MERCAPTOCARBOXYLIC ACIDS AS REAGENTS FOR THE IDENTIFICATION OF CARBONYL COMPOUNDS

Citation preview

INFORMATION TO USERS

This material was produced from a microfilm copy of the original document. While the most advanced technological means to photograph and reproduce this document have been used, the quality is heavily dependent upon the quality of the original submitted. The following explanation of techniques is provided to help you understand markings or patterns which may appear on this reproduction. 1. The sign or "target" for pages apparently lacking from the document photographed is "Missing Page(s)". If it was possible to obtain the missing page(s) or section, they are spliced into the film along with adjacent pages. This may have necessitated cutting thru an image and duplicating adjacent pages to insure you complete continuity. 2. When an image on the film is obliterated with a large round black mark, it is an indication that the photographer suspected that the copy may have moved during exposure and thus cause a blurred image. You will find a good image of the page in the adjacent frame. 3. When a map, drawing or chart, etc., was part of the material being photographed the photographer followed a definite method in "sectioning" the material. It is customary to begin photoing at the upper left hand corner of a large sheet and to continue photoing from left to right in equal sections with a small overlap. If necessary, sectioning is continued again — beginning below the first row and continuing on until complete. 4. The majority of users indicate that the textual content is of greatest value, however, a somewhat higher quality reproduction could be made from "photographs" if essential to the understanding of the dissertation. Silver prints of "photographs" may be ordered at additional charge by writing the Order Department, giving the catalog number, title, author and specific pages you wish reproduced. 5. PLEASE NOTE: Some pages may have indistinct print. Filmed as received.

Xerox University Microfilms 300 North Zeeb Road Ann Arbor, Michigan 48106

L-

LD3907 m - z i ' L w oG7 L o v e r , M y r o n J o r d a n , I 9 2 I4-— 1950 M e r c a p t c c a r b o x y l i c a c i d s as 0L6 reag e n t s for the i d e n t i f i c a t i o n of carbonyl compounds0 N e w Y o r k , 19^4106 typewritten leaves„ tables, • diagrsc 29cm0 T h e s i s (PhoDo) - N e w Y o r k U n i v e r ­ sity, G r a d u a t e S c h o o l , 1 9 5 0 o B i b l i o g r a p h y : p o9 6 - 1 0 6 o

C50661

Xerox University Microfilms, Ann Arbor, Michigan 48106

TH IS DISSERTATION HAS BEEN M IC R O FILM ED E XA C TLY AS RECEIVED.

LIBRARY OF HEW YORK UNIVERSITY UNIVERSITY HEIGHT!3 "V

MERCAPT0CAR30XYLIC ACIDS AS REAGENTS FOR

THE IDENTIFICATION

OF CARBONYL COMPOUNDS

Myron

A

dissertation

in partial Doctor

in

fulfillment

Jordan Lover

the of

department

of

chemistry

the r e q u i r e m e n t s

for

of P h i l o s o p h y a t N e w Y o r k U n i v e r s i t y ,

\

1

History (A)

(B)

Critical review of previous reagents for carbonyl identification.

4

Mercaptals and Mercaptols.

17

III. Discussion (A)

Mercapto-carboxylic acids as reagents for the identification of carbonyl compounds.

(B)

Potentiometric titrations of some bis and tetrakls mercaptocarboxylic acids.

(C)

39

Salts and complex compounds of some thioglycolic icid mercaptals and mercaptols.

IV.

24

Experimental

44 52

Table I

-

Derivatives ofaldehydes

85

Table II

-

Derivatives of ketones

87

Analytic data

90

Table III V.

Summary

95

VI.

Bibliography

96

Mercaptocarboxylic Acids

as R e a g e n t s

for

the I d e n t i f i c a t i o n

of C a r b o n y l C o m p o u n d s

I.

New organic

Introduction

and improved methods compounds

derivatives parameter

now

capable

available

tend

increases

if

measurement,

value

greatly

by

for

derivatives

simple

titration

(1,

data m a y be

obtained.

either

, 9, In

acids

2,

parameter be

of

E a c h new

a

of

quantitative

o f i d e n t i f i c a t i o n is

10,

this

are

5,

6

).

I t is

are known

e a c h case, capable

true

carbonyl data that many

from which

however,

the p r o c e du re s

of g r e a t precision,

u n satisfactory for

such

various

or

other reasons

11). investigation,

as r e a g e n t s

for

is p r o p o s e d .

It has

spontaneously

or

and ketones

4,

compounds In

s e a r c h for

provide molecular weight 3,

lengthy and not

the d e r i v a t i v e s 8

data.

and certainty

and continual

which may

of c a r b o n y l

(7,

the e a s e

purposes

been a long

derivatives

are

the p r e p a r a t i o n

quantitative

additional

of

enhanced.

There has group

this

the i d e n t i f i c a t i o n

to i n v o l v e

of y i e l d i n g

identification; its

for

in

the

th e u s e

identification

long been k nown the p r e s e n c e

to p r o v i d e

of m e r c a p t o c a r b o x y l i c

nearly

of c a r b o n y l

that m e r c a p t a n s

of a catalyst,

quantitative

compounds react,

with aldehydes

yields

of v e r y

stable mercaptals and mercaptols.

By Including a carboxyl

group on the molecule with the mercapto group, carbonyl derivatives may be obtained which have free carboxyl groups capable of being titrated with standard base. There is a small amount of literature on the mercaptals and mercaptols formed by certain mercaptocarboxylic acids. When these old publications were re-examined from this new point of view, the results were promising enough to warrant the present extension and expansion of the work. A systematic study of the reactions of a number of mer­ captocarboxylic acids with carbonyl compounds was planned, in order to find the reagents most suitable for the preparation of derivatives. It was further proposed that enough evidence be gathered concerning the uses and limitations of this class of reagents, and concerning the properties of these derivatives, to permit the establishment of a standard procedure for preparation, purification and analysis of the derivatives. In addition to this primary use of these derivatives, a number of secondary uses seemed worth investigating.

The

specificity of mercaptal and mercaptol formation, and the fact that the derivatives are alkali soluble, suggested that the derivatives could be used for the isolation of carbonyls from natural souroes or reaction mixtures, and for separation of most carbonyls from those which do not react to form mercap­ tals and mercaptols.

-3-

Two additional facts suggested that the derivatives might have uses as reagents for inorganic analysis: (1 )

the derivatives are new, moderately strong polybasic acids, which may have interesting salt forming properties, and

(2 )

the conjunction of divalent sulfur with the carboxylate ion indicates the probability of formation of "inner complexes."

(12 )

The structure of these derivatives also leads to their possible use as germicides in some cases, and penicillin precursors (13) in others.

The latter possible applications,

however, are beyond the immediate scope of this investigation.

II.

(A)

History

Critical review of previous reagents for carbonyl Iden­ tification. To demonstrate the need for new reagents, and to

provide a basis for evaluation of the reagents developed by this investigation, it is necessary to review critically the previous literature on the identification of aldehydea and ketones.

Special attention will be paid to those reagents

and procedures which yield data on molecular weights. It is noteworthy that an overwhelming majority of the reagents proposed for the identification of carbonyl compounds are related to hydrazine.

Phenylhydrazine, the substituted

phenylhydrazines, the aliphatic hydrazines, the hydrazides, and the semlcarbazides are obviously substituted hydrazines;

0-aminoglycolic acid, hydroxylamine and amino-guanidine are at least formally related to hydrazine, since each may be re­ garded as hydrazine with a substituent replacing one amino group. O-aminoglycolic acid (amino oxyacetic acid, carboxylmethoxylamine) was employed by Anchel and the isolation of ketones.

Schoenhelmer for

Its possible use as a reagent for

identification and molecular wdigbt determination does not

*-

seem to have been investigated adequately.

Since O-amino-

glycolic acid is difficult to prepare, its use as a reagent must, in any event, be severely limited.

The method of Borek

and Clarke (15) is the best synthesis of O-aminoglycolic acid, but even when so prepared, the reagent is inordinately expen­ sive. Carboxylmethyl hydrazine (hydrazinoacetlc acid) which was first prepared by Darapsky and Prabhakar (l6 ), was also used by Anchel and Schoenheimer (II4-) for the isolation of ketones. This reagent, too, would seem to have possiblities which have not yet been adequately explored.

Of course, the low molecular

weights of carboxymethyl hydrazine and O-amlnoglycollc acid diminish their possible usefulness as reagents for identification. Aminoguanidine, which was

proposed as a carbonyl reagent

by R. Baeyer (17) in 189)4., no longer seems

to be used

forthat

purpose. The hydrazides generally are not satisfactory reagents for the preparation of derivatives of carbonyl compounds since the derivatives are often not well defined crystalline compounds. PtBeT. Sah seems to have been very active in the inves­ tigation of hydrazides in this

connection, although other

authors are represented in the literature. Ortho, meta and para-nitrobenzene solfonhydrazlde (18)

1-menthydrazide (19 )* ortho-nitrobenzhydrazide (20) metanitrobenz^hydrazlde (21,20a), para-nltrobenzhydrazide (22)

6-

3,5 dlnitrobenzhydrazide (23)# Ortho-bromobenzhydrazide (2I4.) para-bromobenzhydrazide (25 )# meta-bromobenzhydrazide (26) ortho-chlorobenzhydrazide (27 )# meta-chlorobenzhydrazide (28) and para-chlorobenzhydrazide (29 ) have all been proposed as reagents for the Identification of carbonyl compounds. Closely related to the hydrazides are semioxamizide (30) and phenylsemioxamazide (31)•

These form derivatives which

melt too high, and which are difficult to purify. The reagents of Girard and Sandulesco (32, 33# 3k-) t trimethyl (hydrazinocarbonyl methyl) ammonium chloride and l-(hydrazinocarbonylmethyl) pyridinium chloride are hydrazides which have found use only for the isolation of carbonyl com­ pounds.

The derivatives do have a function which is susceptible

to direct titration, but the derivatives are otherwise un­ suited for identification. A large number of substituted phenylhydrazlnes have been proposed as carbonyl reagents, but only a few seem to be of interest. Emil Fischer (35# 36) synthesized phenylhydrazine, and investigated its reaction with carbonyl compounds, including sugars and other alpha-hydroxy carbonyls which form osazones (37). The phenylhydrazones of many low molecular weight carbonyls are low melting, and therefore difficult to purify.

Upon

standing# the phenylhydrazones generally tend to lose ammonia, forming indole derivatives. air.

The reagent itself is unstable in

7-

Beta diketones react with phenylhydrazine to form pyrazolea, although alpha diketones react normally.

The reaction

of other reagents with alpha and beta t'didtetones is of special interest, since, as will be shown later, the mercaptocarboxylic acids do not yield satisfactory derivatives with alpha and beta diketones. Para-nitrophenylhydrazine is a much better reagent than phenylhydrazine (38, 39, ij.0, I|l, ip), since even the lower molecular weight carbonyls yield well defined crystalline derivatives. Furfural and methyl furfural yield good para-nitrophenylhydrazones (I4.3 )• which is interesting since the mercapto­ carboxylic acids fail to yield satisfactory derivatives with furfural•

2 , I4. dinitrophenylhydrazine (Ip, i|5» ip, 14-7) Is especially good for the preparation of derivatives of low molecular weight carbonyl compounds and it also has many uses for the quanti­ tative determination of carbonyls (I4.8 , I4.9 ).

The quantitative

methods permit estimation of the amount of carbonyl compound present, within 10#, but do not permit direct determination of molecular weights. Ortho-nitrophenylhydrazine (50* 3$&) is less useful than the meta (5l> 3^6) and para isomers since it is unstable. 2, 1)., 6 - Trinitrophenylhydrazine has not gained popu­ larity. since its introduction in l89lj.« (52)

A claim has been

made that the melting points in the original paper were in­ accurate (53a)•

-8 -

1-Benzyl, 1-phenylhydrazine (5^,55)» 1-methyl, 1-phenylhydrazine (56, 57), alpha-naphthylhydrazine and beta-naphthylhydrazine (58) ortho-tolylhydrazine (59)» meta-tolylhydrazine (60 ), para-tolylhydrazine (6l) and para-xenylhydrazine (62) have no definite advantages over the other hydrazines pre­ viously mentioned.

The derivatives of the tolyl hydrazines

are unstable. Asym-diphenylhydrazlne (63, 6I4.) is an unstable resgent. Para-thiocyanophenylhydrazine seems to be the newest, and one of the best of the substituted phenylhydrazines. Horii (65) has prepared a large number of para thiocyanophenylhydrazones and is almost entirely responsible for the current acceptance of the reagent. There are a number of phenylhydrazines which would seem capable of yielding molecular weight data by simple titration. Investigation disclosed, however, that these are all unsatis­ factory. Phenylhydrazine-p-sulphonic acid was investigated by Biltz and his co-workers in 1902. (6).

It was then stated

that para-sulfoxylphenylhydrazine reacts with difficulty with aldehydes and ketones and that there is also a tendency to form addition, rather than condensation products.

Veibel (2)

found that phenylhydrazine para-sulphonic acid was not a good reagent for the identification of carbonyl compounds because of its poor solubility.

Finally, the derivatives melt with

decomposition at inconveniently high temperatures (53&) •

-9-

Para-hydrazinobenzoic acid (para-carboxyi-phenylhydrazinefr was first prepared by Emil Fischer (66) in 1882, and has been used fairly extensively as a reagent for aldehydes and ketones (67)*

Anchel and Schoenheimer (ll|.) made use of the

fact that the para-carboxyphenylhydrazones are soluble in aqueous alkali and insoluble in acid.t to isolate certain car­ bonyl compounds.

Their specific interest was the separation

of keto-steroids from other steroidal materials.

Anchel and

Schoenheimer (li|_) have remarked that the para-carboxyphenylhydrazones are autooxidizable, and must be handled in an inert atmosphere. It would seem that the mercaptocarboxylic acids should be strikingly superior to the carboxyhydrazines for the problem enoountered by Anchel and °choenheimer.

This will be discussed

in more detail later. Veibel and Hauge (1) appercelved the possible use of para-carboxy„phenylhydrazine for the preparation of derivatives (of carbonyl compounds) which would permit molecular weight determination by direct titration.

In spite of some obvious

drawbacks, in 1938 this was considered a great advance over previous methods. Veibel and Hauge claim that the derivatives are easy to prepare and purify, and that the titrations yield molecular weights with an accuracy of 0.5# to 1#.

The following serious

objections were pointed out by the authors:

Pirst, decompo­

sition points, not melting points, are obtained, and these are

-1 0 -

at temperatures so high that they are difficult to determine exactly.

Second, since the derivatives are hydrolyzed by

warm acid, carbon dioxide could not be expelled by boiling. The authors claim that for this reason, standard barium hy­ droxide solution had to be used for the titration. In a subsequent paper (2), Veibel (with A. Blaaberg and H. H. Stevens) investigated further the use of para-carboxyphenylhydrazin© and ortho-carboxyphenylhydrazine for the identification of carbonyl compounds.

With beta keto acids,

the ortho isomer reacts normally to yield the hydrazone, ifaile the para compound yields pyrazolones.

The para isomer,

however, reacts normally with acetylacetone while the ortho fields an unidentified substance which is soluble in acid, and insoluble in aLkali.

Both isomers react normally with

alpha and gamma keto acids. The authors continued their investigation in a third paper (3).

They reiterate that it is difficult to determine

the exact melting points of the ortho- and para-carboxy phenylhydrazdnes. ^

o.’

. .

Meta-earboxyphenylhydrazine (meta hydrazinobenzoie acid) was first prepared by Roder (68) and its reaction with carbonyls was Investigated by Willstatter (£)•

Willstatter

found that some derivatives crystallized readily but that many had to be crystallized as their ammonium salts.

This

spoils the possibility of molecular weight determination by simple titration.

-1 1 -

1-Naphthylhydrazine l|.-sulfonic acid, which was prepared by Erdmann (69)* is potentially a good reagent for molecular weight determination but it haa two great disadvantages which were pointed out by Willstatter*

The preparation of derivatives

requires two hours of refluxlng, and the derivatives melt high with decomposition* A mention of Whitmore’s (70) work On nitroguanylhydrazine completes the discussion of the hydrazines. Hydroxylamlne hydrochloride (71# 72) has long been used for the preparation of derivatives of carbonyl compounds, and is still used in a procedure for the determination of car­ bonyls#

Under empirically standardized conditions, it is

possible to titrate the hydrochloric acid liberated by con­ densation of the reagent with carbonyl groups (73)• Trozzolo and Lieber (7i|-) defined the hydearxylamine number which is related directly to the molecular weight and func­ tionality of the compound, as "the number milligrams of potassium hydroxide which is equivalent to the hydroxylamlne required to oximate the carbonyl function in one gram of sample*”

Trozzolo and Lieber claim that this may be important

for the identification of carbonyl compounds.

They admit

howwver, that "the conditions of oximation vary with the molecular weight and structure of the keto compound."

They

list th.9 hydroxylamlne numbers experimentally determined for eight different ketones, and show accuracy varying from a few percent to less than one percent.

By chance, or perhaps

-1 2

by design, Trozzolo and Lieber do not show results for aromatic ketones, which generally cannot be satisfactorily determined by the hydroxylamlne method. The value of the defined hydroxylamlne number is subject to debate.

It should be simple to define a number,

(comparable to the neutral equivalent of acids) which is more obviously related to the molecular weight of the compound. For the preparation of derivatives, hydroxylamine hydrochloride is not especially good, since the low molecular weight carbonyls form moderately soluble oils which are not easy to purify.

Furthermore, ketones do not react readily,

and the aromatic ketones require fairly drastic conditions. While alpha diketones react normally, oximation of beta diketones leads to formation of heterocycles. Semicarbazlde has provided the basis for a number of quantitative methods, many of which have been promulgated as means for the determination of the molecular weights of carbonyl compounds. These methods depend on the fact that semicarbazones may be hydrolyzed, liberating semicarbazlde which is further hydrolyzed to hydrazine, ammonia and carbon dioxides n h 2 .c o .n h n h 2

/

h 2o

. 1 ^ 3 / co2 /

n h 2 .n h 2

In 1903> Rimini (11) analyzed aemlcarbazones by hydrollzing them as indicated, and then oxidizing the hydrazine

-13

with an alkaline solution of mercuric chloride: NH2 .KH2 / 2HgCl2 a N2 / 2Hg / ljHCl. Rimini then measured the nitrogen evolved. Hobson (10) used the same reactions, but instead of measuring the nitrogen evolved, he determined the remaining ammonia,by a micro-KJeldahl method.

In Hobson's method, the

semicarbazones had to be hydrolyzed for seven to eight hours• Veibel (7) described a method which was essentially the same as Hobson's.

Veibel's method, which required one and

one half hours for the determination of a molecular weight, involved hydrolysis of the semicarbazone, oxidation of the hydrazine formed by the hydrolysis, and finally determination of the ammonia formed along with the hydrazine in the hydrolysis. In a later paper, Veibel (l) criticized this method, and claimed that direct titration of para-carboxyphenylhydrazones was better.

Harlay (9) hydrolyzed semicarbazones to

hydrazine, and oxidized the hydrazine with excess standard iodine solution.

The residual iodine was then determined

with standard thiosulfate.

Harlay's method involved the

following steps: 1.

Prolonged hydrolysis of the semicarbazone in a

sealed tube at 100°, with 10% to y0% hydrochloric acid, according to the difficulty of hydrolysis. 2.

Buffering of the acid solution with sodium acetate.

3.Addition of excess decinormal iodine solution. 4. After twenty minutes,titration of the remaining iodine with decinormal sodium thiosulfate solution. Yftien aldehydes are involved,it is necessary to sweep out the aldehyde in a current of steam to prevent formation of a_dazines, which would remove some of the hydrazine. Chemical Abstracts (9) states,”The method cannot be considered as a general one,as it is dependent on the ease of hydrolysis of the compound and may be interfered with by possible secondary reactions depending on the nature of the compounds tested.” t'e same criticism,in fact,may be applied to all of these methods which depend on the hydrolysis of substituted hydrazines. Smith and uheat (8 ) used a similar method for determination of the molecular weights of semicarbazones. They reported that the method also works with para-bromophenylhydrazine, but not with thiosemicarbazide. Smith and ftheat dissolved t e hydrazine compound in concentrated hydrochloric acid, eated if necessary to complete the hydrolysis,and then det­ ermined the hydrazine by the method of Jamieson (75,76). Chloroform was added, and the strongly acid solution of hydrazine was titrated with standard iodate. 4IC j + 5N 2 H 5* *- 2 1 5 % *

IIHjO v HgO+

Tne chloroform layer became colored by the free iodine. Then the titration progressed according to the equation: IO 3

21 2 +- 6 H 3 O

+ 5C1

8 H2 O

+5IC1

At^the end point,the iodine color disappeared from the chloro­ form layer.

-15-

It seems that Smith and Wheat had to add a two-phased titration to the other difficulties Inherent In the method* They reported errors of the order of several per cent. A number of substituted semlcarbazides have been suggested as carbonyl reagents, but only l^-phenyl-semicarbazide (77» 78» 79) seems to have achieved much popularity. are generally easy to prepare and purify.

The derivatives Para-h1trophenyl

semicarbazlde, para-nitrobenzylsemicarbazide, para-nitroxenylsemicarbazide (77» 80), para-xenylsemicarbazide (79)» paratolylsemicarbazide (8l) ortho-tolylsemicarbazide (82), metatolysemicarbazide (83), benzylsemicarbazide (8I4.), alphanapthylsemicarbazide (85), beta-napthylsemicarbazide (86a), 2, Ij. dimit rophenyl semicarbazlde (77» 80) and 3» 5 dinitrophenylsemicarbazide (86b) have all been proposed as reagents for carbonyl compounds.

None seems to be superior to lj-

phenylsemicarbazide. Thlosemicarbazlde is an excellent reagent for aldehydes and ketones, and since the thiosemicarbazones form Insoluble salts with heavy metal cations, procedures may easily be devised for molecular weight determination.

Neuberg and

Niemann (ij.) were primarily interested in using the silver salts of thiosemicarbazones for the isolation of carbonyl compounds, but it is a simple matter to decompose the salt and determine the silver by any standard inorganic procedure. Thiosemicarbazide probably provides the best of the current methods for determination of molecular weights of carbonyl compounds.

-16-

Dime done (5, 5 dimethylcyclohexane - 1, 3 dione) is the one reagent which is obviously better than the mercaptocar­ boxylic acids for certain cases.

Specifically, the mercapto­

carboxylic acids cannot compete with dimedone as reagents for the low molecular weight aliphatic aldehydes.

There are

other applications, however, in which it will be demonstrated that the mercaptocarboxylic acids have many advantages over dimedone. Dimedone reacts with aldehydes in neutral solution, but moderate variations in the pH may be helpful.

The derivatives

are usually well characterized crystalline compounds, which melt at definite temperatures.

The derivatives, which have

enolic structures, may be titrated with standard alkali. Upon heating with mild dehydrating agents "anhydrides*1 (87) are obtained which can no longer be titrated, but ih ich do provide an additional melting point.

It is unfortunate

that no general procedure can be devised for the preparation of these anhydrides. For the determination of molecular weights, dimedone is not too satisfactory, since the derivatives are either mono­ basic or dibasic, depending upon the aldehyde, the temperature or the solvent.

Dimedone has been used for the quantitative

determination of aldehydes, but the titration does not seem to have been used for estimation of molecular weights of unknown aldehydes.

-17-

II. History

(B)

Mercaptals and Mercaptols In 1885, Baumann (88) reported that mercaptans

react with carbonyl compounds in two ways.

One mole of

mercaptal reacts with one mole of carbonyl to form an addition product which is readily decomposed.

Two moles of mercaptan

react with one mole of carbonyl to form a condensation pro­ duct which is extremely stable.

Baumann proposed that the

condensation products of mercaptans with aldehydes (thioacetals) be called "mercaptals," and those of mercaptans with ketones (thioketals) be named "mercaptole"• In a later article, (89) Baumann elaborated on the con­ ditions and limitations of mercaptal and mercaptol formation. Baumann declared that two moles of mercaptan react spontan­ eously with one mole of aldehyde, or with one mole of ketone when anhydrous hydrogen chloride is employed as a catalyst. In each case, heat is evolved, and the reaction goes rapidly to completion.

Baumann further observed that aliphatic alde­

hydes and ketones and aromatic aldehydes react more rapidly when heated.

With mixed ketones, containing an aromatic resi­

due, it is necessary to heat while adding anhydrous hydrogen chloride.

Benzophenone, according to Baumann, reacts with

-1 8 -

mercaptans only ifa.en heated with a strong dehydrating agent, such as zinc chloride. Benzil, phthallc anhydride, and anthraquinone do not react to form mercaptols, whiln furfural, which does form a mercaptal, reacts with additional mercaptan to form higher condensation products. Baumann also states that the heat evolved helps to speed the reaction, but that in some cases, the temperature should be restrained to 60 - 70° C. Autenrieth (90) seems to be the first to have noticed that neighboring groups may Inhibit mercaptol formation. Autenrieth, who was primarily interested in sulfonals, discdvered that chloroacetone gave a very small yield of mercap­ tol when treated with two moles of ethyl mercaptan, and rtien the reaction mixture was heated to force the reaction, three moles of mercaptan reacted with one mole of ketone. Posner noted this, and in a

classic series of papers

investigated and tried to explain the factors which inhibit mercaptol formation.

The effect of substituents on the reac­

tion of aliphatic carbonyl compounds with mercaptans was explained by Posner (91) in terms of induced electron flow. Halogen, hydroxyl, carbonyl, carboxyl, nitro, amido, and aryl groups located alpha, and in some cases beta to the carbonyl group tend to deactivate it for mercaptol formation to a greater or lesser extent.

While Posner*s explanation may not

be entirely acceptable, it is probable that he was on the

-19-

right track.

His conclusions have been adequately verified

in the present investigation. Posner also investigated the reaction of mercaptans with aromatic ketones (91j)»

It seems that the ease of mercaptol

formation depends not only on the ketone, but on the mercaptan as well.

Ethyl mercaptan and benzyl mercaptan react with

aromatic ketones, while amyl mercaptan and phenyl mercaptan do not react readily. As for the carbonyl compounds themselves, Posner found that a nitro group in the ortho position inhibits mercaptol formation, but not as strongly as hydroxyl or amido groups. Meta or para nitro groups do not affect the reaction appre­ ciably. The reaction of diketones with mercaptans is of especial interest in connection with the problem of identification. Posner (91c) found that ethyl mercaptan formed dimercaptols with diacetyl, acetylacetone and acetonylacetone, tfiile monomercaptols were obtained with other 1, 2 and 1, 3 diketones. The diacetyl and acetylacetone dimercaptols were oils which could only be identified by oxidation to the tetra-sulfones. Acetonylacetone, however, did form a solid derivative with ethyl mercaptan.

In a subsequent paper, (91?) Posner ob­

served that with various mercaptans gamma diketones always formed dimercaptols, while certain alpha and beta diketones fielded mono or dimercaptols.

Ruheman (92a, b) commented

that while Posner often obtained mixtures of products by

-2 0 -

re acting unsaturated ketones with mercaptans In the presence of hydrogen chloride or zinc chloride, it was possible to obtain nothing but addition to the ethylenic bond by using a basic catalyst, such as sodium ethylate or piperidine. Ruheman also found that an acetylenic bond adjacent to a ketonlc group inhibits mercaptol formation.

Methoxybenzoylphenyl-

acetylene C^H^C| CCO C^H^OCH^ reacts with only one mole of mercaptan.

This is an extension of Posner's previously

mentioned work on the corresponding ethylenic compounds. Bongartz (9^) noticed that the mercaptal of cinnamaldehyde was unstable to heating with alkali, and decomposed to what apparently was a hemi-mercaptal.

The compound identified

by Bongartz as the hemi-mercaptal might well have been betaphenyl, beta-thioglycolic acid propionaldehyde.

This is mere

speculation, however, and would have to be verified by ex­ periment.

During the present investigation, an attempt was

made to react three moles of thioglycollc acid with one mole of cinnamaldehyde, but only two moles of the mercaptan re­ acted, forming the same compound that Bongartz identified as the mercaptal.

The reaction took place without a catalyst,

evolving a great deal of heat.

Aside from any theoretical

implications, this means that our new routine identification procedure will produce satisfactory results with cinnamalde­ hyde.

However, only oils were obtained when thioglycollc

acid reacted with aliphatic alpha, beta unsaturated carbonyl oompounds.

Further consideration of this factor will be

-2 1 -

reserved for the discussion section of this paper. Sscales and Baumann (93) reacted phenyl mercaptan with keto acids, and obtained results which ought to be compared with Posner's work on deactivation of carbonyls by negative neighboring groups.

Sscales and Baumann reported that pyruvic

and benzoyl formic acids reacted with phenyl mercaptan, forming hemimercaptols with evolution of heat.

When the solution was

heated to 100°C, and anhydrous hydrochloric acid added, the mercaptol was obtained.

Acetoacetic ester and levulinic acid

did not react with phenyl mercaptan. Bongartz (9I+) succeeded in preparing the mercaptoacetic acid mercaptol of acetoacetic ester, but he used more drastic conditions than Sscales and Baumann.

Bongartz's work was

essentially the forerunner of the present investigation, since Bongartz reacted mercaptoacetic acid with a number of aldehydes and ketones, and correctly observed the physical and chemical properties of the resulting thioaeetals and thioketals.

Bon­

gartz' s statements, however, will have to be amplified and modified by the present work. Holmberg and Mattisson (95)» who were cognizant of Bon­ gartz* s publication, prepared the thioglycollc acid and thiolactlc acid mercaptals of formaldehyde and benzaldehyde.

They

investigated the derivatives in more detail than did Bongartz, but Bongartz*s research was much more extensive.

Holmberg and

Mattisson did make the observation that thiolactic acid reacted less vigorously than thioglycollc acid, and that the thiolactic

22

acid mercaptals melted over a range, owing to the presence of optical isomers* Davey (96 ) reacted thioglycollc acid with chloral and chloral hydrate to make lubricating oil additives.

According

to the abstract, he did not characterize the resulting com­ pounds •

%

Mulvaney and Evans (97) recently reported the reaction of aldehydes and ketones with a number of thioglycollc acid esters. Schubert (98 ) reacted simple aldehydes with thioglycollc acid anilide, to form 1-hydroxy alkylthioethers.

These herai-

mercaptals were readily decomposed, but were stabilized by acetylation.

Thioglycollc acid anilide also reacted with

pytuvic acid, quinone and lsatin.

Schubert reacted cysteine

with aldehydes to form easily crystallized condensation prod­ ucts, which also seemed to dissociate readily, but which were also stabilized by acetylation. In a previous paper (99) Schubert reported the reactions of methyl glyoxal and phenyl glyoxal with a number of thiol acids.

Cysteine and thiourea yielded condensation products,

while thioglycollc acid, thioglycollc acid anilide and gluta­ thione yielded addition products with both methyl glyoxal and phenyl glyoxal.

Cysteine betaine, thlosalicyclic acid and

thioslnamine also yielded addition products with phenyl glyoxal. Schubert*s reactions were carried out it dilute, non-dehydrating, almost neutral solutions, and are cited here to show the conditions which should be avoided in the preparation of mercaptals.

-23

In connection with hemi- (or semi-) mercaptal formation, the work of Fromm and Erfurt (100), Schonberg and Schultz (101) and Ryzheva (102) should be mentioned* Hemi-mercaptal formation might lead to erroneous results unless the procedure for the preparation of derivatives were designed to prevent it.

The conditions developed in the course

of the present investigation will minimize any tendency to hemi-mercaptal formation* Just as it has been necessary to intersperse discussion in this history, so is it expedient to include some historical backgrounds in certain portions of the discussion which will follow in the next section. The history of 1, If addition of mercaptans to alpha, beta unsaturated carbonyls, and the history of the formation of metal complexes with organic sulfides, for example, can best be presented along with the discussion of the respective topics*

III.

(A)

Discussion

Mercaptocarboxylic acids as reagents for the identi­ fication of carbonyl compounds. The staff of Hopkin and Williams Research Labora­

tory (53^) have enunciated criteria which they employed in the selection of reagents for the preparation of derivatives: "(a)

Accessibility of the reagent, which usually means,

can it be produced at a reasonable price? M (b)

Stability of the reagent.

"(c)

Simplicity, convenience and speed with ih. ich der­

ivatives can be prepared and recrystallized in reasonably good yield. n(d)

The derivatives should melt within a convenient

temperature range, ideally between 100° and 250°• "(e)

The melting points should differ sufficiently one

from another for the derivatives of closely related com­ pounds, e.g. in an homologous series or for o-, m-, and pisomers. "(f)

The availability of an extensive series of melting

points has been considered desirable but this has not been regarded as essential to the inclusion of some of the newer reagents since these, if they Justify themselves, will eventually

-25-

have further values determined* "(g)

If the reagent provides derivatives having a free

reactive group (e*g. carboxyl) which permits of titration this is considered a strong recommendation*” Consideration of these factors provides a convenient yard­ stick for evaluation of the mercaptocarboxylic acids as re­ agents for preparation of derivatives of carbonyl compounds. Mercaptoacetic acid, alpha mercaptopropionic acid, beta mercaptopropionic acid, 2, 3 dimercaptopropionic acid, and alpha mercaptolauric acid were tried as reagents for carbonyl compounds.

It was thought that alpha-mercaptolauric acid

might be especially good for preparation of derivatives of the low molecular weight aldehydes and ketones, but it was found difficult to use.

Alpha-mercaptolaxiric acid is a solid, not

very soluble in water, and not very reactive as a mercaptan. These factors made it difficult to devise a procedure for the preparation and purification of mercaptals and mercaptols. 2, 3 dimercaptopropionic acid is also solid at room temperature, but it was found possible to use it in a saturated or supersaturated aqueous solution.

Aromatic aldehydes yielded

solid derivatives; aliphatic aldehydes reacted spontaneously to yield oils, while aliphatic ketones reacted in the presence of dry hydrogen chloride to yield oils.

These facts, together

with the necessity of reacting the 2, 3 dimercaptopropionic acid with the carbonyl in exactly molar proportions, make this reagent unsatisfactory for the purposes of this work, since It

- 26 -

is g e n e r a l l y c o n v e n i e n t reagent.

It was

derivatives None c o u l d be weight

error the

in

of t h e

titration

this

since none

carbonyl of t h e

error w i l l

ular weight carbonyl 3

of

t he

solid

accuracy

I t is

in m o l e c u l a r to

of

the

obvious

carbonyl

t he r a t i o

a c i d is

is

therefore

that any

an

error

compound,

in and

of t he m o l e c ­

t o t he m o l e c u l a r It

the m o l e c ­

weight

of

th e

unfortunate

otherwise u n s u i t e d for

that

t he

of d e r i v a t i v e s .

a r e a g e n t for

carbonyl

of d i s a d v a n t a g e s ,

purpose.

of

derivatives which

so li t t l e

compound.

the d e r i v a t i v e

dimercaptopropionic

number

adds

b e m a g n i f i e d as

Alpha-mereaptopropionic as

those

derivative will produce

compound increases.

preparation

provides

of g r e a t e r

calculated molecular weight

that

2,

capable

determination,

to p u r i f y

excess

obtained.

other reagents

inherently

ular weight

a stoichiometric

also found difficult

which were

of tne

to use

Most

important

formed from dl-thiolactic w h i c h w o u l d not be

acid

(thiolactic

compounds,

acid)

and was found

was

tested

to h a v e

which would preclude

i ts

is

derivatives

the f ac t

that

t he

acid are mixtures

e x p e c t e d to m e l t

of

sharply.

use for

optical Holmberg

a that

isomers, and

(150

Mattisson^ p r e p a r e d hyde

the

and formaldehyde,

optical isomerism.

thiolactic acid mercaptals and commented briefly

a c i d is n o t

available

acids.

difficult

through commercial

Rejection

of

t he

effect

T h i o l a c t i c a c i d is n o t as r e a c t i v e

other m e r c a p t o c a r b o x y l i c lactic

on

of b e n z a l d e -

thiolactic

Furthermore,

to prepare,

as

of some

although thio­

i t is n o t r e a d i l y

channels. acid,

alpha-mercaptolauric

acid

-27-

and 2, 3 dimercaptopropionic acid leaves thioglycollc acid and beta-mercaptopropionic acid as the two reagents left for evaluation against the standards of the Hopkin and Williams Research Laboratory Staff, quoted at the beginning of this discussion* (a)

"Accessibility of the reagent:-" Thioglycollc acid (mercaptoacetic acid) is now

commercially available, and may be purchased anhydrous, or as a 70% to 80% solution*

Its use in cosmetics assures that

the commercial supply will continue for many years*

Beta-

mercaptoprop ionic acid is now available In experimental quan­ tities (103), and will probably become available commercially* In any event, thioglycollc acid and beta-mercaptopropionic acid may easily be prepared in any laboratory, from inexpensive starting materials* (b)

"Stability of the reagent:-" Thioglycollc acid and beta-mercaptopropionic acid

may be preserved for long periods of time if protected from air.

Atmospheric oxygen readily oxidizes either to the disul­

fide.

One sample of thioglycollc acid (an 80% solution) used

in this Investigation had been vacuum distilled five years prior to use, aid was found to react satisfactorily with alde­ hydes and ketones.

Samples of pure beta-mercaptopropionic

acid have been stored in this laboratory for months, with no evidence of deterioration. Since ah$iydrous hydrochloric acid is generally employed

-

28-

as a catalyst for mercaptol formation, attempts were made to incorporate the catalyst with the reagent*

Thioglycollc acid

which had been saturated with anhydrous hydrogen chloride was found to react spontaneously with ketones without the need for additional catalysts.

Unfortunately, thioglycollc acid so

treated was unstable, and a white, crystalline;strongly acidic substance slowly formed and precipitated from the solution over a period of several days.

B©ta-mercaptopropIonic acid, sat­

urated at its freezing point with dry hydrogen chloride, apparently is stable, but it reacts more vigorously when ad­ ditional dry hydrogen chloride is bubbled through the reaction mixture. (c)

"Simplicity, convenience and speed with which derivatives

can be prepared and recrystallized in reasonably good yield." The procedure for the preparation of derivatives now involves the following simple steps: 1.

Add a roughly estimated excess of thioglycollc acid

or beta-mercaptopropionic acid to the carbonyl compound. (Experiments were carried out in which the proportion of thioglycollc acid to carbonyl compound was varied from a 50% deficiency to a 200$ excess of the stoichiometric amount of thioglycollc acid. each case.

Satisfactory derivatives were obtained in

This was surprising especially for the case in

which the 50% deficiency if thioglycollc acid was used.

It

is true, however, that in this case the product was discolored and difficult to purify.

It Is possible that the proportions

-29-

of reagents may be more critical in special cases.

Of course,

the optimum conditions would be the use of two moles of the mercaptan to one mole of carbonyl.

It is usually possible,

but not necessary, to guess the approximate molecular weight of a carbonyl compound from its physical properties.

Deriv­

atives are not generally prepared until the identity of the unknown is restricted to a list of possibilities). Most liquid carbonyl compounds dissolve readily in betamercaptopropionic acid, but a few (principally high molecular weight ketones) do not dissolve in 70% to Q0% thioglycollc acid,

Reaction will take place even with two liquid phases.

If solid carbonyl compounds do not dissolve, additional reagent may be added, and the mixture heated on a water bath.

If the

solution remains clear on cooling, proceed to step 2.

If

precipitation occurs, the mixture should be heated with fused zinc chloride in place of dry hydrogen chloride. 2.

Bubble anhydrous hydrochloric acid through the solution

of carbonyl confound in thioglycollc acid or beta-mercapto­ propionic acid for a few minutes. the solution may cloud.

Heat should be evolved, and

(As little as 0.0005 mole will evolve

enough heat to be readily detedted).

If the solution does not

become hot enough, it may be heated for a few minutes on a steam bath.

Furanes, phenols and olefines containing carbonyl

groups should not be heated under any circumstance, since tar formation occurs, and further condensation may also take place. It was found possible to prepare derivatives of polymeric

30-

glyoxal in a 30$ aqueous solution, and of formaldehyde in a 35# aqueous solution. A few of the reactions were carried out on a relatively Uajpge scale —

deci or hemi molar —

and it was found possible

to produce yields after one recrystallization of the order of 90# of theoretical.

Furthermore, after a single recrystalli­

zation, the compounds assayed better than 99$ pure, and in most cases subsequent recrystallization did not change the melting points appreciably. Mercaptoacetic acid seems to be a more vigorous reagent than beta-mercaptopropionic acid, but beta-mercaptopropionic acid forms derivatives with aliphatic carbonyl compounds which are easier to isolate and purify.

It is also a superior re­

agent for compounds which do not dissolve in thioglycollc acid. The seemingly paradoxical observation was made that a 70$ solution of thioglycollc acid reacts more readily than the anhydrous acid, although the reaction Involves splitting out of water.

Bongartz (9ij.) reported that salicaldehyde could

stand for a day in thioglycollc acid solution without reacting, unless a catalyst were added.

In the present investigation,

it was found that 70% thioglycollc acid reacted spontaneously with salicaldehyde in a few minutes. This may be due to the polarity of the solvent, or to the fact that water decreases the solubility of the product in the Reaction medium. 3*

Wait 10 to 30 minutes for the derivative to solidify.

Chill if necessary. !{.. Air dry on porous tile.

-31-

5.

Recrystallize.

Derivatives of most aromatic aldehydes

and aromatic and aliphatic ketones, may be recrystallized from water.

If an oil forms on cooling, more water must be used.

If the derivative is not sufficiently soluble in hot water, the compound may be recrystallized from dilute acetic acid. It Is best to dissolve the compound in hot glacial acetic acid, and add boiling water to the point of Incipient crystallization. Upon cooling, large, well defined crystals are usually ob­ tained. For the few cases In which the derivatives are very soluble In cold water, chlbroform or ether may be used as solvents for recrystallization.

The crystal forms are not as good, but

the compounds obtained are of the required purity. (d)

"The derivatives should melt within a convenient tem­

perature range, ideally between 100° and 2f>0°." The derivatives prepared in the course of the present Investigation generally melted between J0° and 200°, which is not far from what might be considered the ideal melting range. It was noticed that while the bulk of the derivative melted sharply, there was often some evidence of melting (such as the rounding off of crystal corners) several degrees below the actual melting point. (e)

"The melting points should differ sufficiently one from

another for the derivatives of closely related compounds, e.g. in an homologous series or for o-, m-, and p-isomers." Thioglycollc acid and beta-mercaptopropionic acid are

-32-

satisfactory in this respect, but they are not especially good. The tables appended to this dissertation show the melting points of the derivatives prepared or found in the literature. Examination of these melting points does indicate suitable variation in homologous series, and between certain ring sub­ stituted isomers, but the melting point variations are not always adequate. (f)

"The availability of an extensive series of melting points

has been considered desirable but this has not been regarded as essential to the inclusion of some of the newer reagents since these, if they justify themselves, will eventually have further values determined.n Only a handful of these derivatives have previously been reported in the literature.

It must be admitted that the

present modest contribution will be a relatively heavy addition to the literature of these compounds. (g)

"If the reagent provides derivatives having a free re­

active group (e.g. carboxyl) which permits of titration this is considered a strong recommendation." This investigation was conducted for just this reason. The especial excellence of these derivatives, as a class, lies in the fact that they can be titrated with standard base.

The

nature of titration, its limitations, and the precision which may be expected, will be discussed below in the section on potentiometric titrations. The limitations on the preparation of these derivatives

-33-

are inherent in mercaptol formation.

The work of Fosner,

previously cited (91 )# kas indicated the situations in which mercaptol fomation may be expected to proceed with difficulty. All aldehydes and ketones which contain no other functional groups should yield mercaptals and mercaptols when treated by the methods indicated in this thesis.

Alkyl halides (97# 90)

unsaturated compounds (10i).# 97# 92)# nitriles (105# 97)» and diazonium salts (97) also may react with the mercapto-carboxylic acids under the conditions used for the preparation of derivatives of carbonyl compounds.

Alkyl halides would not

be expected to react as readily as the carbonyl function, and diazonium salts would not frequently be encountered in the same molecule with a carbonyl group.

Nitriles would seriously

interfere with the preparation of derivatives; in fact, Condo et al (105) have suggested that thioglycollc acid be used for the identification of nitriles.

The formation of imino thio-

ethers takes place under the same conditions as mercaptols. Again, it is fortunate that carbonyls containing nitrile groups are relatively rare. More serious complications arise with carbonyl compounds containing unsaturated linkages.

In the historical section

of this paper, mention was made of the work of Nicholet (92c, d) Ruheman (92a, b) and especially Posner (91g» h» 1)> who showed that mercaptans added to an olefinlc or acetylenic bond besides condensing with the carbonyl group.

It is obvious that if

such compounds were confused with simple mercaptals, the

results of titration could be misleading. It is fortunate that the alpha-beta unsaturated carbonyls do not usually yield derivatives which could be confused with mercaptols.

As Fosner (91g>

1) and Huheman (92a, b) have

demonstrated, unsaturation adjacent to a carbonyl group in­ hibits mercaptol formation and frequently leads to an oily mixture of products, which is not likely to be mistaken for the well defined, crystalline mercaptol. In the present investigation, one mole of acrolein and one mole of orotonaldehyde were separately treated with one, two and three moles of thioglycollc acid.

No solid derivative

was obtained in any of the six cases, although a vigorous #

exothermal reaction took place in each case.

When volatiles

were removed by vacuum distillation, the residues hardened to amorphous solid masses which resembled polymeric materials. Mesityl oxide, cltral, and citronellal were also reacted with thioglycollc acid, without producing solid derivatives. Citral reacted very vigorously, without a catalyst, yielding a water-insoluble oil.

In spite of its high molecular weight,

the derivative remained fluid at room temperature. Cinnamaldehyde was reported to fora a normal mercaptal with thioglycollc acid (9^4-) •

in the present Investigation,

an attempt was made to react cinnamaldehyde with three moles of thioglycollc acid, but only two moles reacted, producing the previously reported mercaptal.

A possible explanation

lies in the fact that the ethylenic linkage is conjugated with

the ring, vfoich may aid the competing reaction of mercaptal formation*

Once the mercaptal has formed, two sulfide linkages

are present in an allyl position, which might be expected to decrease the reactivity of the double bond still further. As previously mentioned in this paper, other substituents in the molecule may be expected to inhibit mercaptol formation* Posner (91 ) indicated that nitro, amido and hydroxyl groups inhibit mercaptol formation in aromatic carbonyls, and that this inhibition Is especially strong in the ortho position* It was also observed that halogen, carbonyl, carboxyl and aryl groups in alpha, and often beta positions inhibit mercaptol formation with aliphatic carbonyl compounds* In the present Investigation, it was found that diacetone alcohol, benzal acetophenone, benzal acetophenone dibromide, benzil, diacetyl and ortho-hydroxyacetophenone were among the carbonyl compounds which did not yield derivatives under or­ dinary conditions.

Acetyl acetone yielded a solid which was

difficult to purify, but acetonyl acetone easily yielded a solid dimercaptol.

Glyoxal also formed a dimercaptal, even

in dilute aqueous solution and without a catalyst.

One attempt

was made to prepare the monomercaptal of glyoxal, but when equilibrium was obtained, the reaction mixture was found to consist of dimercaptal and unreacted glyoxal.

Para-hydroxy-

acetophenone reacted readily with thioglycollc acid, in contrast with the ortho compound, but it was noticed that heating the reaction mixture caused the formation of colored substances*

It has been mentioned in the literature (9I4-) and noticed In this Investigation that mercaptal formation with salicalde­ hyde Is somewhat Inhibited, but reaction takes place even without a catalyst.

Meta-hydroxybenzaldehyde also seemed to

be inhibited, but vanillin reacted readily. It is evident, then,that owing to the many limitations on mercaptol formation, the mercaptocarboxylic acids can never entirely replace traditional reagents for the identification of aldehydes and ketones.

However, as was pointed out in the

critical review of previous reagents, the other reagents also have more or less restricted applicability, and the mercapto­ carboxylic acids do have certain unique advantages.

In this

investigation it has been demonstrated that thioglycollc acid and beta-mercaptopropionic acid are valuable supplementary reagents for the identification of carbonyl compounds. Thioglycollc acid and beta-mercaptopropionic acid are superlative reagents for almost all simple aromatic aldehydes and ketones, good reagents for aliphatic ketones, and satis­ factory reagents for most aliphatic aldehydes.

When their

limitations and merits are recognized, they are powerful tools, not only for identification, but also for separation and iso® lation of carbonyl compounds. When regarded from the point of view of separations, the limitations of mercaptol formation become positive assets. was found possible to separate an alicycllc ketone from a similar compound having an ethylenic linkage adjacent to the

It

-

keto group.

37-

Equal volumes of isophorone and cyclohexanone

were mixed, an excess of 72% thioglycollc acid added, and dry hydrogen chloride bubbled through the solution.

After re­

frigeration, the reaction vessel was found to contain a white, crystalline solid which was identified as the mercaptol of cyclohexanone; a red oil, which was the reaction product of isophorone and thioglycollc acid; and a clear liquid, which contained water, hydrogen chloride, and the excess|of thioglycolic acid.

Furthermore, the same amount of solid was

obtained when cyclohexanone alone was reacted with thioglycolic acid, and an identical volume of red oil was obtained when isophorone alone was reacted with thioglycolic acid. Mercaptals and mercaptols may be split to the carbonyl compound and mercaptan by refluxing with strong, aqueous hydro­ chloric acid (9lj.).

It is thps possible to recover the carbonyl

compounds. Since the derivatives are soluble in aqueous alkali, and generally insoluble in acid, it is possible to extract carbonyl substances from reaction mixtures or natural sources.

Anchel

and ^choenheimer (li|.) employed para-hydrazinobenzoic acid, hydrazinoacetic acid, and O-aminoglycolic acid for the isolation and separation of keto-steroids.

The mercaptocarboxylic

acids should be superior for this purpose since both the re­ agents and derivatives are more stable, the derivatives may be presumed to be better crystallized, the derivatives contain two carboxyl groups which are stronger acids than the single

-

38-

carboxyl groups in the reagents used by Anchel and Schoenheimer (llj.), and finally, the mercaptocarboxylic acids are more easily obtained, and are less expensive than the other reagents.

The greater number of carboxyl groups per molecule

of derivative, and the greater strength of the acids should simplify the process of extraction with aqueous d.kali.

-39-

III.

(B)

Discussion

Potentiometric titrations of some bis and tetrakls m

mercaptocarboxylic acids. In order to determine the sharphess and validity of the titration end points, potentiometric titrations were carried out on a number of representative derivatives.

Pre­

vious investigators (3» 106) working on analogous problems used a method of trial and error to determine the proper in­ dicators.

Potentiometric titrations provide a simple method

for selection of indicators, and at the same time furnish a good deal of information concerning the acids being titrated. A Beckman model G pH meter, using glass and calomel electrodes, was employed to follow the course of the titration. Decimolar solutions of carbonate-free sodium hydroxide were titrated into 0.1$ to 0 .25$ aqueous or dilute alcoholic solu­ tions of the derivatives.

In performing the titrations, the

procedures which would be followed in determination of unknowns were used.

The derivatives were recrystallized only once, and

were dessicator dried.

The calibration of all apparatus used

was checked, and the pH meter was compared with two buffers, one acid and one alkaline, before use.

It was found that

accuracy of better than 1$ could usually be obtaL ned with

no additional precautions.

TShen neutral equivalents were

determined on a micro scale, the accuracy was often not better than plus or minus 2%*

On a

micro scale, between six and

ten milligrams of derivative was dissolved in 5 ol. of $0% aqueous ethanol which had been neutralized to phenolphthalein. The titration was then performed with 0.01N sodium hydroxide solution.

Just before the end point was reached, the acid

solution was boiled to expel carbon dioxide.

Results of the

micro titrations are included in table III. The following results were obtained for the potentiometric titrations shown on the attached graphs: Figure 1

Calculated Neutral Equivalent Found 158.2

159-3

2

ll&.

lij-5.7

3

151.8

157.

k

97.6

98.1*.

Figure 1 shows the potentiometric titration of the thio­ glycolic acid - piperonal derivative.

It will be noticed that

the end point is sharp, and that the pH break in the region of the end point is quite large.

This is, in fact, the titra­

tion curve of a moderately strong acid. Figure 2 is the curve of the potentiometric titration of the thioglycolic acid - salicaldehyde derivative.

It is

obvious here that the end point is almost, but not quite, as sharp as that in figure 1.

It is also evident that the height

of the pH break in figure 2 is less than that in figure 1, yet

at a point corresponding to three equivalents of base there is no break due to the hydroxyl group.

Furthermore, the end

point is sharp enough to yield the required accuracy. This is in contrast to figure 3» where the effect of the hydroxyl group is more in evidence.

Here, the thioglycolic

acid derivative of para-hydroxyacetophone was titrated under the same conditions as the salicaldehyde derivative, yet the end point is not at all sharp, and the height of the pH break is greatly diminished.

In this case, it is difficult to obtain

a neutral equivalent accurate to much better than

(This

might possibly be improved by matching empirically determined indicator color standards, or titrating potentiometrically to a calculated or empirically determined pH)•

Even with this

relatively poor accuracy, this represents a great improvement over previous literature.

Veibel, et al (3 ) who prepared and

titrated para-carboxylphenylhydrazones, found difficulty in titrating the derivative of salicaldehyde, and declared it impossible to titrate derivatives of aromatic aldehydes and ketones having para-hydroxyl groups. It Is possible to explain the relative success of the thioglycolic acid derivatives in these cases.

If it can be

shown why a para-hydroxyl is more acidic than an ortho­ hydroxyl group in these derivatives, an explanation of the 1

titration curves follows directly.

It must be recognized that

the para-hydroxyl compound titrates like a typical phenol, and that the hydrolysis of the phenylate ion obscures the

titration end point. The explanation must then be sought in terms of the re­ pressed ionization of the ortho-hydroxyl group.

There are two

factors, the combination of which probably accounts for this «

phenomenon.

First, It is presumably difficult to remove a

proton from the vicinity of a doubly charged anion.

Second,

there is a strong probability of chelation, as hydrogen bonding occurs between the hydroxyl group and the sulfide linkage, forming a six membered chelate ring.

As will be shown later,

this tendency to form chelates should Increase as the pH of the solution rises.

Thus, chelation and other electrostatic

forces weaken the acidity of the phenolic group to a point where the molecule titrates almost as it would If the phenolic group were not present. Interesting results were obtained in the potentiometric titration of the thioglycolic acid derivative of glyoxal.

This

compound, which is a tetrabasic acid, yields the titration curve shown in figure \\.»

It may be noted that only one break

is evident, and this occurs when four equivalents of base have been added.

On electrostatic grounds alone, it might be ex­

pected that removal of a proton from a triply charged negative ion would require an enormous amount of energy, yet even the fourth ionization constant of this derivative must be fairly large, as gauged from the titration curve. This is probably due to the presence of a sulfide link on each of the four alpha carbons.

It may be recalled that

thioglycolic acid is stronger than acetic acid by an order of magnitude.

Divalent sulfur located that close to any carboxyl

group may be expected to Increase the acidity of that group, and it might also be expected to function as a sort of electro­ static buffer against induced charges from other parts of the molecule. Potentiometric titrations of beta-mercaptopropionic acid derivatives indicated that the derivatives were apparently somewhat weaker acids than the thioglycolic acid derivatives.

Ill*

(C)

Discussion

Salts and complex compounds of some thioglycollc acid mercaptals and mercaptols* Almost a century ago, the first publications appeared

which described the reaction of organic sulfides with salts of heavy metals to form addition compounds (107).

Since

that time these compounds have been investigated in great detail, and with the appearance of Werner's co-ordination theory, the formation of such compounds was adequately ex­ plained (108, 109, 110, 111, 112, 113).

For over fifty years,

these compounds have been recognized as co-ordination complexes. In 1897, Werner (112) prepared compounds of the type (CH^^S^dlg; in 1898 Werner and Pfeiffer (111) prepared compounds like 2( (CH^^S )SnClj^j and in 1910 Tschugaev and Subbotin (113) made compounds like c2h5

Tt:l

—

C2^

s-----i c2h5

ci2

Tschugaev and Subbotin were primarily interested in the stereoisomers obtained, but it seems obvious that the Pt is involved in a chelate ring. Phillips (110) in an excellent paper concerning the

formation of addition compounds with monosulfides, discussed compounds of the type R — S— >Hgl 2 'fr R Tschugaeff (llif.) prepared compounds of the series R.S.(CHg^.S.R, and measured their tendency to form complexes.

The greatest

tendency to complex formation was found where n ■ 2, indicating a five-membered chelate ring. plex formation was evident.

Where n • 0»

3 or

no com­

With R ■ ethyl, for example, the

coordination compound was found to have the formula CuCl2 (C2H£)2 S2(CH2 )2 «

®

Morgan and Ledbury (115) extended Tschugaeff1s work by going systematically through the periodic table and reacting metallic ions with dlmethyldithiolethylene.

They concluded

that those metals which form insoluble inorganic sulfides are those which will also form stable complexes with organic sul­ fides.

As an illustration of this, they found that in group

two of the periodic table, complexes become more stable with increasing atomic weight.

Magnesium ion forms a complex in

anhydrous ether, but the complex dissociates rapidly.

Mercuric

ion forms stable complexes, with some reduction to mercurous. The compounds prepared by Morgan and Ledbury (115) were assigned structures like this: ch3

CH2 -------- S v

^ZnBrp

/

CHo --------. 2 I CH^

Bennet (116) also applied the concept of residual valence to

the complex compounds of some organic disulfides. Bongartz (9U-) commented briefly that some thioglycolic acid mercaptals and mercaptols reacted with salts of the trans­ ition metals, and that decomposition took place.

At the time

of his work (1888), werner's theory was apparently not widely accepted, for it is certain that what Bongartz called "de­ composition" was really complex formation. In 1911* Rambefg and Tiberg (117a) prepared ethylene bisthioglycolic acid for the express purpose of testing its co­ ordinating properties.

They obtained compounds of this type

with copper and bivalent platinum: CHoC=0 H2c — S'

HPC — S' 2 \

o

o / C ^C -O

Twenty years later, Reuterskiold (118) studied propylene bisthioglycolic acid in connection with the formation of inner complexes with metals. Compounds of this sort, in which the metal ion is bound by primary valence forces to an ionized acidic portion of the molecule, and by secondary valence forces to a basic group in the same molecule, are called "inner complexes" (12).

It is

almost axiomatic that inner complex?:are more stable than or­ dinary complexes (119 )* This discussion of the coordinating properties of organic

sulfides, and the nature of inner complexes,is a preliminary to an explanation of some properties of thioglycolic acid mercaptals and mercaptols.

These derivatives were found to change

the color of solutions

of transition ions, which is presumptive

evidence of complex formation.

However, the ordinary deriva­

tives would have to form inner complexes like these: SCH„C - 0

R

The four membered chelate ring which is formed must be pre­ sumed to be unstable, and experiment has shown that the comp­ lexes formed with these derivatives are not especially stable. In fact, it Is doubtful that the complexes formed are inner complexes. The thioglycolic acid dimercaptal of glyoxal seems to be an important exception to this general observation.

-o 0

C -

0 c h 2--

s — ch:— /' 2 H-C — -C-H

c* CT 0

\ 0

S-CH.I ^

2

C ■=—

0

\

0 In this compound, it is evident that the chelate ring contains five atoms, which is^the most stable configuration for dithiochelates.

‘ ^wo carboxyl groups are also sterically able to form

-I^S-

salts with the chelated metal Ion.

Thus, it could confidently

be predicted that 1, 1, 2, 2 tetrakls thioglycolic acid ethane would form Inner complexes, at least with the transition metals. There Is one additional factor which would be expected to in­ crease the stability of the chelate.

The two free carboxyl Ions

on the molecule should enhance the basicity of the co-ordinating sulfur by inducing electron flow.

In fact, this compound is

the sulfur analog of ethylene diamine tetra-acetic acid, which is one of the most powerful chelating agents known (119)• H 0 0 C — CHov ^ N - CH — H 0 0 C — CH^ 2

CH— 2

N ^

^ CH COOH 2 CHgCOOH

Schwarzenback (119) h&s published a great deal of work con­ cerning the theory and applications of this and related nitrilo acetic acids. Potentiometric titrations were carried out on solutions of 1, 1, 2, 2 tetrakls thioglycolic acid ethane in the presence of added foreign salts, but the resulting curves could not be interpreted by the methods of Schwarzenback (119a, b, 1) or Calvin and Wilson (120) because the original compound was too strongly acidic. During the titrations, however, color changes were noted which were interpreted as indications of inner complex formation. When cuprlc ion was first added to a solution of the complexing agent, a brown precipitate formed, which formed a blue solution upon dilution.

The first addition of alkali turned the solution

emerald green, and after titration strong acidification ren­

dered the solution colorless.

These phenomena readily lend

themselves to interpretation in terms of complex formation, but it must be admitted that other interpretations are possible. Cobalt, nickel and chromium aL so seemed to form complexes similar to the copper complex. Trivalent iron was found to behave differently from the other transition metals, and evidence was later secured which indicated that the carboxyl group, and not the sulfur, was involved in the coordination sphere of the iron.

At a pH of

two, a dilute solution of ferric nitrate formed a heavy pre­ cipitate with a dilute aqueous solution of 1, 1, 2, 2 tetrakls thioglycolic acid ethane, and this precipitate did not dis­ solve even after extreme dilution.

The precipitate was so

Insoluble that no coloration was obtained when a large amount of molar potassium thiocyanate solution was added at a pH of about 2.

It was possible to dissolve the precipitate with

fairly strong acid, and at a pH above 9» tk® precipitate decom­ posed to form ferric hydroxide. Ferrous ion formed no precipitate when treated with the same reagent in an acid medium, but addition of hydrogen per­ oxide alone did not react with the same reagent, proving that the precipitation was not merely an oxidation phenomenon. Treadwell ahd Fisch (122) titrated ferric chloride with acetate ion in aqueous solution.

Their method was applied to

the titration of ferric nitrate with an aqueous solution of 1, 1, 2, 2 tetrakls thioglycolic acid ethane.

The millivolt

-50-

scale of a Beckman model 0 pH meter was used to measure the potential between bright platinum and calomel electrodes dipping Into the solution, as the acid was slowly added.

The

potential slowly dropped as the reagent was added, and the point of the greatest rate of change of potential was taken as the equivalence point.

This point eould not be chosen without

possible ambiguity, but calculation from fchat seemed to be the best point indicated that three molecules of the reagent were associated with five ferric ions.

This is not regarded as

proof, nor is the coordination pattern clear. However, this seems to tie in with the work of Treadwell and Pisch (121) on complex formation of mono-and di-carboxylic acids with ferric chloride.

By analogy, it seems that the

precipitate may be related to the well-known basic ferric ace­ tate, but forms in a more acidic medium because the acid is ten times stronger than acetic acid.

This is in accord with

the observations that the precipitate dissolves in strong acid, but becomes less soluble as the solution becomes more nearly neutral. Zirconium, in the form of zirconyl ion, was titrated in the same manner with an aqueous solution of 1, 1, 2, 2 tetrakls thioglycolic acid ethane.

The potential between bright plati­

num and calomel electrodes dropped steadily as reagent was added.

When addition of the reagent was completed, the solution

which originally contained 0.1% of Z nOC^ was filled with a voluminous precipitate, and it had a

pH of 2.2.

When sodium

-5 1 -

hydroxide solution was added to pH - 5» the potential between the electrodes dropped greatly.

Finally, when solid sodium

bicarbonate was added to pH s 7» the precipitate dissolved completely, and the potential dropped still further. From these data, it is possible to postulate that Zirconium (IV) forms an insoluble comples or salt with 1, 1, 2, 2tetrakis thioglycolic acid ethane in acid media, which becomes a soluble complex in neutral media.

Connick and McVey (123)

reported that only oxalic acid, in the series of aliphatic dibasic acids from oxalic to glutaric, showed appreciable complexing tendencies with zirdonium.

They were unable to offer

a satisfactory explanation for this behavior. The fact that 1, 1, 2, 2 - tetrakis thioglycolic acid ethane is a pH sensitive precipitant for zirconium seems to indicate its possible use for the separation of hafnium and zirconium. Fractional precipitation, extraction by a method similar to that used by Huffman and ^eaufait (I2J4.), or anion exchange resins (125) would seem to be reasonable methods for employing this new reagent for separation of hafnium and zirconium. Bie separation of hafnium and zirconium is

only remotely

related to the identification of carbonyl compounds and has therefore not been expensively explored in this investigation. In view of the current intensive interest in the problem of separating hafnium and zirconium however, it was thought de­ sirable to include this fragmentary discovery in this disser­ tation.

-52-

IV.

Experimental

The nature of the reactions, and the structures of the derivatives may be summarized by the following equations: R

R^ C = 0 / 2HSCH-C00H

-—

*

R*'

c R/

Rv

\

SCH2C00H

SCHgCOOH R

C-» 0 / 2HSCH2CH2D0QH

^ c ^ SCHpCHoCOOH 2 2

R*/

^

R ^

R^

SCH2CH2C00H

SCH(CH3)C00H

C s 0 / 2HS - CH(CHo)COOH-^

C 1/ \ R SCH(CH^)COOH

'/ R'

%

R ^ / S - ^ G R r

C - 0 / HSCH2CH(SH)C00H R /

I r

/

S

R and R* may be alkyl, aryl or hydrogen

CH I COOH

-52-a

The author is indebted to the B. P. Goodrich Chemical Co. for furnishing samples of beta-chloropropionic acid end bota•ehlorepropionic eeid and beta-isothioureidopropionic acid, and to Mr. Emil Maxion who generously supplied a number of carbonyl compounds used in this investigation. Physical constants and analytical data on new compounds will be presented in tabular form at the end of this section, for more convenient reference. The reaction of glyoxal with thioglycolic acid: Twenty - three and five - tenths grams (0 .12 5 mole) of a 30*8$ solution of polymeric glyoxal in water was dissolved in 61^.1 grams (0 .5 mole) of 71«9$ thioglycolic acid.

The solution,

ih ich evolved heat after a brief induction period, was allowed to stand overnight. The solution was then refluxed on a water bath for six hours, under 200 ml. of a benzene - toluene solution.

A

water trap was placed in the condenser system, and water was drawn off at intervals, as it accumulated.

After four hours,

gradual withdrawal of the hydrocarbon mixture was begun.

When

most of the calculated amount of water had been removed, dis­ tillation was stopped, and the solution was permitted to stand for several hours.

The reaction flask was then found to be

filled with a solid mass of white crystals, which was suction filtered and air dried. 55 grams.

The slightly moist crystals weighed

The filtrate, which was slightly cloudy, was dis­

tilled until about 50 ml. remained.

The liquid separated into

-53'

two layers, and a small additional yield was recovered from the bottom, aqueous layer.

The product was recrystallized

from water in several batches, with recycling of the solvent. The total product obtained was lj2 .1 grams, an

yield.

It was also found possible to carry out the reaction by removing the water under vacuum, instead of by distillation with benzene.

The most convenient preparation, however, was

only carried out on a small scale.

The reagents were mixed

in the same proportions, and anjsydrous hydrogen chloride was bubbled through the solution.

The hydrogen chloride acted as

a catalyst for mercaptal formation, and decreased the solubility of the derivative by the common ion effect, and by effectively removing much of the solvent.

Chilling produced a crop of

crystals in a matter of minutes* The reaction of glyoxal with beta-mercaptopropionic acid: 0 .ll|.5 ml* (0.001 mole) of 30.8# glyoxal was added to O.lj. ml. of beta-mereaptopropionic acid.

Within a few minutes there

was evidence of crystallization, and in about thirty minutes a large, solid mass had formed under the aqueous portion. When this solid was air dried on porous tile, it became evi­ dent that the yield was unsatisfactory. was found to provide an excellent yield;

The following variation 0 .1 )4 .

3151 of 3° * 8 #

glyoxal was dissolved in O.I4. ml of beta-mercaptopropionie acid, which had previously been saturated with ah|iydrous hydrogen chloride.

Heat was evolved, and within a few minutes

sition of crystals began. solid dried on porous tile. from a minimum of water.

depo­

The mixture was chilled, and the The product was recrystallized

The reaction of glyoxal with thiolactic acid: O.II4.5 ml (0.001) mole of a 30*8# aqueous solution of poly­

meric glyoxal was dissolved in 0.If. ml. of thiolactic acid (0.352 ml. =

O.OOI4 mole).

There was

of heat, nor otherapparent evidence

no immediate evolution of reaction.

Only an

emulsion was obtained after refrigeration. The reaction of acetonyl acetone with thioglycolic acid: Forty ml. (0 *£4. mole) of 714# thioglycolic acid was dissolved in ll.lf grams (0 .1

mole) of acetonylacetone, and anhydrous

hydrogen was passed through

the reaction mixture. The mix­

ture befiame hot immediately, and had to be cooled by appli­ cation of an ice bath. to be complete —

In ten minutes the reaction seemed

an orange colored solid was the only material

visible in the flask.

The solid was allowed to stand for

four hours in an atmosphere of hydrogen chloride, and was then broken up to air dry on porous tiles. orange color diaappeared.

In drying, the original

The product was recrystallized

from water, yielding 35*1 grams. The reaction of acetonyl acetone with beta-mercep topropionic acid: 0.059 ml. (0.0005 mole) of acetonyl acetone was dissolved

in 0 .2 ml.

(O .I7 6

ml. = 0.002 mole) of beta-mercaptopropionic

acid, and anhydrous hydrogen chloride was added.

The solution

soon became hot, clouded, and within five minutes had com­ pletely solidified.

After drying on porous tile, the product

was recrystallized from water.

The reaction of acetonyl acetone with thiolactic acid: 0.059 ml* (0.0005 mole) of acetonyl acetone was dissolved in 0.22 ml. (0.176 ml. = 0.002 mole) of thiolactic acid, and anhydrous hydrogen chloride was bubbled through until the solu­ tion clouded. solidify.

Prolonged refrigeration caused the mass to

The product was dried, and then recrystallized from

dilute acetic acid. The reaction of acetyl acetone with thioglycolic acid: It was found very difficult to prepare the dimereaptol of acetyl acetone.

Five varying procedures were tried, but

none was satisfactory. procedure:

The following is probably the best

Four ml. of 71«9$ thioglycolic acid (O.Ol^ mole)

was dissolved in one ml. (0 .0 1 mole) of acetyl acetone.

An­

hydrous hydrogen chloride was slowly passed into the solution which was cooled with an ice bath when necessary. found that heating led to tar formation). then placed in a

(It was

The solution was

refrigerator for several hours.

A yellow,

waxy solid was formed, which was difficult to recrystallize from water in reasonable yield. The reaction of acetyl acetone with beta-mercaptopropionic acid: 0.05 ml. |0.0005 mole) of acetyl acetone was dissolved in 0.2 ml. of beta-mercaptopropionic acid which had been pre­ viously saturated with anhydrous hydrogen chloride.

Heat was

evolved, and the solution, which clouded, was placed in a refrigerator.

The next day a yellow solid mass was found,

which was not easily purified by recrystallization from water. The reaction of diacetyl with thioglycolic acid: No satisfactory derivative could be obtained for diacetyl. Forty ml. of 7b$ thioglycolic acid (O.lj. mole) was added to 8.8 m. of diacetyl (0 .1 mole). Anhydrous hydrochloric acid was passed through the reaction mixture, while the flask was cooled with an ice bath wnen necessary.

The reaction mixture became

deep yellow, then orange, and finally dark red, but did not solidify.

Vacuum distillation concentrated this solution to

a heavy syrup, which became a brown wax upon cooling.

This

could not be crystallized. The reaction of vanillin with thioglycolic acid: 8*i{. grams (0.05 mole) of vanillin was dissolved in 10 ml. (0 .1 mole) of 71*9# thioglycolic acid.

The solution became

cold initially (probably due to the heat of solution of the vanillin), but the solution soon gave evidence of a vigorous (not violent) exothermal reaction. for one hour on a steam bath.

The solution was heated

Cooling produced a syrup, but

addition of distilled water, heating, and then cooling pro­ duced a crop of large, well defined crystals.

Recrystalliza­

tion from water yielded 6.5 grams of derivative. The reaction of vanillin with beta-mercaptopropionic acid: 0.168 gm. (0.001 mole) of vanillin was heated on a water bath with 0.2 ml. (0.176 ml. s 0.002 mole) of beta-mercapto­ propionic acid, until the vanillin dissolved. Immediate evidence of reaction.

There was no

The solution was placed in

-57-

a refrigerator, ihere it solidified in a few hours.

The product

was recrystallized from water. The reaction of vanillin with thiolactic acids 0.168 gm. (0.001 mole) of vanillin was added to 0.21 ml. of thiolactic acid.

The mixture was then heated gently until the

vanillin dissolved. solid derivative.

Rifrigeration did not produce a satisfactory Anhydrous

hydrogen chloride was then bub­

bled through the oil previously obtained.

Upon refirgeration,

this yielded a semi-solid mass. The reaction of piperonal with thioglycolic acid: 7*5 grams (0.05 mole) of piperonal was dissolved in 10 ml. (0 .1 ) mole of 71*9# thioglycolic acid. the solution became very warm.

Within a few minutes,

When the reaction had sub­

sided, the solution was heated for one hour on a steam bath, and it crystallized upon cooling.

The derivative was easily

recrystallized from a large volume of water. Ihe reaction of piperonal with beta-mereaptopropionic acid 0.150 gram (0.001 mole) of piperonal was added to 0.2 ml. (0.176 ml = 0.002 mole) of beta-mercaptopropionic acid, and the mixture was heated to dissolve the piperonal.

Refriger­

ation produced a semi-solid mass, but when anhydrous hydrogen chloride was bubbled through this mixture, crystals were ob­ tained.

The product was recrystallized from water.

The reaction of piperonal with thiolactic acids0.150 gram (0.001 mole) of pipironal was gently heated with 0.21 ml. (0.176 ml. - 0.002 mole) of thiolactic acid vntil

-58-

the piperonal dissolved*

When a semi-solid was found after

refrigeration, dry hydrogen chloride was bubbled through it. Additional refrigeration produced crystals suspended in heavy syrup.

Drying on porous tile removed the syrup, leaving a

small crop of crystals. The reaction of benzaldehyde with thioglycolic acid was reported by Bongartz (9k)» 611(1 by Holmberg and Mattisson (9 5 )In the present investigation, it was found possible to carry out the reaction without a catalyst.

5*3 grams (0.05 mole) of

benzaldehyde was dissolved in 10 ml. (0.1 mole) of 71*9$ thio­ glycolic acid.

When the reaction had subsided, the solution

was heated for one hour on a steam bath.

The crystals obtained

upon cooling were recrystallized from water. The-^reaction of benzaldehyde with beta-mercaptopropionic acid: 0.106 ml. (0.001 mole) of benzaldehyde was dissolved in 0.2 ml. (0.076 ml. s 0.002 mole) of beta-mercaptopropionic acid. There was no evidence of reaction until dry hydrogen chloride was bubbled through the solution.

Upon cooling, a solid

formed which was air dried on porous tile and recrystallized from water. The reaction of benzaldehyde with 2 , 3-dimercaptopropionic acid: 0.19 ml. (0.182 ml. - 0.01 mole) of an aqueous solution of 2, 3*di1nercaptopropionic acid (1.00 gram of 2, 3-dimercapto propionic acid per 1.3 ml. of solution) was added to 0.1

-59

ml. (0.001 mole) of benzaldehyde, and dry hydrogen chloride was bubbled through the solution.

An emulsion formed which

slowly crystallized upon refrigeration.

The product was re­

crystallized from dilute acetic acid. The reaction of n - heptaldehyde with thioglycolic acid: 1.3 grams (0.01 mole) of freshly distilled n-heptaldehyde was reacted with 2 ml. (0 .0 2 mole) of 80# thioglycolic acid. solution warmed spontaneously.

The

Anhydrous hydrogen chloride was

then passed through the solution, causing the evolution of more heat.

Upon chilling, a solid separated.

The reaction of n - heptaldehyde with beta-mercaptoprop­ ionic acid: 0.13 ml* (0.001 mole) of n-heptaldehyde was dissolved in 0.2 ml. of beta-mercaptopropionic acid.

Heat was evolved, and

crystallization began almost immediately.

It was found, how­

ever, that upon drying on porous tile, the yield was not satisfactory. When the same procedure was repeated with betamercaptopropionic acid which had been saturated with anhydrous hydrogen chloride, an excellent yield was obtained. product was recrystallized from water.

The

The reaction of n-

heptaldehyde with thiolactic acid: 0.13 ml (0.001 mole) of n-heptaldehyde was added to 0.2 ml. of thiolactic acid. formed.

The mixture became warm, but no solid

After the addition of anhydrous hydrogen chloride,

an emulsion was thon obtained. The reaction of n-butyraldehyde with thioglycolic acid: -

-6o-

0*09 ml* (0.001 mole) of freshly distilled n-butyraldehyde was dissolved in 0.2 ml. (0.002 mole) of 71*9^ thioglycolic acid. The solution rapidly became warm, but when no solid formed, anhydrous hydrogen chloride was bubbled through the solution until it became cloudy.

Chilling then produced crystals.

The reaction of n-butyraldehyde with beta-mercaptoprdpionic acid: 0.09 ml (0.001 mole) of n-butyraldehyde was dissolved in 0.2 ml. (0.176 ml. s 0.002 mole) of beta-mercaptopropionic acid. The solution soon became warm, and began to deposit crystals within a few minutes.

Better yields were obtained, howwver,

when the beta-mercaptopropionic acid was previously saturated with dry hydrogen chloride. The reaction of n-butyraldehyde with thiolactic acid:0.09 ml. (0.001 mole) of n-butyraldehyde was dissolved in 0 .2 ml. of thiolactic acid. formed.

Heat was evolved, but no solid

ury hydrogen chloride was then added, and the clear

solution became an emulsion. The reaction of anisaldehyde with thioglycolic acid: 3*ij. grams (0.025 mole) of para-anisaldehyde was dissolved in 5 ml. (0.05 mole) of 71»9# thioglycolic acid.

when the

evolution of heat had ceased, the solution was placed in an ice bath, where it rapidly crystallized.

The product was air

dried on porous tile, and recrystallized from water.

A

series of reactions was then carried out in which the ratio of the reagents was varied.

0.13 ml. (0.001 mole) of anisal­

dehyde was added to 0.01 ml. (0.001 mole) of 71*9# thioglycolic acid.

The series was continued by adding

0 .002,

-61-

0 .003, 0 .004, and

0.008 moles of 7 1 .9p thioglycolic

acid to 0.001 mole of anisaldehyde.

After addition of dry

hydrogen chloride, each produced an excellent yield of white, crystalline derivative. The reaction of anisaldehyde with beta-mercaptopropionic acid: 0.13 ml. (0.001 mole) of anisaldehyde was dissolved in 0.2 ml. (0 .176 ml. - 0.002 mole) of beta-mercaptopropionic acid.

After

fifteen minutes, the solution was found to be cloudy and viscous.

Chilling caused the solution to solidify.

The

product was easily recrystallized from water. The reaction of anisaldehyde with thiolactic acid: 0.13 ml. (0.001 mole) of anisaldehyde was dissolved in 0.2 ml. of thiolactic acid.

There was no apparent reaction.

An­

hydrous hydrogen chloride was bubbled through the solution, which then solidified when refrigerated.

The product was

recrystallized from water. The reaction of glucose with thioglycolic acid: 9*0 grams (0.0£ mole) of glucose was dissolved in 10 ml. (0.1 mole) of 7

1

thioglycolic acid by heating the initial

slurry on a steam bath for one hour. clear after refrigeration.

The solution remained

When a portion of the solution

was saturated with anhydrous hydrogen chloride, the solution became hot, and turned to a deep violet color.

Another por­

tion was dried by vacuum distillation at 115°C., forming a syrup which solidified to a glass.

A third portion was ex­

tracted with diethyl ether, and the resulting emulsified

-

62-

aqueous layer treated with benzene which precipitated a crystalline solid.

This was not the expected product.

The reaction of phenyl n-propyl ketone with thioglycolic acid: 0.2 ml. of 71.9# thioglycolic acid was added to 0.l£ ml. of phenyl n-propyl ketone. Anhydrous hydrogen chloride was bubbled vigorously through the mixture for about two minutes, while heat was evolved and the mass solidified.

The product was

recrystallized from dilute acetic acid. The reaction of citral with thioglycolic acid: 0.17 nil* of citral (0.001 mole) was dissolved in 0.2 ml. (0.002 mole) of 7l|$ thioglycolic acid.

The solution soon

became warm, and a second liquid phase separated.

Passing

anhydrous hydrogen chloride through the mixture did not pro­ mote formation of a solid phase. The reaction of citral with beta-mercaptopropionic acid:0.17 ml* (0.001 mole)of citral was dissolved in 0.2 m. (O.176 ml. m 0.002 mole) of beta-mercaptopropionic acid.

There was

no appreciable evolution of heat, but the solution became yellower and more viscous.

Hydrogen chloride did not cause

foimation of a solid derivative. The reaction of furfural with thioglycolic acid was re­ ported by Bongartz (9i{-)* wko observed that mercaptal formation was not the only reaction.

In the present investigation, it

was found possible to prepare several mercaptals of furfural, but the purification of these derivatives was difficult.

The

-63-

heat evolved by the reaction causes further condensation.

On

a decimolar scale, the reaction mixture containing furfural and thioglycolic acid became so hot that tar formation took place rapidly.

On a millimolar scale tar formation seemed to

be minimized. O.O83 ml. (0.001 mole) of furfural was dissolved in 0.2 ml. (0.002 mole) of 71»9# thioglycolic acid. soon became warm, and gradually turned oragge.

The solution Refrigeration

produced well-defined crystals covered with a black tar.

Re­

peated recrystallization from water produced tan colored crystals, which seemed to darken on standing in air. Tne reaction of furfural with beta-mercaptopropionic acid: 0.083 ml. of furfural (0.001 mole) was dissolved in 0.2 ml. of beta-mercaptopropionic acid.

The solution slowly became

yellow and more viscous, but gave no other evidence of reaction. Upon refrigeration, a tan colored solid was obtained, which was recrystallized from water, with the use of decolorizing charcoal.

The yield obtained was small, since the derivative

seems to be very soluble in cold water. The reaction of furfural with thiolactic acid: 0.083 ml* (0.001 mole) of furfural was dissolved in 0.2 ml. of thiolactic acid.

The solution darkened, and its viscosity

increased, but there was no apparent evolution of heat nor precipitation.

The solution gradually became a black oil after

several weeks of refrigeration.

The reaction of salicaldehyde with thioglycolic acid was reported by Bongartz (9k-)» who claimed that no reaction took place with anhydrous thioglycolic acid unless a catalyst was employed.

In the present investigation, it was found that a

71•9% solution of thioglycolic acid reacted spontaneously and vigorously with salicaldehyde.

6.1 grams (0.05 mole) of sali-

caldehyde was dissolved in 0.1 mole of 71*9$ thioglycolic acid. The solution became hot after standing briefly, and crystallized when cooled after heating for one hour on a steam bath. The reaction of salicaldehyde with beta-marcaptopropionie acid: 0.12 ml. (0.001 mole) of salicaldehyde was dissolved in 0.2 ml. of beta-mercaptopropionic acid.

In about ten minutes the

solution clouded and became very viscous.

Addition of dry

hydrogen chloride caused the solution to turn red. Bongartz (9^1-) reported that benzophenone reacted with thioglycolic acid when zinc chloride was used as a catalyst. In the present investigation, it was found possible to use dry hydrogen chloride instead, which simplifies the procedure. i|..f>6 grams (0.025 mole) of benzophenone was added to 5*0 ml. (0 .0 5 mole) of Jl»9% thioglycolic acid.

The benzophenone did

not dissolve entirely, but the heat evolved when dry hydrogen chloride was passed into the mixture melted the benzophenone. Upon cooling, the entire mass solidified. The reaction of benzophenone with beta-mercaptopropionic acid: -

65-

O.ld gram (0.001 mole) of benzophenone was dissolved In 0.2 ml. of beta-mercaptopropionic acid.

When dry hydrogen chloride

was bubbled through the solution, it began to cloud, and crystallized within thirty minutes.

The product was recrys­

tallized from dilute acetic acid. The reaction of benzophenone with thiolactic acid: 0.18 gram (0.001 mole) of benzophenone was heated gently with 0.2 ml. of thiolactic acid until a

clear solution resulted.

When treated with dry hydrogen chloride, this produced an emulsion. The reaction of salicaldehyde with thiolactic acid: 0.12 ml. (0.001 mole) of salicaldehyde was dissolved in 0.2 ml. of thiolactic acid.

Anhydrous hydrogen chloride was added,

and the mixture refrigerated, but only an oil was obtained. The reaction of methyl n-amyl ketone with thioglycolic acid: 2.5 grams (0.025 moles) of methyl tf-amyl ketone was dissolved in 5 ml. (0 .0 5 moles) of 71*9% thioglycolic acid.

The solution

was placed in an ice bath and treated with anhydrous hydrogen chloride until a second phase Separated. entire mass solidified.

Upon chilling, the

The product was recrystallized, with

some difficulty, from chloroform. The reaction of methyl n-amyl ketone with beta-mercapto­ propionic acid: 0.II4. ml. (0.001 mole) of methyl n-amyl ketone was added to 0.2 ml of beta-mercaptopropionic acid.

Anhydrous hydrogen chloride

66-

was added until heat was evolved and the solution clouded. Upon cooling, a solid was obtained which was recrystallized from dilute acetic acid. The reaction of methyl n-arayl ketone with thiolactic acid: O.lif. ml. (0.001 mole) of methyl n-amyl ketone was dissolved in 0.22 ml. (0.176 ml. = 0.002 mole) of thiolactic acid, and anhydrous hydrogen chloride was added until the so lution be­ came warm and clouded.

The solid obtained upon refrigeration

was recrystallized from dilute acetic acid. The reaction of veratraldehyde with thioglycolic acid: 2.1 grams (0.0125 mole) of veratraldehyde was dissolved in 2.5 mi. (0.025 mole) of 71*9$ thioglycolic acid.

Heat was evolved,

and when anhydrous hydrogen chloride was passed through the solution, a second phase separated.

Refrigeration produced

a solid which was recrystallized from water. The reaction of veratraldehyde with beta-mercaptopropionic acid: 0.168 gram (0.001 mole) of veratraldehyde was heated with 0.2 ml. of beta-mercaptopropionic acid until a clear solution was obtained.

Anhydrous hydrogen chloride was then bubbled through

the solution.

The solid obtained upon cooling was easily

recrystallized from water, in excellent yield. The reaction of ortho-hydroxyacetophenone with thioglycolic acid: Five ml. (0 .0 5 mole) of 71»9# thioglycolic acid was dissolved in 3 *if3 grams (0.025 mole) of ortho-hydroxy acetophenone.

Dry

-67-

hydrogen chloride was passed intoAsolution, which turned yellow, but did not solidify. two liquid layers.

Addition of water caused formation of

The same results were obtained when the

experiment was repeated. The reaction of para-hydroxyacetophenone with thioglycolic acid: 3«4 grams (0.025 mole) of para-hydroxyacetophenone was dissolved in 5 ml. (0.05 mole) of 71•9% thioglycolic acid, and anhydrous hydrogen chloride was bubbled through the solution, which turned red.

Refrigeration produced a solid derivative, which

was recrystallized from water. The reaction of methyl isobutyl ketone with thioglycolic acid: O.lif ml. (0.001 mole) of methyl isobutyl ketone was dissolved in 0.2 ml. of 71*9$ thioglycolic acid, and anhydrous hydrogen chloride was bubbled through until heat was vigorously evolved. The solution rapidly solidified when chilled.

The derivative

was recrystallized with difficulty from chloroform. The reaction of methyl isobutyl ketone with beta-mercapto propionic acid: O.llj. ml. of methyl isobutyl ketone was dissolved in 0 .2 ml. of beta-mercaptopropionic acid which had previously been sat­ urated with anhydrous hydrogen chloride.

The solution became

hot and a second liquid phase separated.

When refrigerated,

a solid formed which was air dried on porous tile. The methyl isobutyl ketone used in the two reactions

-68

described above was distilled before use* The reaction of phloroglucinol with thioglycolic acid: 1*3 grams (0*01 mole) of phloroguclnol was mixed with 6 ml* (0 .0 6 mole) of

thioglycolic acid*

Dry hydrogen chloride

was added, which heated the solution suffioiently to dissolve the phloroglucinol.

The solid obtained upon cooling proved

to be starting material. \

The reaction of cyclohexanone with thioglycolic acid:1.03 ml. (0.01 mole) of cyclohexanone was dissolved in 2 ml. of 80# thioglycolic acid.

The solution was set in an ice

bath and dry hydrogen chloride was bubbled through it.

As

soon as the second phase began to appear, the solution was set aside.

Within five minutes, it had completely solidifeid.

The product was easily recrystallized from water. The reaction of cyclohexanone with beta-mercaptopropionic acid: 0.103 ml. (0.001 mole) of cyclohexanone was dissolved in 0.2 ml. (0.176 ml. s 0.002 mole) of beta-mercaptopropionic acid.

Anhydrous hydrogen chloride was bubbled through the

solution until heat was evolved, and the solution began to cloud.

The solution solidified within a few minutes.

The

product was recrystallized from water. The reaction of cyclohexanone with thiolactic acid: 0.103 ml. of cyclohexanone was added to 0.2 mo. of thiolactic acid.

Anhydrous hydrogen chloride was passed through the

solution until an emulsion formed. produced a solid derivative.

Prolonged refrigeration

The reaction of isophorone with thioglycolic acid: 1*1). ml. (0.01 mole) of isophorone was dissolved in 2 ml. of

80% thioglycolic acid.

Anhydrous hydrogen chloride was passed

through the solution which turned red, but did not solidify. Identical results were obtained when redistilled isophorone was used.

No solid derivative could be obtained.

The use

of this reaction to separate isophorone and cyclohexanone was described in the discussion section of this paper. The reaction of methyl ethyl ketone with thioglycolic acid: 0.7 gram (0.01 mole) of methyl ethyl ketone was dissolved in 2 ml. (0.02 mole) of 7

thioglycolic acid, and anhydrous

hydrogen chloride was passed through the solution, which was subjected to external cooling.

As soon as a second phase

began to appear the solution was set aside, and within five minutes had completely solidified.

The product was re­

crystallized from water. The reaction of methyl ethyl ketone with beta-mercaptopropionic acid: 0.09 ml. (0.001 mole) of methyl ethyl ketone was dissolved in 0.2 ml. of beta-mercaptopropionic acid, and anhydrous hydrogen chloride was bubbled through the solution until heat was evolved.

The solid which f o m e d on cooling was recrystallized

from water. The reaction of methyl ethyl ketone with thiolactic acid: -

-70-

0.09 ml* of methyl ethyl ketone was dissolved in 0.2 ml. of thiolactic acid.

Anhydrous hydrogen chloride was bubbled

through until the solution clouded and heat was evolved.

The

solid which formed on chilling was recrystallized from water. The reaction of acetone with beta-mercaptopropionic acid: 0.072 ml. (0.001 mole) of acetone was added to 0.2 ml. of beta-mercaptopropionic acid.

Anhydrous hydrogen chloride was

passed through the solution, which soon clouded.

At room

temperature, crystallization was well advanced within thirty minutes.

When an attempt was made to recrystallize the com­

pound from a minimum of water, an oil was obtained, but dissolving the oil in a larger amount of hot water and then cooling produced a crop of beautiful crystals. The reaction of acetone with thiolactic acid: 0.072 ml. (0.001 mole) of acetone was dissolved in 0.2 mole of thiolactic acid, and anhydrous hydrogen chloride was bub­ bled through the solution.

After a brief period of induction

nf induction the solution became warm, then clouded.

The

solution was allowed to stand at room temperature for ten nimutes, during which time the entire mass crystallized.

The

product was recrystallized from water. The reaction of formaldehyde with beta-mercaptopropionic acid: 0.09 ml. of a 35# aqueous solution of formaldehyde (0.001 mole) was dissolved in 0.2 ml. of beta-mercaptopr H WO

O «rt

■H O

Aldehyde Acetaldehyde Acrolein Benzaldehyde n-butyraldehyde Cinnamaldehyde

st