which is’ 80-95$ of the theoretical amount#

The crude material was recrystallized from ethanol- water until the melting point was constant, 89-90°.

Mixed melting point of this product with the pyrrole obtained from 2-methyl-4-cyanomethyl-5-carboxylic acid pyrrole by Benary's procedure (22) showed no depression.

Analysis Calculated for Found C 7H 8Nb (1 2 0 .2 ) Carbon 70.0 69.6

Hydrogen 6.7 7.0

Hltrogen 23#3 23.6

The above procedure was in yield and quality of product superior to the method given in the literature (22).

The latter uses distillation of the pyrrole carboxylic acid over solid potassium hydroxide or over sand. For comparison the distillation over sand was performed, and

70-80 per cent of the theory of the decarboxylated pyrrole was obtained. The product was of poor quality and melted between 70 and 85°. 55 Bromlnatlon of 2-me thvl-4-cyahometh;yl pyrrole

a. The directions for broraination given by Fischer and Muller (24) were followed carefully. About 0.5 g.

2-methyl-4-cyanomethyl pyrrole was dissolved in 1 m l . of glacial acetic acid. To this was added 4 ml. of glacial acetic acid containing 2 g. of bromine. Contrary to the reference the evolution of hydrogen bromide was steady but not vigorous. Likewise a precipitate did not form immediately. Rather it was approximately 30 min. before a solid began to appear. This was filtered, washed well with glacial acetic acid and ether, and allowed to dry in air. On standing the initial product gradually decomposed to a black, insoluble, unmelting mass. Duplica tion of the procedure, given in the above reference, was thus not achieved.

b. By variation of reaction conditions a satisfactory bromination product was obtained. In 5 ml. of glacial acetic acid was dissolved 0.5 g. 2-methyl-4-cyanomethyl pyrrole. After this solution had cooled in an ice bath, to a semisolid mush, a solution of 2.0 g. of bromine in

5 ml. of glacial acetic acid was added portionwise during a five-minute period with continued cooling and intermittent shaking. Within two minutes a precipitate fonned. This was suction filtered immediately and washed several times with distilled water to yield 0.21 g. of white product melting with decomposition at 163-7#C . 56

Note 1. If the reaction mixture is allowed to warm to room temperature, It darkens rapidly and the

precipitate tends to dissolve. Note 2. The crude material sublimed in part beginning

at approximately 135*C. to give a material melting

at ’182-4* C .

The brominated pyrrole is readily soluble in ether, hot chloroform, acetic acid, acetone, ethanol, methanol

and dioxane. It is moderately soluble in hot benzene and

insoluble in petroleum ether and water.

For analysis the crude product was recrystallized

from ethanol-water until the melting range was constant

at 184-5®C

Analysis Calculated for Found C 7H 7NaBr (199.1)

Carbon 42.2 41.6

Hydrogen 3.54 3.7

Nitrogen 14.1 14.3

Bromine 40.2 40.8, 39.9

ti The product of Fischer and Muller is compared with the new material in Table III. 57 Table III

Comparison of the bromination product with

the material reported by Fischer and M&ller.

n Item t Fischer and Muller

Color J V/hite Yellow

Solubility [Readily soluble in Relatively insoluble 'ether and acetic in ether and acetic acid iacid. ______L______» Melting range j184-5* 167#

Analytical j identical results i L r Crystal form • Silken, feathery Needles i needles.

Synthesis of 2-chloro-5-cyanomethyl-5-carboxylic acid pyr role. Fig. XIII. from 2-methyl-4-cyanomethyl pyrrole.

A solution of 5 g . (0.042 mole) 2-methyl-4-cyanomethyl pyrrole in 75 ml. anhydrous ethyl ether was }3laced in a

500 ml. 3-neck flask which had been fitted with a mechanical

stirrer and a dropping funnel. The third neck was vented

through a calcium chloride tube. For cooling the flask was surrounded with an Ice bath. After the solution had cooled to 10# , 23.5 g. (0.174 mole) sulfuryl chloride was added dropwise with stirring during the next 20 minutes.

Once the addition was complete the flask was stoppered and left overnight in a refrigerator. The ether solution, to which fresh ether was added from time to time to maintain 58 the volume, was extracted with about thirty successive

20 ml. portions distilled water until it was neutral to Congo red test paper. On evaporation of the ether the yellow-brown oily residue was suspended in water. After several hours, crystallization occurred. The crude product melting at 155-160* was readily soluble in acetone, ethanol, hot glacial acetic acid, hot ethyl acetate, and b % sodium carbonate solution, moderately soluble in ether and cold ethyl acetate, and insoluble in petroleum ether, ligroin, water, benzene, and chloroform.

After successive recrystallizations from acetone-chloroform, a product melting at 180-181®, was obtained.

Analysis Calculated for Found C OjjNjgC 1 (184.6)

Carbon 45.6 45.5

Hydrogen 2.73 3.0

Nitrogen 15.2 15.1

Chlorine 19.2 19.3

Oxygen 17.3 -•

Conversion of 2-methyl-4-cyanomethy1 pyrrole into a substance having a three banded spectrum.

To a solution of 1,0 g. (0.0083 mole) of the pyrrole in 10 ml. of anhydrous ethyl ether was added 2.55 g.

(0.019 mole) sulfuryl chloride. Heat was evolved, and the solution turned reddish-brown. After being warmed 59

on the steam bath for 20 seconds the mixture was placed

in a refrigerator overnight. This solution was then

diluted with 75 ml. of ether. In the ensuing extraction with distilled water, the aqueous extract became

reddish-browr. while the ether solution remained straw

yellow in color. After about ten 15 ml. portions of

distilled water had been used, it was noticed that the

residue on the stirring rod used to test the acidity

of the ether layer was changing from dolorless to rose

on exposure to air. The spectrum of this colored residue

in glacial acetic acid was I 539-(5o3.5)-528; II

515-(508)-501; III very faint - 480; 409 E.A. II, I;

III. The spectrum of the aqueous extract was I 501-(482.0)

462.5; 419 E.A. The rose hued substance with three

banded spectrum became colorless injether or its vapor

but reverted to the colored form on further exposure to

a i r .

On standing the ether solution gradually lost its

ability to give this colored material.

Note: Several experiments made to obtain additional

amounts of this substance were unsuccessful.

The ether solution, to which ether was added from

time to time to maintain the volume, was washed with about ten additional 15 ml. portions of distilled water until it was neutral to Congo red test paper. After

evaporation of the ether, the residue was boiled In water 60 for about 20 minutes to give a reddish brown mass, soluble in ether and ethanol, and a nearly colorless aqueous solu tion, which was placed in the refrigerator overnight.

About 50 mg. of cream colored needles, melting at 140-150*, with partial sublimation beginning at 110*, was filtered off, washed with ice water and dried in air. The crude product was easily soluble in ethanol, dioxane, amyl acetate and acetone. It was moderately soluble in hot benzene and nearly insoluble in ether and chloroform. The amount of material was insufficient for purification.

Attempted lead tetraacetate oxidation of 2-methyl-4- cyanomethyl-5-carbethoxy pyrrole.

A 500 ml. three neck flask was fitted with a mechanical stirrer, a thermometer and a calciun chloride tube, and 5 g. (0.026 mole) 2-methyl-4-cyanomethyl-5- carbethoxy pyrrole was dissolved in 150 g. of glacial acetic acid. In the course of a half hour 11.5 g.

(0.026 mole) freshly prepared lead tetraacetate was added in approximately 1 g. portions with vigorous stirring.

The reaction mixture was maintained at 25-35* for an hour, then at 55-60* for another hour, and finally at 90* for

3 hours. By means of a water aspirator the acetic acid was removed at 40-50*. The brown viscous residue was dissolved in 30 mi. of chloroform, and this solution was extracted with distilled water, first with 40 ml., then 61 with two 10 ml. portions . After it had been dried over anhydrous sodium sulfate, the chloroform solution was concentrated to about 10 ml. The semi-solid residue was extracted with ether, and the solution filtered.

The crude residue was recrystallized three times from benzene and yielded, then, white needles w ich melted at 148-150*. Mixed melting point with 2-methyl-4- cyanomethyl-5-carbethoxy pyrrole showed no depression.

Analysis Calculated for Found CioHiaOaNa (192.2)

Nitrogen 14.6$ 14.5$

Hydrolysis of 2-methyl-4-cyanomethyl-5-carbethoxv pyrrole to the corresponding 5-carboxvlie acid. Fig. X.

Five g. pyrrole ester, 25 ml. 95$ ethanol and 3 g. of potassium hydroxide (pellets) was placed in a 50 m l . flask and refluxed for 24 hours. The potassium salt of the pyrrole carboxylic acid soon began to precipitate.

After the reaction mixture had cooled, the salt was removed by filtration from the mother liquor, washed with a little 95$ ethanol and dried. The impure salt, about five g., was placed in about 25 ml. distilled water; the solution was stirred for a short time, and filtered to remove a small amount of insoluble material (chiefly unhydrolyzed starting material). After thorough chilling in the refrigerator, the solution was carefully neutralized 62 with cold 10$ sulfuric acid. The colloidally precipitated crude acid was filtered, washed acid-free to Congo red with distilled water, and dried. Usually about 2 g. of crude product charring at about 260° (65$ of the theoretical) was obtained. Synthesis of 2-methyl-4-cyanomethyl-5-formyl pyrrole ,

Fig. XIV, by the Adams-Levine modification (25) of the

Gattermann method.

A three neck 250 ml. flask was fitted with a gas entry tube, a gas-tight Hershberg stirrer and a reflux condenser with a calcium chloride tube. The entire apparatus was placed in a hood because of possible HCH fumes. Into this flask was placed 10 g. (0.083 mole) of 2-inethyl-4-cyanomethyl pyrrole, 110 g. chloroform which had been dried over calcium chloride, and 13 g.

(0.11 mole) of zinc cyanide, technical grade. The reaction mixture was cooled in an ice bath under stirring to less than 10#; anhydrous hydrogen chloride gas was introduced with continued stirring to prevent a temperature rise above 10# . At the end of about an hour the stirrer became stalled by a sticky reddish-brown colored precipi tate . The introduction of hydrogen chloride was then stopped, and the reaction mixture was allowed to stand over night at room temperature. In the morning the mixture was again cooled; then hydrogen chloride was rapidly passed 63 through the reaction mixture for 15 to 20 min. while the vessel was shaken intermittently by hand. After this period the flask was allowed to stand for several hours in an ice bath. The colorless supernatant liqxxor was decanted; the precipitate was taken up in 100 ml. of cold distilled water and filtered quickly. The residue was suspended tv/ice more in 50 ml. of water and filtered.

After the total filtrate had been combined, it was warmed to about 60* on the steam bath to complete the hydrolysis of the imine hydrochloride. On standing the aldehyde precipitated as pinkish needles. After filtering, washing with distilled water and drying in air, 7-3 g. of aldehyde were obtained, 55-65^o of the theoretical yield. The needles melted at 202-6® with sublimation. The pyrrole aldehyde was readily soluble in hot ethanol, acetic acid, hot isopropanol, methanol, acetone and hot ethyl acetate, and moderately soluble in boiling water and hot dioxane.

The solubility was quite low in cold water, cold dioxane, cold ethyl acetate, ether, chloroform and benzene. For analysis the crude product was purified by recrys talliza- tion from boiling water, then from dioxane followed by vacuum sublimation. This gave white needles melting at

217®. 64 Analysis Calculated for Found C eH aNaO (148.2)

Carbon 64.9 64.7

Hydrogen 5.44 5.5

Nitrogen 18.9 19.0

Oxygen 10.8

Note 1: One experiment was made using potassium cyanide

rather than zinc cyanide. No reaction occurred.

Note 2: During the hydrolysis of the inline hydrochloride,

some unreacted starting material could be recovered

by extracting the water insoluble residue with ethyl

ether.

2,4-Dinitrophenylhydrazone of the

pyrrole aldehyde (41).

To a solution of 0.5 g. 2 ,4-dinitrophenylhydrazine

in 30 ml. of 95>1 ethanol containing 1 ml. concentrated hydrochloric acid was added 0.25 g. of the aldehyde.

The mixture was refluxed for 15 min. until the solution was homogeneous. Later an orange-red precipitate was

filtered off. After recrystallization from acetone-alcohol

the derivative, on heating was still solid at 350®.

Oxime of the pyrrole aldehyde (41).

A mixture of 0.5 g. 2-methyl-4-cyanomethyl-5-formyl pyrrole, 0.5 g. hydroxylamine hydrochloride, 1 ml. of 65 pyridine and 10 ml. of 95^ ethanol was refluxed for 1,5 hours in a 2 5 ml. Erlenmeyer flask fitted with an air condenser. The ethanol was then removed by evaporation on a water bath. When cool, the residue was taken up in

10 ml. of distilled water, filtered and dried. This crude product was recrystallized from e tkanol-v/ater until the melting point remained at 272-3®.

Analysis Calculated for Found C eH e0Na

Carbon 58.9 58.9^

Hydrogen 5.56 5.3

Nitrogen 25.7 26.0

Oxygen 9.8

Attempts to convert 2-methyl-4-cyanomothyl-5-formyl pyrrole to 2-methyl-4-cyanomethyl-5-carboxvlic acid. a. Using potassium permanganate (42).

To a suspension of 0.25 g. of the aldehyde in 10.5 ml. of 0.5^ sodium hydroxide solution, 5)j aqueous potassium permanganate was added portionwise until a pink color persisted. The solution was then made acid to Congo red test paper and treated with 10?o sodium hydrosulfite solution to convert the manganese oxide to soluble manganese sulfite.

The insolubles were filtered, washed and air dried. This material melted at 212-4° with partial sublimation. Mixed 66 melting point with 2-methyl-4-cyanomethyl-5-formyl pyrrole

showed no depression.

b. Using hydrogen peroxide. (42).

A mixture of 5 m l . of 5?o sodium hydroxide and 6 ml.

of 3^0 hydrogen peroxide was heated to 65°, 0.25 g. of

the pyrrole aldehyde was added and heating, at 65°, was continued for 15 min. Th^ mixture was cooled in an ice bath to 5® and acidified with 10£> sulfuric acid. The product, after filtration, washing and drying, melted at 208-10° with partial sublimation. Mixed melting point with the starting material showed no depression. c. Attempted Cannizzaro reaction,

A suspension was prepared fro;. C.25 g . £-methy1-4- cyanomethyl-5-formyl pyrrole and 2.5 ml. of 50;J potassium hydroxide. Prolonged standing or heating produced no reaction.

Synthesis of 5.51-dimethyl-5.51-dlcyanomethyl dipyrryl- r.e thane. Elg- *V. In 15 ml. of methanol in a 50 ml. Erlenmeyer flask v/as dissolved 1.00 g. (6.S millimoles) 2-r.;ethyl-i-cyanome thyl-5-f ormyl pyrrole and 0.81 g. (6.8 millimoles) of

2-methyl-4-cyanomethyl pyrrole. After the dropwise addition of 1.0 ml. of an aqueous solution containing 48/a by weight of hydrogen bromide, a condenser was attached and the reac tion mixture was refluxed xor 15 minutes. During this 67 period the color changed from straw-yellow to dark red.

The pinkish-red platelets which formed on standing were filtered, washed with 50$ methanol, and air dried. These platelets, melting at 280-290*, weighed about 1,0 g.

On recrystallization from ethanol-water the condensation product melted at 320-325*. Mixed melting point with

5,5*-dimethyl-3,5 1-dicyanomethyl dipyrrylmethane showed no depression.

Identical treatment of the aldehyde, or of the a-free pyrrole alone gave no product.

A drop of the original reddish-brov/n mother liquor in ...etnanol-e ther showed a weak absorption spectrum.

I 501-(489)-476; 430 E.A.

Note: All spectral data In this thesis are given in

millimicrons (m^i) .

Synthesis, of 5.5 *-dimethyl-3.31-dicyanomethyl dipyrryl me thene hydrobromide. Fin:. XVI.

For this synthesis 1.48 g. (0.010 mole) 2-v..ethyl-

4-cyanomethyl-5-formyl pyrrole and 1,20 g. (0.010 mole)

2-methy1-4-cyanone thy1 pyrrole was dissolved in 6 ml. of 96% formic acid in a 25 m l . Erlenmeyer flask, and

1,2 ml. 43$ aqueous hydrobromic acid was added. After

Note: The use of 92$ formic acid gave a mixture of the

desired dipyrrylmethene hydrobromide and the symmetrical dipyrrylmethane. 66 some time the semi-solid mass was suction filtered, washed with a small quantity of foraic acid, then with 20% ethanol, and finally dried. One obtained 1,7 g. of beautiful purple-black microscopic needles, which sintered at about 220# , but which did not melt as high as 350*.

The dipyrrylmethene hydrobromide was quite soluble in hot acetic «.cid and formic acid and insoluble in water, ether, benzene and chloroform. The spectrum in glacial acetic acid was I 501-(485)-468; 415 E.A.

For analysis the crude dipyrrylmethene hydrobromide was recrystallized three times from aqueous ethanol.

Analysis Calculated for Calculated for Found Cj.BH l4N4 .HBr (Ca.BHl4K4 )a ‘HBr (331.1) (581.5)

Nitrogen 16.9 19.3 19.1, 19.4

Bromine 24.1 13.7 13.0, 13.6

Attempted preparation of 5.5.51-trimethyl-4-carbethoxy-

3* —cyanomethyl dipyrrylmethene hydrobromide.

a. From 2-methyl-4-cyanomethyl-5-ffcrmyl pyrrole and 2,4-dimethyl-3-carbethoxy pyrrole.

Three ml. of 9 4 formic acid was placed in a 25 ml.

Erlenmeyer flask. In this was dissolved with warming

0.444 g. (0.0030 mole) 2-methyl-4-cyanomethyl-5-formyl pyrrole and 0.501 g. (0.0030 mole) 2,4-dimethyl-5-carbethoxy pyrrole. With vigorous agitation 0.4 ml. 4 3 % hydrobromic acid was then added dropwise. After several hours, purple 69 red iridescent needles were removed by filtration, washed first with a little glacial acetic acid, then with ethyl ether, and allowed to dry. The product appeared aqua and yellow-brown when examined microscopically under polarized light. After recrystallization from ethanol the product melted at 211-215®. The picrate was prepared and recrystallized from ethanol. This derivative melted at

194-6®.

The spectrum of the dipyrrylmethene hydrobromide dissolved in glacial acetic acid was taken:

I 478-(470.5)-463; 440 E.A.

On treatment with ammonium hydroxide the free dipyrrylmethene was formed from the corresponding hydro bromide. This crude product melted at 180-190®.

By mixed melting point this dipyrrylmethene hydrobro mide was shown to be identical with known SjSjS'jS1- tetrameth.yl-4,4 1 -dicar. ethoxy dipyrrylme thene hydrobromide .

(43). The spectrum of a solution of this known dipyrryl methene in ethanol was

I 478.5-(471.3)-464.0; 408 E.A.

Under the same reaction conditions as used for the above dipyrrylmethene synthesis the 2-rnethyl-4-cyanomethyl-5-formyl pyrrole alone did not form dipyrrylmethene.

b. Using 2,4-dimethyl-o-caruethoxy-5-formyl pyrrole and 2-methyl-4-cyanomethyl pyrrole. 70

A mixture of 1.00 g. 2-methyl-4-cyanomethyl pyrrole, 1.62 g. 2, 4-dime thyl-3-carbethoxy-5-l’ormyl pyrrole, 1 ml. of 48^o hydrobromic acid and 30 ml. of methanol was refluxed for two hours. The product which separated on s tanding was shown by mixed melting point to be identical with

3,5,31,51-tetramethyl-4,4’-dicarbethoxy dipyrrylmethene hydrobromide. Preparation of a dipyrrylmothane from 2-methvl-4-cyanomethyl-5-f ormyl pyrrole and 2-methyl-5-cyano pyrrole .

Flit. XX.-.. To a solution of 1.48 g. of the pyrrole aldehyde and

1.06 g. of the a-free pyrrole in 5 ml. of 96p formic acid was added 1.2 ml. of 40)o hydrobromic acid. Immediately the reaction mixture became semisolid. The orange brown crystal® were filtered, washed with hot glacial acetic acid and dried in air. The crude product did not melt but sintered at about 235-40* with darkening from about 205°.

A drop of the mother liquor in glacial acetic acid showed the following spectrum although a solution of the substance obtained showed none:

I 511-(505)-498....443; 404 E.A,

The compound was soluble in hot glacial acetic acid, dilute hydrochloric acid, and pyridine, moderately soluble in hot ethanol and almost insoluble in water, chloroform, benzene and acetone. In spite of much effort 71

the dipyrrylmethane could not be recrystallized

satisfactorily from any solvent or combination of solvents.

As a result the unpurified initial product was subjected to elemental analysis:

Analysis Calculated for Found c 14h 14n * (238.3)

Nitrogen 23.5 25.1, 28.2

Formation of a dipyrrylmethene from 2-methyl-5-cyano

pyrrole. Fip:. XXII.

a. Preparation of 2-methyl-3-cyano-5-formyl

pyrr ole (10) , Fig. XXI.

The Adams-Levine modification (25) of the Gattermann

aldehyde synthesis was used for

6.0 g. 2-nethyl-o-cyano pyrrole, 13 g. zinc cyanide,

45 m l . anhydrous ether

and 45 ml. anhydrous chloroform ,

and yielded 3.85 g. (57)o) 2-methyl-5-cyano-5-formyl pyrrole, melting at 191-6°.

b. Preparation of dipyrrylmethene.

A mixture of 0.75 g. 2-methyl-5-cyano pyrrole and

0.95 g. 2-methyl-3-cyano-5-formyl pyrrole was dissolved in

4.5 ml. of hot 96$> formic acid. After the addition of

1.0 ml. of 48^a hydrobromic acid to the cooled solution a pinkish brown precipitate formed immediately. This was 72 filtered and washed with acetone. The spectrum of the

crude product in glacial acetic acid was found to be:

I 509-(484)-459; 408 E.A. This substance did not melt but gradually turned black

beginning at about 210*. It was soluble in pyridine and

hot 96/j formic acid and nearly insoluble in water,

acetone, ethanol, methanol, chloroform, ether, benzene ethyl acetate and acetic acid.

Since satisfactory crystals of the dipyrrylmethene

could not be obtained when it was dissolved in any

combination of the above solvents, the original product

was used for analysis.

Analysis Calculated for Pound

(222.2)

Nitrogen 25.2 25.3, 25.7

Br canine - 0.0

Attempted synthesis of a dipyrrylmethene hydrobi^omide from

2-methvl-5-cyano-5-formyl pyrrole and 2.4-dimethyl-5-carbe-

thoxy pyrrole. Fig. XXIII.

A mixture of 1.34 g. (0.01 mole) of the pyrrole

aldehyde and 1.67 g. of the a-free pyrrole were dissolved

in 5 ml. of 92/o formic acid. To this was added 5 ml. of

48^ hydrobromic acid. Immediately a large amount of

beautiful orange precipitate formed. This was filtered

and washed with glacial acetic acid and ether. The crude 73 material melted at 193-6*, and in glacial acetic acid had the following spectrum: I 574.5; II 497.5-(462.0)-427.0; II; I; 407.5 E.A.

It was soluble in glacial acetic acid, hot ethanol, and pyridine, moderately soluble in 9 2 % formic acid, hot bonzene and nearly insoluble in ethyl ether, acetone and water.

After recrystallization from formic acld-benzene the dipyrrylmethene was analyzed.

Analysis Calculated for Pound CigHgoNgO^Br (425.3)

Bromine 13.8 19.1, 19*7

Mixed melting point with 3,3 ' ,5,51 -totramethyl-

4,4'-dicarbethoxy dipyrrylmethene hydrobromide showed no depression.

Chloromethvlation of ”Weiss11 pyrrole . 2.4-dimethyl-5- carbethoxy pyrrole. a. 2,4-Dimethyl-5-carbethoxy pyrrole, Pig. XXIV.

”Knorr pyrrole”, 2,4-dimethyl-3,5-dicarbethoxy pyrrole,

(44) was selectively hydrolyzed with concentrated sulfuric acid and decarboxylated with sand.

b. Chloromethylation, Pig. XXV.

A 500 ml. 3 neck flask was fitted with a gas entry tube, mechanical stirrer, and a dropping funnel and was vented through a calcium chloride tube. The apparatus 74 was placed in a fume hood and the flask was packed In an

ice hath. Six g. (equivalent to 0.20 mole formaldehyde)

paraformaldehyde was suspended in 75 ml. of glacial

acetic acid. To this, with stirring and rapid introduc tion of anhydrous hydrogen chloride, was added dropwise

in 15 minutes a solution of 33.4 g. (0.20 mole) of

"Weiss1' pyrrole in 200 ml. of glacial acetic acid, after

the cherry red reaction mixture had been stirred for another

30 minutes under ice cooling, it was poured into about

one liter of ethyl ether, and placed in the refrigerator.

After 24 hours crystals began to form slowly. Precipita

tion was judged to be complete after three days. The pink

product was suction filtered, washed with a little ice

cold benzene, then with ethyl ether, and air dried. This material, 14.4 g. (36/6 of theory), melted at 150-151®.

It was readily soluble in hot benzene, acetone, chloroform

and hot carbon tetrachloride, moderately soluble in boiling

ethyl ether, and virtually insoluble in ice cold ethyl

ether, petroleum ether, water or ligroin.

For analysis a portion of the chloromethylated product was recrystallized from benzene, until the melting point was 164-6®. 75

Analysis Calculated for Found C i 0HX4NC1 (215.7)

Carbon 55.6 55.4

Hydrogen 6 .69 6.5

Nitrogen 6.54 6.6

Chiorine 16.4 15.3

Oxygen 14.8

Conversion of 2 .4-dimethyl-5-chloromethyl-5-carbethoxy pyrrole to 2 .2!.4.4'-tetramethyl-5.51-dicarbethoxy dipyrrylmethane. Fin. XXVI. In 3 m l . of 95/b ethanol was dissolved 0.167 g. of the chloronethylated pyrrole. To this was added dropwise with stirring 1 ml. 10,2 hydrochloric acid and 5 nl. water. Within seconds a colloi al white precipitate formed. In order to coagulate the precipitate the mixture was warmed on a steam bath for a few minutes, and left undisturbed for three hours. The reaction product was filtered care fully through quantitative filter paper, washed with dis tilled water, and dried. The amount obtained melted at

227-29*, and weighed 0.134 g. (theoretical yield). The identity of this compound with 2,2’,4,41-tetramethyl-5,51 - dicarbethoxy dipyrrylmethane was established by mixed melting point determination. 76 Condensation of 2.4-dimethyl-3-chlorotnethvl-5-carbetheory

pyrrole and pyridine.

When 0,550 g. (2.55 millimoles) 2,4-dimethyl-3-

cnloromethyl-5-carbethoxy pyrrole was dissolved in pyridine, there was slight evolution of heat and t'ne reaction mixture Became turbid with a white amorphous precipitate.

This was filtered off, washed with several small portions

of fresh pyridine, and dried. The crude product, melting at 168-170a , weighed 0.727 g. ( = theoretical yield).

The product was very soluble in water, but insoluble in benzene, acetone or pyridine.

Analysis Calculated for Found CiB^XB^aNaCl (294.8) Nitrogen 9.47 9.70

Chlorine 12.0 11.2, 11.9

Synthesis of 2 .4-dimethyl-5-cyanomethyl-5-carbethoxy pyrrole. Fig. XXVII. from the corresponding 5-chloromethyl compound.

Ten g. (0.046 mole) 2,4-dimethyl-3-chloromethyl-5- carbethoxy pyrrole was suspended in 150 ml. of ethyl ether in a 500 ml. separatory funnel. This mixture was shaken for about 10 minutes with a solution of 10 g. (0.155 mole) potassium cyanide in 25 ml. of distilled water. During this time the suspended pyrrole went into solution forming a light yellow ether layer which quickly became colorless. 77

^.fter separation, the ether layer was washed three times with 20 ml. portions of distilled water. On evaporation of the ether solution to dryness, a light yellow-brown residue, melting at 150-157®, was obtained. This crude product weighed 9.2 g. which is 96/» of the theoretical amount..

The crude material was purified by recrystallization first from benzene, then from ethanol-water and gave beautiful white needles melting at 162-163°. A melting point of 163° has been reported for this pyrrole, obtained by a different method (11).

Analysis Calculated for Found Ci x Hj,402M8 (206.2)

Carbon 64.1 63.8

Hydrogen 6,84 6.84

Nitrogen 13.6 13.3

Oxygen 15.5 attempted oxidation of 2 .4-dimethyl-3-cyanomethyl-5- carbethoxy pyrrole to the corresponding 2-hydroxymethyl derivative.

A solution of 4,50 g. 2 ,4-dimethyl-3-cyanomethyl-5- carbethoxy pyrrole, melting at 157-9°, in 135 ml. of glacial acetic acid was placed in a 500 ml. three-neck round bottom flask fitted with a mechanical stirrer and a thermometer and vented through a calcium chloride tube.

To this was added with vigorous stirring 9.7 g. lead 78 tetraacetate. After the reaction mixture had stood for

38 hours at room temperature, the lead tetraacetate had reacted completely (shown by absence of lead dioxide when the reaction mixture was tested with chloroform- water) .

Note: One run was made in which the temperature was

maintained at about 90° during the reaction period.

Nothing but tars were isolated.

After the mixture had been transferred to a Claisen flask, the acetic acid was removed at 30-35° using a water aspirator. The residue was taken up in cnloroforn-water, and the water layer was extracted twice with small portions of chloroform. The combined chloroform layer and extract was then washed with small portions of water, filtered through anhydrous sodium sulfate and evaporated to dryness.

The yellow residue, melting at 100-110°, v/as soluble in hot ethanol, hot methanol, hot benzene, and hot acetic acid.

After extraction with ethyl ether, to remove the starting material, the crude substance v/as recrystallized from methanol-water. The resulting product melted over a range from 130-150°. Further recrystallization from glacial acetic acid gave a material melting at 123-150°.

Use of other solvents or solvent pairs showed no improvement in purity. 79

Preparation of 2-chloromethyl--4-»methyl-5-cyanomethyl-5-

carbethoxy pyrrole. Fig* XXVIII*

Five g. (0.024 mole) 2,4-dimethyl-5-cyanomethyl-5-

caroethoxy pyrrole was dissolved In 50 ml. of anhydrous

chloroform. To this solution was added under vigorous

stirring‘3.8 g. (0.028 mole) sulfuryl chloride. Within

thirty seconds a reaction began. The solution darkened,

sufficient heat was evolved to bring the solution to

boiling and a tan colored solid precipitated. On standing

two or three minutes the mother liquor changed to a

greenish color.

The solid was removed by suction filtration, washed

i'irs b with a little fresh cold chloroform then with a

small amount of cold ethyl ether. This washing removed

the adhering color, leaving the filter cake a delicate

cream color. The yield of crude product v/as 3.8 g. (59p)

of microscopic needles melting sharply at 178-18C®.

This pyrrole was readily soluble in acetone, ethanol, methanol, moderately soluble in hot benzene, hot chloroform

and slightly soluble in water, cold ethyl ether, petroleum

ether, and ligroin. On recrystallization from any one of

the above solvents or any solvent pair, the melting range broadened and became lower. Because of this difficulty

the initial crude product was used for analysis. 80 Analysis Calculated for Found CxlKxaCsNaCl (240.7)

Carbon 54.9 53.6

Hydrogen 5.44 5.6

Nitrogen 11.6 11.3

Chlo’rine 14 .8 14.1, 15.4 Oxygen 13.3

A value of 227 (theory 241) was found for the molecular weight (Micro Rast Method).

Hydrolysis of 2-chloromethyl-4-methyl-5-cyanomethvl-5- carbethoxy pyrrole to 4 .41-dimethyl-3.3*-dicyanomethyl-5.

5 *-diearbethoxy dipyrrylmethane. Fin. XXIX. For this reaction 0.33 g. 2-chloromethyl-4-:..ethyl-3- cyanomethyl-5-carbethoxy pyrrole was refluxed in 12.5 ml. of 15/£ axjueous ethanol for three hours on a steam bath.

The suspension which had formed was cooled and filtered to give 0.25 g. of product, which after washing and drying in air, melted at 120-185°. This was extracted repeatedly with hot benzene, to remove unreacted starting material, leaving a white insoluble residue melting at 182-5°.

This substance was soluble in ethanol, acetone, glacial acetic acid and hot methanol and practically insoluble in water, benzene, petroleum ether and ligroln. It was recrystallized from ethanol-water until the melting range remained at 187-9°. 81 Molecular weight determinations In camphor gave values

of 390 and 381. Mixed melting point with 4,41-dimethyl-

3,3 ’-dicyanomethyl-5,51-dicarbethoxy dipyrrylmethane

prepared from the corresponding bromomethyl compound (45)

showed no depression.

Analysis Calculated for Found

(396.4)

Nitrogen 14.14 13.9

Synthesis of 2.4-dimethyl-5-cyano-5-carbethoxv pyrrole.

Fig. XXXI. from 2.4-dimethyl-3-aldoxime-5-carbethoxy pyrrole. Fig. XXX.

The following table shows the results of experiments

to extend Fischer’s work (46) with small quantities to

larger scale preparations

Table IV

Extended preparation of 2,4-dimethyl-3-cyano-5-

carbethoxy pyrrole

Ischer Substance S* /a% »»,,...... ? Prepared used yield ;; g. r ~ ~ ~ i Sj used yield ------ti""------*•*■- ii Figure XXX 20 95 Si 0.98 not given ii Figure XXXI 7 89 || 0.2 not given ii ii

Attempted oxidation of 2 .4-dlmethvl-5-cyano-5-carbethoxv pyrrole with lead tetraacetate.

a. Using molar amounts of reagent and pyrrole. 82 A 500 ml. round bottom flask v/as fitted with, a mechanical stirrer and vented through a calcium chloride

tube. In this was placed 1,92 g. (0.01 mole) 2 ,4-dimethyl-

5-cyano-5-carbethoxy pyrrole, melting point 167-9*,

and 100 ml. glacial acetic acid. After the pyrrole had dissolved (about 30 min.), 4.43 g. (0.01 mole) lead

tetraacetate was added portionwise with vigorous stirring

over a period of 25-30 min. During the addition no heat was evolved.

After standing overnight at room temperature the

yellow mixture v/as heated at 85° for 30 min., and

the solvent was removed at 45° using a water aspirator.

The residue was taken up in chioroform-water (io),

the water extract was washed tv/ice with small portions.

of chloroform, and these were then combined with the

original chloroform layer. After removal of the chloroform

by evaporation, the residue was recrystallized from

glacial acetic acid-water to give cream colored crystals

melting in a range from 130-150*. No single molecular

species could be isolated, in spite of numerous attempts.

A portion of the crude mixture was refluxed for 15 min. with an excess of 10% sodium hydroxide solution. After

filtration to remove a small amount of undissolved

material, the solution was cooled in an ice bath, and

neutralized with 10$ sulfuric acid. Brown flakes were 83 filtered off, washed with distilled water until the filtrate was neutral to Congo red test paper, and dried. T^is crude product melted over a range beginning at about 210* with partial sublimation beginning at about

150*. The sublimate melted at 253-5* with decomposition.

Mixed melting point with a sample of 8,4-dimethyl-3- cyano-5-carboxylic acid pyrrole s..owed no depression,

b. Using 2 moles of lead tetraacetate per

mole of pyrrole. The oxidation described in part a. was repeated with

0.02 mole lead tetraacetabe and 0.01 mole of pyrrole.

The reaction mixture was heated at 50* for one hour, at 90° for 2 hours and allowed bo stand overnight at room temperature. After hoating to 90® for an additional

8 hours, the crude product was isolated in the manner described in section a. above to give 0.56 g. of light yellow crystals melting at 88-94®. This material was soluble in glacial acetic acid, hot water, ethyl ether, benzene, acetone, chloroform and ethanol, and nearly in soluble in cold water, petroleum ether and ligroin. After three recrystallizations from aqueous ethanol beautiful silken needles melting at 106-108® were obtained. 84

Analysls CalculatedCi4H*oC)*Na for Found (280.3)

Carbon 60.0 59.5

Hydrogen 7.2 6.6

Nitrogen 10.0 10,3

Oxygen 22.8

Synthesis of 2-chloromethyl-4-methyl-5-cyano-5-carbethoxy pyrrole.. Fig. 3QQCIII.

In this experiment 3.0 g. (0.016 mole) 2,4-dimethyl-

3-cyano-5-carbethoxy pyrrole was dissolved in 50 ml. of anhydrous chloroform in a 100 ml. round bottom flask. To this was added all at once with stirring 2.3 g. (0.017 mole) of sulfuryl chloride. The brown solution immediately turned yellow-orange. It v/as refluxed on a water bath for thirty minutes and cooled. In order to isolate the product and to prevent the formation of the oily reaction products the mixture was evaporated to dryness in a stream of air. The residue, 3.57 g., was cream colored with orange red crusts. This crude material, melting at

115-130*, was soluble in ethanol, ether, acetone and chloroform, moderately soluble in hot benzene and nearly insoluble in water, petroleum ether, and ligroln.

Microscopic examination indicated a mixture of materials was present. The desired pyrrole was isolated by fractional extraction with cold benzene in which the impurities were 85 less soluble than the product. A few milligrams of material, melting at 137-9# , was isolated and analyzed.

Analysis Calculated for Pound C*oH n 0 aNaCl (226.7)

Carbon 53.0 49.7, 50.8

Hydrogen 4.89 5.36

Nitrogen 12.4 12.4

Chlorine 15.6 15.2 Oxygen 14.1

Frledel-Crafts synthesis of 2.4-dimethvl-3-pror>ionyl-

5-carbethoxy pyrrole. Fig. XXXIV.

One-hundred ml. carbon disulfide, which had been dried over anhydrous calcium chloride, was placed in a

1-liter flask fitted with a reflux condenser and with a calcium chloride drying tube. To this was added 50 gm.

(0,3 mole) vacuum distilled 2,4-dimethyl-5-carbethoxy pyrrole and 32.5 g. (0.35 mole) fresh propionyl chloride.

During the next 15 min. 52 g. (0.39 mole) granular anhydrous aluminum chloride was added in five or six portions.

Hydrogen chloride gas was evolved vigorously, and the solu tion turned reddish orange. After the reaction mixture had been refluxed for 2.5 hours, a solid cake had formed in the bottom of the flask. The addition product was hydrolyzed by adding 200 ml. of distilled water dropwise through the condenser to the refluxing mixture. After the 86 large lumps had been broken up with a stirring rod, the product was filtered, washed with distilled water and dried. There was thus obtained 68 g. (close to the theoretical yield) of light yellow product melting at

125-135°. After one recrystallization from methanol- water the melting point was 134-8° (47).

Clepimensen reduction of 2.4-dimethyl-3-proplonyl-5- carbethoxy pyrrole. Fig. XXXV.

In a 250 ml. flask was placed 20 g. mossy zinc.

The zinc was etched twice with 25 ml. 10$ hydrochloric acid and amalgamated by shaking for five minutes with a mixture of 20 ml. distilled water, 2.0 g. mercuric chloride and 1 ml. concentrated hydrochloric acid. After the spent liquor had been decanted, 40 ml. of methanol and

5 g. 2,4 -dimethyl-3-propionyl-5-carbethoxy pyrrole was added to the amalgamated zinc. Under refluxing a solution of 10 ml. of concentrated hydrochloric acid in 20 ml. of distilled water was added, followed by tv/o other portions of 2*5 ml. conc. hydrochloric acid at intervals of 1 hour.

After refluxing overnight the hot mixture was filtered, and the residual xinc was washed with a few ml. of boiling methanol. The combined hot filtrate was diluted with hot water until it was slightly turbid and allowed to stand overnight. Later lavender colored needles were filtered off, washed with aqueous 4 0 % methanol, and dried. This first crop, melting at 85-8°, weighed 3.1 g. which is 65$ of the theoretical amount. 87

On repeated recrystallization from methanol-water, white needles were obtained melting at 97-8®. Since no

2,4-dimethyl-3-propyl-5-carbethoxy pyrrole (48) was available for mixed melting point, the pyrrole was

subjected to elementary analysis.

Analysis Calculated for Pound CxaHXoO,N (209.3)

Carbon 68.8 69.1

Hydrogen 9.15 9.13

Nitrogen 6.69 6.4

Oxygen 15.3

Clemmensen reduction of 2.4-dimethyl-3-butyrl-5-carbethoxy pyrrole. Fig. XXXVII.

a. 2,4-dimethyl-3-butyrl-5-carbethoxy pyrrole, Fig.

XXXVI 9 was prepared with a yield of 93/0 by the method of

Fischer and Schubert (49) fro::: butyrl chloride and 2,4-

dimethyl-5-carbethoxy pyrrole with aluminum chloride in

carbon disulfide. The crude material, melting point

111-115®, was recrystallized from methanol-water to give a product melting at 113.5-115®.

b. Reduction,

The butyrl pyrrole was reduced by the same procedure used with 2 ,4-dimethyl-3-propionyl pyrrole. The first

crop of product weighed 3.0 g. (64/£ of the theoretical amount) and melted at 91-3®. For analysis the crude 88 material was recrystallixed from methanol-water until the

melting point was constant at 100.5-101° (50).

Analysis Calculated for Pound

(223.3) Carbon 69.9 69.0

Hydrogen 9.48 9.6

Nitrogen 6.27 6.0

Oxygen 14 *3

Condensation of succinic anhydride with 2.4-dimethyl-3-

carbethoxy pyrrole to form 2.4-dlmethyl-5-(v-ketobutyric

acid)-5-carbethoxy pyrrole. Fig. XXXVIII.

Into a 1000 ml. 3-neck round bottom flask which pre

viously had been fitted with a I-Iershberg stirrer and a

reflux condenser vented through a calcium chloride drying

tube were placed 33.5 g. (0.20 mole) 2,4-dimethyl-5-carbe-

thoxy pyrrole, 21 g. (0.21 mole) succinic anhydride and

275 ml. carbon disulfide (dried over calcium chloride).

The suspension was heated to reflux, and then with vigorous

stirring 58.6 g. of granular anhydrous aluminum chloride

was added portionwise over a period of abcut thirty minutes.

Note: There was no evidence of reaction in the cold. The

evolution of hydrogen chloride became quite steady,

however, when the reaction mixture was refluxed on

a Glasco mantle.

At this point the reaction mixture was a homogeneous

solution. As refluxing continued an orange colored hard 89 precipitate began to form; so the stirrer had to be stopped as the amount of precipitate increased. The heating was continued overnight. Then the red-orange cake was decomposed by the careful dropwise addition of about 200 ml, of distilled water through the reflux condenser. The condenser was then arranged for downward distillation, and the carbon disulfide was distilled from the mixture. After cooling the slurry was filtered off and washed with distilled water to give 32 g. of crude material melting at 120-180*. This product was extracted with several portions of aqueous 5/u sodium hydroxide solution.

Neutralization of the cold alkaline solution gave a white precipitate which v/as readily soluble in methanol, ethanol, isopropanol, acetone, glacial acetic acid and boiling ethyl acetate. It was only poorly soluble in ether, benzene and cold ethyl acetate and insoluble in chloroform and water. The product was recrystallized from ethyl acetate until the melting range was constant at

195-7*. The neutral equivalent of this was found to be

262 (theory 267)

Analysis Calculated for Pound CxaHxrOoN (267.3)

Carbon 58.4 58.1

Hydrogen 6,41 6.7

Nitrogen 5*25 5.4

Oxygen 29.9 90

Summary

1. Improved methods were developed Tor the preparation of the following compounds: a. p-aminocrotonic acid ethyl ester, b. 2 ,6-dimethyl-4-chloromethyl-1,4-dihydro-3,5-

dicarbethoxy pyridine,

c. 2,6-dimethyl-4-cyanomethyl-l,4-dihydro-3,5-

dicarbethoxy pyridine, d. 2-methyl-4-cyanomethyi-5-carbethoxy pyrrole, and e. 2-methyl-4-cyanomethyl-5-carboxylic acid pyrrole.

2. 2-Methyl-4-cyanomethyl pyrrole was synthesized by a new method,

3. From this pyrrole the following substances were synthesized:

a. 2-methyl-4-cyanomethyl-5-bromo pyrrole,

b. 2-chloro-3-cyanomethyl-5-carboxylic acid pyrrole,

c. 2-methyl-4-cyanomethyl-5-formyl pyrrole and its

(l) 2,4-dinitrophenylhydrazone and (2) oxime, 4* A number of new dipyrryl-compounds were prepared, namely a, 5,5'-dimethyl-3,31-dicyanomethyl dipyrrylmethene

hydrobromide ,

b, 5,51-dimethyl-4-cyano-3’-cyanomethyl dipyrryl

me thane

c, 5,5 '-dimethyl-4,4 1 -dicyano dipyrrylmethene. 91 5. Chloromethylation was used for the first time in

the pyrrole series to prepare 2,4-dimethyl-3-chloromethyl-

5-carbe thoxy pyrrole.

6. A novel synthesis of 2,4-dimethyl-3-cyanomethyl-5-

carbethoxy pyrrole from this c-iloromethylated pyrrole was performed.

7. The preparation (46) of 2 ,4-dimethyl-3-cyano-5- carbethoxy pyrrole was extended to a larger scale.

8. Sulfuryl chloride reactions yielded

a . 2-chloromethyl-4-methyl-3-cyanomethyl-5- carbethoxy pyrrole and b. 2-chloromethyl-4-methyl-o-cyano-5-carbethoxy pyrrole.

9. The possibility of oxidizing an a-methyl group in a substituted pyrrole to the a-hydroxymethyl group was investigated in several cases.

10. The diethylacetal of 4-methyl-3-cyano-2-formyl-5- carbethoxy pyrrole was synthesized.

11. Carbon disulfide as solvent is an improvement in the synthesis of 2,4-dimethyl-5-propionyl-5-carbethoxy pyrrole.by the I riedeT-Grafts method.

12. The Willgerodt reaction was unsuccessful with

a. 2,4-dimethyl-3-propionyl-5-carbethoxy pyrrole, and b. the corresponding 3-butyryl pyrrole. 92 13. Clemmenssn reduction was extended to the preparation of

a, 2 ,4-dimethyl-3-propyl-5-carbethoxy pyrrole, and b. 2,4-dimethyl-4-butyl-5-carbethoxy pyrrole.

14* 2,4-Dimethyl-3-(y-ketobutyric acid)-5-carbethoxy pyrrole ’resulted from the succinoylation of 2,4-dimethyl-

5-carbethoxy pyrrole.

15, Several new pyrrole derivatives obtained in the course of this dissertation were subjected to the conditions of possible porphyrin formation. No porphyrin with nitrile function could be synthesized. This finding is in agreement with the reports of other investigators who also observed the extraordinary resistance which the nitrile group imparts on formation of the porphine ring system. Bibliography

Fischer, H., Muller, K., and Leschhorn, 0. "Uber

Keto-phylloporphrine und ihren tlbergang in Desoxo- phyllerythrin-Derivate.n A n n . . 523 (1956), p. 182. n

244 (1936), pp. 45, 50 and 54.

Fischer, H., and Rothemund, P. n^fber Pyrrolnitrile und einige ihrer Umsetzungen." Ber.. 63^ (1930), p. 2250.

Fischer, H., and Wassenegger, H. "Versuche zur synthese von Porphyrinen rnit Nitrilfunktion.I!

Ann. . 46JL (1928), p. 294.

Fischer, H. and Orth, H. Die Chemie des Pyrrols

Leipzig 1934 to 1940, two volumes in three parts

(volume II, part 2, by Fischer, H. and Stern, A.); seized by the Alien Property Custodian, 1943, and reproduced by Edwards Brother, Inc., Ann Arbor,

Michigan, 1943, volume I, pp. 14-18.

Rothemund, P. "Chlorophyll”, Medical Physics. Vol. I.

Chicago: Year Book Publishers, 1944, pp. 155-157.

Reference 5, Band I, p. 21.

Rothenrund, P. "Formation of Porphyrins from Pyrrole and Aldehydes." Am. Chem. Soc ., (1935), p. 2010

"A New Porphyrin Synthesis. The Synthesis of Porphin.

J . Am. Chem. Soc.. (1936), p. 626. 94 9. Reference 6, p. 167. «» 10. Strain, W. H. "Tiber 2-Methyl-3-cyan-pyrrol." Ann. . 499 (1932), pp. 40 ff.

11. Fischer, H., and Neber, M. "Synthesen a-aub3tltulerter Pyrrole." Ann. . 496 (1932), p. 14. 12. Beriary, E., "Elne Synthese von Pyrrol-Verbindungen aus Dihydro-pyridin-Derivaten." Ber. . 53 (1920),

p . 2218.

13. Sledel, W., and Winkler, F. "Oxydatlon von

Pyrrolderivaten rait Bleitetraacetat. Heuartige

Porphyrinsynthesen." Ann.. 5 5 ^ (1942), pp. 162-201.

14. Reference 5, p. 2251.

15. Fischer, H.f and Kuller, A. "Synthese einer 'Jetramethyl-

porphin-tetraessigsaure. Ein Beitrag zuin Konstitu-

tionsproblem des Uroporphyrins." Zh_ physiol. Chem. .

246 (1937), p. 38.

16. Reference 15, p. 41.

17. Reference 12, p. 2220.

18. Collie, J. N. "Ueber die Einwirkung des Ammoniaks auf Acetessigester." Ann.. 226 (1884), p. 301.

19. Conrad, M., and Epstein, W. "Ueber die Einwirkung des Ammoniaks auf Acetesslgester und dessen Derivate."

Ber.. £$,(1887), p. 3054. 2 0 . Duisberg, C. "Beitrage zur Kenntniss dea Acetessig- esters." Ann.. 2^.3, (1882), p. 171. 95

21. Benary, E. "Synthase von Pyridin-Derivaten aus

Dichlor-ather und (3-Amino-crotonsaureester. "

• ♦ Ber., 44 (1911), p. 490; "Uber Pyridin-Derivate aus » tr Dichlor-ather und p-Amino-crotonsaureester, sowie

verwandte Amino-verbindun^en II." Ber. . 51 (1913),

p . *569.

22. Reference 12, p. 2223.

23. Corwin, A. H., "The Chemistry of Pyi-role and Its

Derivatives", Heterocyclic Compounds . Vol. I.

New York: John Wiley and Sons, Inc., 1950, p. 316.

24. Reference 15, p. 42. 25. Adams, R., and Levine, I. "Simplification of the

Gattermann Synthesis of Hydrony Alaehydes." J . Am.

Chem. Soc.. 45 (1925), pp. 2575-7; Adams, R. , and

Montgomery, E. "Simplification of the Gattermann

Synthesis of Aromatic Aldehydes. II," J_s. Am. Chem.

Soc. . 46 (1924), pp. 1519-21.

26. Fischer, H., and Zerweck, V/. "Zur Kenntnis der

Pyrrole, 4. Mitteilung: liber Pyrrol—Aldehyde (II)

und uber Pyrrol-nit rile ." Ber.. 56 (5-923), pp. 519-20.

27. Fischer, H. and Zerweck, W. "Zur Kenntnis der » _ Pyrrole, 1. Mitteilung: Uber Pyrrol-Aldehyde.

Ber. . 55.(1922) . p. 1947. 96

28. Fischer, H., and Schubert, M. "Synthetische Versuche

mit Blutfarbstoff-Spaltproduckten und Komplexsalz-

Bildung bei Dipyrryl-methenen (I. Mitteilung).n

Ber.. 5g (1923), pp. 1209-10.

29. Reference 5, Band I, p. 77.

30. Reference 3, p. 2254.

31. Lutz, R. E., and Bailey, P. S. "The Use of the

Bromo-^md Chloromethylation Reactions in the

Synthesis of Some Dialkylaminomethyl-2,5-diphenyl -

furans.'1 J. Am. Chem. Soc.. £8 (1946), p. 2002.

32. Reference 5, Band I, p. 349.

33. Reference 11, p. 6.

34. Fischer, H. , Weiss, B., and Schubert, LI. "Einige

Umsetzungen des 2,4-Dimethyl-pyrrols•” Ber.. 56r (1923), p. 1200.

35. Reference 3, p. 2257.

36. Shriner, R. L., and Fuson, R. C. The Sv3tematic

Identification of Organic Compounds. 2nd. ed.

New York: John Wiley and Sons, Inc. 1940, p. 132;

Lucas, H. J., and Pressman, D. Principles and Prac

tice in Organic Chantf at-ny. New York: John Wiley

and Sons, Inc., 1949, pp. 302-11.

37. Turner, D. L. *Vflllgerodt-Kindler Reaction with a

Pyrrole." J. Am. Chem. Soc.. J0^(1948), pp. 3961-2. 97 38. Carmack, M. and Spielman, M. A. "The Willgerodt

Reaction", OrFanic Reactions. Vol. III. New York:

John Wiley and Sons, Inc., 1946, p. 96.

39. Johnson, A. Improved Synthesis of Certain Substituted

Pyrrols and Investi^ations of the Chlorophyll in

Datura Stramonium. Pale-7". Dissertation, The Ohio

State University, 1948, p. 39.

40. Niederl, J. B., and Niederl, V. I.Iicromethods of

Quantitative Organic Analysis. 2nd. ed. New York:

John Wiley and Sons, Inc., 1942, pp. 151-60.

41. McElvain, S. M. The Characterization of Orranic

C om pounds . New York: The I.lacliillan Company, 1949,

pp. 198-9.

42. Shriner, R. L. and Puson, R. C. The Sys tematic

Identification of Organic Compounds. 3rd ed. New York:

John Wiley and Sons, Inc., 1948, p. 170.

43. Piloty, 0., Krannich, W., and Will, H. "Zur

Konstitution des Blutfarbstoffs: Dipyrrylmethen-

Derivate mit Farbstoff-charakter, III." Ber. . 47

(1914), p. 2544.

44. Reference 39, p. 35.

45. Reference 15, p. 39.

46. Reference 34, p. 1201. ii 47. Fischer, H., Goldschmidt, M. and Nussler, W. "Synthese

der Tetramethyl-tetrapropyl-porphine I-IV und von

Octo-propylporphin." Ann.. 486 (1931), p. 13. 98 48* Reference 47, p. 20.

49. Reference 5, p. 205.

50. Fischer, H. and Bertyl, M. "Synthase vcn Tetramethyl-

tetrapropylbilirubinoiden, von Tetramethyl-tetrabutyl

porphyrin I, II and IV, von Tetramethyl-tetraisobutyl

porphyrin I, sowie von Tetramethyl-dipropylporpnin-

dipropionsaure XIII." Z. physiol. Chem.. 229 (1934),

*p. 48. •• 99 AUTOBIOGRAPHY

I, Thomas Harvey Curry, was born on October 7, 1921

In Sullivan County, Indiana. My high school education was received at Union High School, Dugger, Indiana, from which I 'was graduated in 1939. In 1942 I received a

B.S. degree in Chemical Engineering from Purdue University.

From 1943 to 1945 I was employed by Holston Ordnance Works,

Tennessee Eastman Corporation at Kingsport, Tennessee.

After attending Antioch College for a brief time as a special student I was employed as research assistant by Dr. Clyde S. Adams at Antioch College from 1946 until

I entered The Ohio State University as a graduate student in September 1947. During the years 1947-1950 I was a

C. F. Kettering Fellow while I completed my courses at

The Ohio State University and began my experimental work towards the degree of Doctor of Philosophy at the Kettering

Foundation at Yellow Springs, Ohio. In the academic years

1950-51 and 1951-52 I was a half-time instructor in chemistry at Antioch College, continuing my experimental work on a part-time basis. Since then I have been completing my thesis research as a Kettering Fellow at the Foundation's laboratories.