• TABLE OF CONTENTS
HIDE
 Title Page
 Acknowledgement
 Preface
 Table of Contents
 List of Tables
 Introduction
 Preparation of intermediates
 Synthesis of alkylthiomethylpi...
 The structure of the products of...
 Synthesis of arylthiomethylpip...
 Summary
 Bibliography
 Biographical items
 Copyright














Title: Derivatives of piperazine. XIX. thioether derivatives of piperazine and substituted piperazines.
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Title: Derivatives of piperazine. XIX. thioether derivatives of piperazine and substituted piperazines.
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Table of Contents
    Title Page
        Page i
    Acknowledgement
        Page ii
    Preface
        Page iii
    Table of Contents
        Page iv
        Page v
        Page vi
        Page vii
        Page viii
        Page ix
    List of Tables
        Page x
    Introduction
        Page 1
        Page 2
        Page 3
        Page 4
    Preparation of intermediates
        Page 5
        Page 6
        Page 7
    Synthesis of alkylthiomethylpiperazines
        Page 8
        Page 9
        Page 10
        Page 11
        Page 12
        Page 13
        Page 14
        Page 15
        Page 16
        Page 17
        Page 18
        Page 19
        Page 20
        Page 21
        Page 22
        Page 23
        Page 24
        Page 25
        Page 26
        Page 27
        Page 28
        Page 29
        Page 30
        Page 31
        Page 32
        Page 33
        Page 34
        Page 35
        Page 36
    The structure of the products of the reaction of arylthiols with formaldehyde and piperazines
        Page 37
        Page 38
        Page 39
        Page 40
        Page 41
        Page 42
        Page 43
        Page 44
        Page 45
        Page 46
        Page 47
        Page 48
        Page 49
        Page 50
        Page 51
        Page 52
        Page 53
        Page 54
        Page 55
        Page 56
        Page 57
        Page 58
        Page 59
        Page 60
        Page 61
    Synthesis of arylthiomethylpiperazines
        Page 62
        Page 63
        Page 64
        Page 65
        Page 66
        Page 67
        Page 68
        Page 69
        Page 70
        Page 71
        Page 72
        Page 73
        Page 74
        Page 75
        Page 76
        Page 77
        Page 78
        Page 79
        Page 80
        Page 81
        Page 82
        Page 83
        Page 84
        Page 85
        Page 86
        Page 87
        Page 88
        Page 89
    Summary
        Page 90
        Page 91
        Page 92
        Page 93
        Page 94
        Page 95
        Page 96
        Page 97
        Page 98
        Page 99
        Page 100
        Page 101
    Bibliography
        Page 102
        Page 103
    Biographical items
        Page 104
        Page 105
    Copyright
        Copyright
Full Text










DERIVATIVES OF PIPERAZINE XIX

THIOETHER DERIVATIVES OF PIPERAZINE

AND SUBSTITUTED PIPERAZINES











By
DONALD E. BUTLER


A DISSERTATION PRESENTED TO THE GRADUATE COUNCIL OF
THE UNIVERSITY OF FLORIDA
IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE
DEGREE OF DOCTOR OF PHILOSOPHY









UNIVERSITY OF FLORIDA
June, 1958

















ACKNOWLEDGEMENTS


The author wishes to acknowledge the aid and assist-

ance received from the members of his Graduate Supervisory

Committee. He wishes especially to thank Dr. C. B. Pollard,

Chairman, whose direction and friendship have been sources

of inspiration during this work.

Thanks are expressed to staff members and fellow

graduate students for assistance and encouragement. Mrs.

V. M. Gibson has been especially helpful in proofreading

and in the preparation of tables.

The author wishes to thank Parke, Davis and Company

for providing a Fellowship which enabled him to complete

this investigation.

Appreciation is expressed to his parents who have

always encouraged and inspired him to travel the sometimes

difficult path of scientific training.














PREFACE


The subject matter of this dissertation is divided

into six chapters. The first chapter contains the

introduction with reasons for undertaking this research.

The second chapter contains information on the preparation

or commercial sources of the intermediates used in this

research. In the third chapter the syntheses and physical

constants of the alkylthiomethylpiperazines are presented.

The fourth chapter presents the proof of structure of the

product obtained when an arylthiol is reacted with

formaldehyde and a piperazine. The syntheses and physical

constants of the arylthiomethylpiperazines produced are

presented in the fifth chapter. The sixth chapter contains

a summary of the investigation carried out and the

conclusions reached.

The yields of the thioethers are based upon the

quantity of the particular piperazine used in the synthesis.

All temperatures refer to the Centigrade scale and the

Centigrade symbol is omitted. Melting points are corrected

and were determined with a thermometer calibrated against a

Bureau of Standards corrected thermometer.

References are listed in the manner used by journals

of the American Chemical Society. Abbreviations of

journal names are those used by Chemical Abstracts.

iii













TABLE OF CONTENTS


ACKNOWLEDGEMENTS. . . . . .

PREFACE . . . . . .

LIST OF TABLES. . . . . . .

Chapter


Page

. . . . 11

. . . . iii
x


I INTRODUCTION. . . . . . . .

II PREPARATION OF INTERMEDIATES. . . .

A. General Discussion . . .

B. Experimental . . . . . .

III SYNTHESIS OF ALKYLTHIOMETHYLPIPERAZINES .

A. General Discussion . . . .

B. Experimental . . . . . .

Bis-1,4-ethylthiomethylpiperazine .

Bis-1,4-ethylthiomethyl-2-methyl-
piperazine. . . . . . .

Bis-l,4-ethylthiomethyl-trans-2,5-
dimethylpiperazine. . . . .

1-Phenyl-4-ethylthiomethylpiperazine

1-(2-Methylphenyl)-4-ethylthio-
methylpiperazine. . . . .

1-(3-Methylphenyl)-4-ethylthio-
methylpiperazine. . . . .

1-(4-Methylphenyl)-4-ethylthio-
methylpiperazine. . . . .

1-(2-Chlorophenyl)-4-ethylthio-
methylpiperazine. . . . .


. 1

* 5

5
. 6

. 8

. 8

. 9

. 13


. 14


15

. 16


. 17


18


. 19


. 20











TABLE OF CONTENTS--Continued


Page

1-(3-Chlorophenyl)-4-ethylthio-
methylpiperazine. . . . . 21

1-(4-Chlorophenyl)-4-ethylthio-
methylpiperazine. . . . . 22

1-(2-Methoxyphenyl)-4-ethylthio-
methylpiperazine. . . . . 23

1-Methyl-4-ethylthiomethyl-
piperazine. . . . .. . . 24

Bis-l,4-n-butylthiomethylpiperazine 25

Bis-1,4-n-butylthiomethyl-2-methyl-
piperazine. . . . . . . 26

Bis-1,4-n-butylthiomethyl-trans-2,5-
dimethylpiperazine. . . . . 27

1-Phenyl-4-n-butylthiomethylpiper-
azine . . . . . . . 28

1-(2-Methylphenyl)-4-n-butylthio-
methylpiperazine . . .... . 29

1-(3-Methylphenyl)-4-n-butylthio-
methylpiperazine. . . . . 30

1-(4-Methylphenyl)-4-n-butylthio-
methylpiperazine. . . . . 31

1-(2-Chlorophenyl)-4-n-butylthio-
methylpiperazine. . . . . 32

1-(3-Chlorophenyl)-4-n-butylthio-
methylpiperazine. . . . . 33

1-(4-Chlorophenyl)-4-n-butylthio-
methylpiperazine. . . . ... 34

1-(2-Methoxyphenyl)-4-n-butylthio-
methylpiperazine. . . . . 35












TABLE OF CONTENTS--Continued


Page


1-Methyl-4-n-butylthiomethyl-
piperazine. . . . . . .

IV THE STRUCTURE OF THE PRODUCTS OF THE
REACTION OF ARYLTHIOLS WITH FORMALDEHYDE


AND PIPERAZINES . .


A. General Discussion . . .

B. Proposed Methods of Attack .

1. Infra-red Analysis. . .

2. Ultraviolet Studies . .

3. Oxidation Studies . . .

4. Reduction Studies . . .

5. Mass Spectroscopic Analysis

C. Discussion of Results. . .

1. Infra-red Analysis. . .

2. Ultraviolet Studies . .

3. Oxidation Studies . . .

4. Reduction Studies . . .

5. Mass Spectroscopic Analysis

6. Theoretical Reason for the
Experimental Results. .

D. Experimental . . . . .


. . 37

. . 39

. . 39

. . 40

. . 40

. . 41

. . 42

. . 43

. . 43

. 45

. . 45

. . 49

. . 50


. . 51

. . 52


1. Preparation of Isopropyl Diethyl-
aminomethyl Sulfide . . .

2. Preparation of Bis-1,4-phenyl-
thiomethyl-trans-2,5-dimethyl-
piperazine. . . . . .


. . . . . 37











TABLE OF CONTENTS--Continued


Page

3. Preparation of Bis-1,4-phenyl-
thiomethylpiperazine. . . 54

4. Preparation of Bis-1,4-(4-methyl-
phenyl)thiomethyl-trans-2,5-di-
methylpiperazine. . . . 54

5. Infra-red Spectra . . . . 55

6. Ultraviolet Spectra . . . 55

7. Oxidation of Bis-1,4-phenylthio-
methyl-trans-2,5-dimethyl-
piperazine. . . . . . 56

a. Oxidation Using Potassium
Permanganate. . . . . 56

b. Oxidation Using Hydrogen
Peroxide. . . . . . 56

8. Oxidation of Bis-1,4-(4-methyl-
phenyl)thiomethyl-trans-2,5-
dimethylpiperazine. . . . 57

a. Oxidation Using Potassium
Permanganate. . . . . 57

b. Oxidation Using Hydrogen
Peroxide. . . . . .. 57

9. Preparation of Diphenyl Disulfide 58

10. Preparation of Di-p-tolyl Di-
sulfide . . . . . . 59

11. Reduction of Bis-1,4-phenylthio-
methyl-trans-2,5-dimethyl-
piperazine. . . . . . 59

12. Preparation of Trithiophenyl-
methane . . . . . . 60

13. Mass Spectrograph . . . . 60


vii












TABLE OF CONTENTS--Continued


Page

V SYNTHESIS OF ARYLTHIOMETHYLPIPEBAZINES. . 62

A. General Discussion . . . . 62

B. Experimental . . . . . . 62

Bis-1,4-phenylthiomethylpiperazine. 66

Bis-1,4-phenylthiomethyl-2-methyl-
piperazine. . . . . . . 67

Bis-1,4-phenylthiomethyl-trans-2,5-
dimethylpiperazine. . . . . 68

1-Phenyl-4-phenylthiomethylpiperazine 69

1-(2-Methylphenyl)-4-phenylthio-
methylpiperazine. . . . . 70

1-(3-Methylphenyl)-4-phenylthio-
methylpiperazine. . . . . 71

1-(4-Methylphenyl)-4-phenylthlo-
methylpiperazine. . . . . 72

1-(2-Chlorophenyl)-4-phenylthio-
methylpiperazine. . . . . 73

1-(3-Chlorophenyl)-4-phenylthio-
methylpiperazine. . . . . 74

1-(4-Chlorophenyl)-4-phenylthio-
methylpiperazine. . . . . 75

1-(2-Methoxyphenyl)-4-phenylthio-
methylpiperazine. . . . . 76

1-Methyl-4-phenylthiomethylpiperazine 77

Bis-l,4-(4-methylphenylthiomethyl)-
piperazine. . . . . . . 78

Bis-1,4-(4-methylphenylthiomethyl)-2-
methylpiperazine. . . . . 79

Bis-1,4-(4-methylphenylthlomethyl)-
trans-2,5-dimethylpiperazine. . 80

viii











TABLE OF CONTENTS--Continued


Page

1-Phenyl-4-(4-methylphenylthio-
methyl)piperazine . . . . 81

1-(2-Methylphenyl)-4-(4-methylphenyl-
thiomethyl)-piperazine. . . . 82

1-(3-Methylphenyl)-4-(4-methylphenyl-
thiomethyl)-piperazine. . . . 83

1-(4-Methylphenyl)-4-(4-methylphenyl-
thiomethyl)-piperazine. . . . 84

1-(2-Chlorophenyl)-4-(4-methylphenyl-
thiomethyl)-piperazine. . . . 85

1-(3-Chlorophenyl)-4-(4-methylphenyl-
thiomethyl)-piperazine. . . . 86

1-(4-Chlorophenyl)-4-(4-methylphenyl-
thiomethyl)-piperazine. . . . 87

1-(2-Methoxyphenyl)-4-(4-methyl-
phenylthiomethyl)-piperazine. . 88

1-Methyl-4-(4-methylphenylthio-
methyl)piperazine . . . . 89

VI SUMMARY . . . . . . . . . 90
BIBLIOGRAPHY. . . . . . . . . . 102

BIOGRAPHICAL ITEMS. . . . . . . . . 104

















LIST OF TABLES





INFRA-RED PEAKS OF THE CONDENSATION
PRODUCTS. . . . . .. . .

ULTRAVIOLET DATA. . . . . . .

PHYSICAL AND ANALYTICAL DATA OF
ALKYLTHIOMETHYLPIPERAZINES. . . .

PHYSICAL AND ANALYTICAL DATA OF
ARYLTHIOMETHYLPIPERAZINES . . . .


Table


1


Page














CHAPTER I


INTRODUCTION


At the present time, therapeutically active synthetic

chemical compounds are used in virtually every phase of

medicine with at least some degree of success. There is

no apparent limit to the range of application of these

chemicals and their importance to the health and happiness

of mankind is incalculable.

The primary purpose of this research was to produce

compounds which might exhibit some type of desirable
pharmacological action. A second purpose of this work,

which arose after its initiation, was to elucidate the

structure of the products which were produced. If the

structures of currently used pharmaceuticals are examined,

it is noted that a large number contain amine, diamine,

or amino ether groups. A number of these drugs also

contain the piperazine nucleus. A few examples of drugs

containing the latter nucleus or an amino ether group

which illustrate the wide pharmacological spectrum of this

type of drug are:

(a) Hetrazan*,


CH3-N S N-C-N(CH2CH3)2


*Registered Trademark











piperazine prepared by Kushner, et al.,1 is effective

against filariasis, loaisis, and onchocerciasis.

(b) Antepar*,
H --
H-N -H HOOC-CH2C(OH)(COOH)CH2COOH

a piperazine salt prepared by Pollard and Prigot,2 is

effective against oxyuriasis and ascariasis.

(c) Di-Paraline*,

C1 CH-S -CH3

a piperazine prepared by Hamlin, et al.,3 is a useful

antihistaminic.

(d) Atarax*,

ClG CH-S N-CH2CH20 C2CH20H

a piperazine derivative, is used as a tranquilizer.

(e) Benadryl*,

S H'"-0-CH2CH2-N(CH3)2

an amino ether prepared by Rieveschl,4,5 is considered

the drug of choice in the field of antihistaminics.

Consideration of these and other pharmaceutically

useful chemicals led to the preparation of a series of

thioether derivatives of piperazine and substituted

piperazines of the following type structures.


*Registered Trademark











(a) The disubstituted type:

R2
RE1-S-CH2-N S N-CH2-S-R1

R2

R1 = (CH3CH2-,CH3CH2CH2CH2-, S,CH )

R2 = (H-,CH3-).

(b) The monosubstituted type:


R3-N S N-CH2-S-R1



R1 = (CH3CH2-,CH3CH2CH2CH2-, ,CH3 )


R= (CH 3-, K0 10x -":
OCH3 Cl Cl




CH3 CH3

This dissertation describes the preparation and
physical properties of these compounds and the proof of
structure of those compounds containing an arylthiomethyl
group.
All of the new compounds prepared during this research
project will be submitted to Parke, Davis and Company for








4


pharmacological testing. Reports from these testing

programs will be utilized in further synthetic studies.














CHAPTER II


PREPARATION OF INTERMEDIATES


A. General Discussion


The thiols used in this research are all commercial-

ly available. The ethyl, n-butyl, and p-cresol thiols

were obtained from Eastman Organic Chemicals and the

thiophenol was obtained from Evans Chemetics, Inc.

Some of the piperazines used were obtained commercial-

ly. Piperazine, itself, was obtained from the Dow Chemical

Corporation. The 2-methyl and the trans-2,5-dimethyl

piperazines were obtained from the Wyandotte Chemical

Corporation. The N-methyl piperazine was purchased from

the Union Carbide Chemicals Company, a division of Union

Carbide Corporation.

All of the other piperazines (1-arylpiperazines)

used in this research were synthesized in this laboratory.

Numerous methods have been used to synthesize 1-aryl-

piperazines. The two most practical methods for the

laboratory preparation of these compounds in sizable

quantities are those of Pollard, et al.,6*7 and Prelog,

et al.8,9

In the method of Pollard, et al.,6,7 the arylamine

hydrochloride is heated together with diethanolamine












hydrochloride for a period of six to eight hours at 220-

2400 to yield the dihydrochloride of the 1-arylpiperazine.

The dihydrochloride is then treated with concentrated
alkali to produce the free amine. The free amine (1-aryl-

piperazine) is fractionated at reduced pressure to remove

unreacted starting materials.

The method of Prelog, et al.,8,9 consists of heating

the free arylamine with a bis-B-haloethylamine hydrohalide

in either methanol or ethanol for twelve to sixteen hours

to give the hydrohalide salt of the 1-arylpiperazine. The

free base is liberated by treatment with concentrated alkali

and purified by fractionation at reduced pressure.

The procedure of Pollard, et al.,697 was used for the

preparation of the 1-arylpiperazines except in the

preparation of the 1-(2-methoxyphenyl)piperazine. The

starting materials were commercially available and the

reaction time is much shorter than that of Prelog, et al.,8,9

making the former method more useful. The 1-(2-methoxy-

phenyl)piperazine was prepared by the method of Prelog,

et al.,8,9 because the yields in this case are much

higher.


B. Experimental


The following 1-arylpiperazines were prepared:

1-Phenylpiperazine

1-(2-Chlorophenyl)piperazine











1-(3-Chlorophenyl)piperazine
1-(4-Chlorophenyl)piperazine
1-(2-Methylphenyl)piperazine
1-(3-Methylphenyl)piperazine
1-(4-Methylphenyl)piperazine

1-(2-Methoxyphenyl)piperazine
The alumina used in purification of most of the
products was non-alkaline (almost neutral), activity
grade 1 for chromatographic analysis and was obtained
from M*Woelm.Eschwege.














CHAPTER III


SYNTHESIS OF ALKYLTHIOMETHYLPIPERAZINES


A. General Discussion


The type of reaction by which these compounds were

synthesized is generally known as the Mannich reaction.

This reaction involves the condensation of ammonia or a

primary or secondary amine with formaldehyde and a

compound containing an active hydrogen. In the resulting

reaction an aminomethyl or substituted aminomethyl group

replaces the active hydrogen. If the compound containing

the active hydrogen has more than a single active hydrogen

both can be replaced to give a disubstituted product. The

possibility of disubstitution also arises when a primary

amine is used in the reaction.

The first worker to observe this reaction was

Tollens,10 who isolated a tertiary amine from the reaction

of acetophenone, ammonium chloride, and formaldehyde.

Mannich11 was the first to recognize the generality of the

reaction and in 1917 began a detailed study of the reaction.

An excellent review of the Mannich reaction may be found in

Organic Reactions.12

McLeod and Robinson,13 in 1921, found that ethyl and

isopropyl mercaptans react with diethylamine and formaldehyde












to yield the corresponding diethylaminomethyl alkyl sulfides.

Thus, they were the first workers to use mercaptans as the

active hydrogen source in the Mannich reaction. Renshaw and

Searle14 used this method to prepare several other alkyl-

thiomethylamines as intermediates in the preparation of

compounds of the formocholine type. Renshaw and Searle14

did not obtain analyses on the products they used as inter-

mediates but concluded that the reaction between aliphatic

mercaptans, formaldehyde,and secondary amines was of general

applicability. The one other recorded instance of the

preparation of such alkylthiomethylamines is that of Pollard

and Parkin.15 These investigators prepared a number of

ethylthiomethylpiperidines by a method different from that

of McLeod and Robinson.13 Pollard and Parkin15 prepared

an intermediate halomethyl alkyl sulfide that was then re-

acted with the particular piperidine to produce the alkyl-

thiomethylpiperidine.


B. Experimental


The general procedure employed for the synthesis of
the alkylthiomethylpiperazines was the same for each

compound except for the particular method of purification.

It is subsequently described. This procedure is followed

by individual data sheets which tabulate the equation for

synthesis, purification method, yield, molecular formula,

molecular weight, melting or boiling point, refractive











index (if liquid), analytical data, and some solubilities
of each piperazine derivative.
There are two general types of equations for synthesis,
depending upon the piperazine used, i.e., whether the final
product has one or two alkylthiomethyl groupings. These
two types are:
I. R2
H-N S N-H + 2 CH20 + 2 R1-SH >

R2


R1-S-CH2-N S N-CH2S-R1
R2



R3- -H + CH20 + R1-SH >


3- -CH2-S-R1

R1 = (CH3CH2-,CH3CH2CH2CH2-)

R2 = (H-,CH3-)

R3 = (CH3- 0 *1
OCH3 Cl C1


1CH3 ,H3 CH30 ).
CH CH3












The two procedures differ only in the amounts of form-

aldehyde and mercaptan necessary for complete reaction. In

all cases 0.10 mole of the particular piperazine was used.

As indicated by equation I, in the case of bis-substitution

possibilities, 0.20 mole of formaldehyde and 0.20 mole of

mercaptan were required. In the same manner, equation II

indicates that only 0.10 mole of formaldehyde and 0.10

mole of mercaptan were required when the piperazine was

already monosubstituted.

The particular piperazine (0.10 mole) was placed in

a 250 ml. Erlenmeyer flask which had been modified by

adding a ground glass joint at the neck and an addition

side arm fitted with a ground glass joint to accommodate

a dropping funnel. The correct amount of mercaptan was

then slowly added with stirring. The ground glass neck

of the Erlenmeyer flask was fitted to a dry ice-isopropyl

alcohol condenser to prevent the loss of mercaptan from

the reaction vessel. In some cases solidification occurred.

At this point or after stirring for fifteen minutes, the

proper amount of a 35% formalin solution was added in a

single portion. The resulting mixture was then stirred

and heated at reflux for four to six hours. After allow-

ing the reaction to cool to near room temperature, the

resulting product was extracted with three 50 ml. portions

of ether. The ether extracts were dried over anhydrous

potassium carbonate for one to five days. The dried ether












solution was decanted and the ether removed at reduced

pressure. The crude products were dissolved in anhydrous

ether and the resulting solutions were passed through a

column packed with aluminum oxide (non-alkaline, almost

neutral, activity grade 1 for chromatographic analysis).

The alumina absorbs any unreacted starting materials.

The purified solutions were evaporated at reduced'pressure

and final purification was carried out by recrystalli-

zation or vacuum distillation.













Bis-1.4-ethvlthiomethvlpiperazine


Equation for Synthesis:



H- S -H + 2CH20 + 2C2H5-SH




C2H5-S-CH2-N S N-CH2-S-C2H5


Purification Method .
Yield . . . .
Molecular Formula .
Molecular Weight. .
Boiling Point . .
Refractive Index (25)


* .


* . .


* . .


Distilled at 0.30mm.
40%
C10H22N2S2
234.42
140-1/0.30mm.
1.5314


Analytical Data:


Carbon, %:


Calculated:

Found:


Hydrogen, %:


Calculated:

Found:


Nitrogen, %:


51.24

51.60



9.46

9.28


Calculated: 11.95

Found: 11.85


Sulfur, %:


Calculated: 27.36


Found:


26.90


Solubilities:


Ethanol. . . .
Methanol . . .


Benzene. .
Ether. .
Water. .
5 % HCl..
5 % NaOH .
Chloroform


. *
* .


* . .
* .
* 9 .
* . .
* * .
* 9 9 .


Soluble
Soluble
Soluble
Soluble
Decomposes very slowly
Reacts
Decomposes slowly
Soluble


* .
. .


* .













Bis-1.4-ethylthiomethyl-2-methylpDierazine

Equation for Synthesis:

CH3
/---13

H-N S f -H + 2CH20 + 2C2H5-SH --->


CH3

C2H5-S-CH2-N -CH2-S-C2H'


Purification Method . .
Yield . . . . .
Molecular Formula . .
Molecular Weight. .. .
Boiling Point . . .
Refractive Index (25) .


S. . Distilled at 0.4mm.
S. . 32%
. . C11H24N2S2
S. . 248.44
S. . 126-126.5/0.4mm.
. 1.5283


Analytical Data:


Carbon, %:


Nitrogen, %:


Calculated: 53.18


Found:


53.42


Hydrogen, %:


Calculated:

Found:


Sulfur, %:


Calculated: 9.74


Found:


9.61


Calculated:

Found:


Solubilities:


Ethanol. .
Methanol .
Benzene. .
Ether. . .
Water. . .
5 % HCl. .
5 % NaOH ,
Chloroform .


* .
* . .
* . .
* . .

. . .
. . .


Soluble
Soluble
Soluble
Soluble
Decomposes very slowly
Reacts
Decomposes slowly
Soluble


11.28

11.10


25.81

25.6













Bis-1.4-ethvlthiomethvl-trans-2.5-dimethvliperazine

Equation for Synthesis:

CH3

H- -H + 2CH20 + 2C2H5-SH >

CH3

CH3


C2H5-S-CH2--



Purification Method .


Yield . . .
Molecular Formula
Molecular Weight.
Melting Point .

Analytical Data:


Carbon, %:

Calculated:

Found:


54.91

54.72


Hydrogen, %:


-CH2-S-C2H5


* S


* S S


* a a


Recry.---Methano3
49%
C12H26N2S2
262.47
57.1-58.8


Nitrogen, %:


Calculated: 10.68


Found:


10.83


Sulfur, %:


Calculated:

Found:


9.99

9.98


Calculated: 24.43


Found:


24.6


Solubilitiest


Ethanol. .
Methanol .
Benzene. .
Ether. .
Water. .
5 % HCl. .
5 % NaOH .
Chloroform


. S .

. . .
* S S S S
* S S *
. . .

. . .
. . .
. S .


Soluble
Soluble hot
Soluble
Soluble
Decomposes very slowly
Reacts
Decomposes slowly
Soluble













1-Phenvl-4-ethyvlthomethyvlpierazine


Equation for Synthesis:



OA-H + CH20 + C2H5-SH 3





OS N-CH2-S-C2H5


Purification Method . .
Yield . . . . .
Molecular Formula . .
Molecular Weight. . .
Melting Point . . .


S . .
. . .
. . .
* . .
* . .


Recry.---Ethanol
64%
C13H20N2S
23 .37
79.8-81.9


Analytical Data:


Nitrogen, %:


Calculated: 66.06


Found:


Hydrogen, %:


Calculated:

Found:


65.95



8.53

8.42


Calculated: 11.85


Found:


11.72


Sulfur, %:


Calculated: 13.56


Found:


13.2


Solubilities:


Ethanol. .
Methanol .
Benzene. .
Ether. .
Water. .
5 % HC1. .
5 % NaOH .
Chloroform


*
. .
. . .
* 0 S
0 .
. . .
. . .
S . .
. .t .


Soluble hot
Soluble hot
Soluble
Soluble
Decomposes very slowly
Reacts
Decomposes slowly
Soluble


Carbon, %:












1- (2-Methvlyhenyl) -4-ethvlthlomethvlnioerazine

Equation for Synthesis:



S H + CH20 + C2H5-SH -

CH3




H-CH2-S-C2H5
CH3


Purification Method .
Yield . . . . .
Molecular Formula . .
Molecular Weight. . .
Boiling Point . . .
Refractive Index (25) .


* . .


Distilled at 0.40mm.
52%
C14H22N2S
250.40
158-158.5/0.40mm.
1.5617


Analytical Data:


Nitrogen, %:


Calculated: 67.16


Found:


Hydrogen, %:


Calculated:

Found:


67.40



8.86

9.29


Calculated: 11.19


Found:


11.0


Sulfur, %:


Calculated: 12.81


Found:


12.70


Solubilities:


Ethanol. .
Methanol .
Benzene. .
Ether. . .
Water. . .
5 % HCl. .
5 % NaOH .
Chloroform .


* * *
* . .
. .
. *
. . *


* * *


Soluble
Soluble
Soluble
Soluble
Decomposes very slowly
Reacts
Decomposes
Soluble


Carbon, %:












1-(3-Methyvlhenyl)-4-ethvlthiomethvlTi-Derazine


Equation for Synthesis:


+ CH20 + C2H5-SH




*CH2-S-C2H5


Purification Method .
Yield . . . . .
Molecular Formula . .
Molecular Weight. . .
Boiling Point . . .
Refractive Index (25)


* . .


Distilled at 0.30mm.
41%
C14H22N2S
250.40
172-4/0.30mm.
1.5723


Analytical Data:


Carbon, %:


Nitrogen, %:


Calculated: 67.16


Found:


Hydrogen, %:


67.50


Calculated: 11.19


Found:


11.2


Sulfur, %:


Calculated:

Found:


8.86

8.85


Calculated: 12.81


Found:


12.6


Solubilities:


Ethanol..
Methanol .
Benzene..
Ether. ..
Water. ..
5 % HC1. .
5 % NaOH .
.Chloroform


* . *

. . .


Soluble
Soluble
Soluble
Soluble
Decomposes very slowly
Reacts
Decomposes slowly
Soluble


. .













1-(4-Methyvlhenyl)-4-ethvlthiomethylpiperazine

Equation for Synthesis:



CH3 Q S N-H + CH20 + C2H5-SH >




CH3 \NS -CH2-S-C2H5


Purification Method .
Yield . . . . .
Molecular Formula . .
Molecular Weight. . .
Melting Point . . .
Boiling Point . . .


* @ @

*
*
. . .
. . .
. . .


Distilled at 0.4mm.
52%
C14H22N2S
250.40
29-30.5
154-154.5/0.4mm.


Analytical Data:


Nitrogen, %:


Calculated: 67.16


Found:


Hydrogen, %:


Calculated:

Found:


67.39



8.86

8.74


Calculated: 11.19


Found:


11.28


Sulfur, %:


Calculated: 12.81


Found:


13.05


Solubilities:


Ethanol. . .. ..
Methanol . . .
Benzene. . . .
Ether. .. . . .
Water. . . . .
5 % HC1 . . .
5 % NaOH . . .
Chloroform . . .


Soluble
Soluble
Soluble
Soluble
Decomposes very slowly
Reacts
Decomposes slowly
Soluble


Carbon, %:













1-(2-Chlorophenvl)-4-ethvlthiomethylviperazine

Equation for Synthesis:



N H + CH20 + C2H5-SH >

Cl


Purification Method .
Yield . . . .
Molecular Formula . .
Molecular Weight. . .
Boiling Point .. .
Refractive Index (25) .


Distilled at 0.30mm.
57%
C13H19ClN2S
270.82
158-158.5/0.30mm.
1.5775


Analytical Data:


Carbon, %:


Calculated:

Found:


Nitrogen, %:


57.65

57.70


Hydrogen, %:


Calculated: 10.35


Found:


10.40


Sulfur, %:


Calculated:

Found:


Calculated: 11.84


7.07

6.92


Found:


12.06


Solubilities:


Ethanol. .
Methanol .
Benzene. .
Ether. .
Water. .
5 % HC1. .
5 % NaOH .
Chloroform


* S S S
* . .
* S S S S
* S S *
* S S S *
* S S S
S S * S
S S S S


Soluble
Soluble
Soluble
Soluble
Decomposes very slowly
Reacts
Decomposes slowly
Soluble












1-(3-Chlorophenl)- 4-ethvlthlomethvliperazine


Equation for Synthesis:


+ CH20 + C2H5-SH >


SII S -CH2-S-C2H5
Cl


Purification Method .
Yield . . . . .
Molecular Formula . .
Molecular Weight. . .
Boiling Point . . .
Refractive Index (25) .


* 9


Distillation at 0.50mm.
45%
C13Hi9ClN2S
270.82
185.5-186/0.50mm.
1.5879


Analytical Data:


Carbon, %:


Nitrogen, %:


Calculated: 57.65


Found:


57.80


Hydrogen, %:


Calculated:

Found:


Sulfur, %:


Calculated:

Found:


7.07

6.65


Calculated:

Found:


Solubilities:


Ethanol. .
Methanol .
Benzene. .
Ether. . .
Water. . .
5 % HCl. .
5 % NaOH .
Chloroform .


. S 9 9
. 9 9 9


* S 9 ~
* 9 5


Soluble
Soluble
Soluble
Soluble
Decomposes very slowly
Reacts
Decomposes slowly
Soluble


' 9


10.35

10.50


11.84

11.72













1-(4-Chlorohenyvl)-4-ethyvlthiomethvlpinerazine

Equation for Synthesis:



Cl N S -H + CH20 + C2H5-SH




CIs -CH2-S-C2H5


Purification Method .
Yield . .
Molecular Formula . .
Molecular Weight .
Melting Point . . .


* S


* . S
* S S
* S S

* . S


Recry.---Ethanol
42%
C13H19ClN2S
270.82
68.7-71.8


Analytical Data:


Carbon, %:


Calculated:

Found:


Nitrogen, %:


57.65

57.65


Hydrogen, %:


Calculated: 10.35


Found:


10.40


Sulfur, %:


Calculated:

Found:


Calculated: 11.84


7.07

7.14


Found:


11.9


Solubilitiess


Ethanol..
Methanol .
Benzene..
Ether. ..
Water. .
5 % HC1..
5 % NaOH .
Chloroform


SS S ~
* S S S
* S S S

* S S S S
* S S S
* S S S S
* S S S S


S S S
* S


Soluble hot
Soluble hot
Soluble
Soluble
Decomposes very slowly
Reacts
Decomposes slowly
Soluble












1-(2-Methoxvhenvyl)-4-ethvlthlomethvlilterazine

Equation for Synthesis:



Q N S N-H + CH20 + C2H5-SH --

OCH3



N S N-CH2-S-C2H5

OCH3


Purification Method .
Yield . . . . .
Molecular Formula . .
Molecular Weight. . .
Boiling Point . . .
Refractive Index (25) .


Distilled at 1.30mm.
62%
C14H22N20S
266.40
180-180.5/1.30mm.
1.5704


Analytical Data:


Nitrogen, %:


Calculated: 63.12


Found:


Hydrogen, %:


Calculated:

Found:


63.30


8.32

8.17


Calculated: 10.52


Found:


10.63


Sulfur, %:


Calculated: 12.03


Found:


11.8


Solubilities:


Ethanol . . .
Methanol . . .
Benzene. . . .
Ether. . . . .
Water. . . . .
5 % HCl. . . .
5 % NaOH . . .
Chloroform . .


. . Soluble
. . Soluble
* . Soluble
. . Soluble
* . Decomposes very slowly
* . Reacts
. . Decomposes
. . Soluble


Carbon, %:












1-Methyl-4-ethvlthiomethyvliperazine


Equation for Synthesis:



CH3- N-H + CH20 + C2H5-SH -




CH3-N -CH2-S-C2H5


Purification Method .
Yield . . . . .
Molecular Formula . .
Molecular Weight. . .
Boiling Point . . .
Refractive Index (25) -


* .. .
* . *


Distilled at 0.7mm.
64%
C8H18N2S
174.30
76-78/0.7mm.
1.5008


Analytical Data:


Carbon, %:


Calculated: 55.12


Found:


Hydrogen, %:


Nitrogen, %:

Calculated: 16.08


55.01


Found:


16.0


Sulfur, %:


Calculated: 10.41


Found:


10.39


Calculated: 18.40


Solubilities:


Ethanol. . . .
Methanol . . .
Benzene. . . .
Ether. . . . .
Water. . . . .
5 % HCl. . . .
5 % NaOH . . .
Chloroform . . .


Soluble
Soluble
Soluble
Soluble
Decomposes very slowly
Reacts
Decomposes slowly
Soluble


Found:


18.1












Bis-1.4-n-butvlthiomethvlT)lerazine


Equation for Synthesis:



H-N S N-H + 2CH20 + 2C4H9-SH ---




C4H9-S-CH2-QS -CH2-S-C4H9


Purification Method .
Yield . . . . .
Molecular Formula . .
Molecular Weight. . .
Melting Point . . .


* a * *
* . a .


Recry.---Ethanol
52%
C14H30N2S2
290.49
43.5-46.6


Analytical Data:


Carbon, %:


Nitrogen, %:


Calculated:

Found:


Hydrogen, %:


Calculated:

Found:


57.89

57.90


10.41

10.05


Calculated: 9.65


Found:


9.60


Sulfur, %:


Calculated: 22.08


Found:


22.25


Solubilities:


Ethanol. .
Methanol .
Benzene. .
Ether. .
Water. .
5 % HC1. .
5 % NaOH .
Chloroform


Soluble hot
Soluble hot
Soluble
Soluble
Decomposes very slowly
Reacts
Decomposes slowly
Soluble













Bis-1.4-n-butvlthiomethyl-2-methylpiperazine

Equation for Synthesis:

CH3

H-( S N-H + 2CH20 + 2C4H9-SH -


CH3

C4H9-S-CH2- JN-CH2-S-C4H9


Purification Method .
Yield . . .
Molecular Formula .
Molecular Weight. . .
Boiling Point . . .
Refractive Index (25) .


* . .
* . . .
* . . .
* . . .
* . . .


Distilled at 0.075mm.
54%
C15H32N2S2
304.55
157-158/0.075mm.
1.5157


Analytical Data:

Carbon, %:

Calculated:

Found:


Hydrogen, %:


Calculated:

Found:


Nitrogen, %:


59.14

59.11



10.59

10.34


Calculated: 9.20


Found:


9.29


Sulfur, %:


Calculated: 21.05


Found:


21.3


Solubilities:


Ethanol. .
Methanol .
Benzene. .
Ether. .
Water. .
5 % HCl. .
5 % NaOH .
Chloroform


. . .
* . *

* . .
. . .

. . .
. . .


* . Soluble
. . Soluble
. . Soluble
. . Soluble
. Decomposes very slowly
S. Reacts
S. Decomposes slowly
S. Soluble













Bis-1.4-n-butvlthiomethvl-trans-2.5-dimethylpilerazine

Equation for Synthesis:

CH3

H-N S -H + 2CH20 + 2C4H9-SH )

CH3



C4H9-S-CH2- S -CH2-S-C4H9

CH3


Purification Method .
Yield . . . . .
Molecular Formula . .
Molecular Weight. . .
Melting Point . . .


Analytical Data:

Carbon, %:

Calculated:

Found:


* . .
* . .
* U *

* S *


Recry.---Ethanol
48%
C16H34N2S2
318.57
32.4-34.5


Nitrogen, %:


60.33

60.42


Hydrogen, %:


Calculated: 8.79


Found:


8.65


Sulfur, %:


Calculated:

Found:


10.76

10.62


Calculated: 20.13


Found:


19.85


Solubilities:


Ethanol. .
Methanol .
Benzene. .
Ether. .
Water. .
5 % HC1. .
5 % NaOH .
Chloroform


. U ~ U ~
* S S ~ U
* . S
. U S U
. S ~ S
. S ~ *
S U ~ ~ U
S 5 4 5 ~


Soluble hot
Soluble hot
Soluble
Soluble
Decomposes very slowly
Reacts
Decomposes slowly
Soluble













1-Phenvl-4-n-butvlthiomethvyloperazine


Equation for Synthesis:




OS + CH20 + C4H9-SH



SN-CH2-S-C4H9


Purification Method .
Yield . . . .
Molecular Formula . .
Molecular Weight. . .
Boiling Point . . .
Refractive Index (25) .


* 9 S 0
* a 9
* . 9
* 9 9
* 9 9 9
-. 9


Distilled at 0.7mm.
58%
C15H24N2S
264.42
179-180/0.7mm.
1.5637


Analytical Data:


Carbon, %:


Nitrogen, %:


Calculated: 68.13


Found:


68.19


Hydrogen, %:


Calculated:

Found:


Sulfur, %:


Calculated:

Found:


9.15

9.11


Calculated:


Found:


12.13

12.2


Solubilities:


Ethanol. *
Methanol .
Benzene. .
Ether. . .
Water. .
5 % HC1. ..
5 % NaOH .
Chloroform .


* * *
. *
* . *
* * *
. 9 9 *
* 9 9 9
. . .
* 9 9 9
. . .9
. . .


. 9 9

. 9 9
. 9 9
9 9 9

9 9 .


Soluble
Soluble
Soluble
Soluble
Decomposes very slowly
Reacts
Decomposes slowly
Soluble


10.60

10.4













1-(2-Methylphenvl)-4-n-butvlthiomethvlpiperazine

Equation for Synthesis:



S-H + CH20 + C4H9-SH >

CH3


fY\S-CH2-S-C4H9

CH3


Purification Method .
Yield . . . . .
Molecular Formula . .
Molecular Weight. . .
Boiling Point . . .
Refractive Index (25) .


* .


* . .
* . .


* . .
* 9 9


Distilled at 0.170mm.
64%
C16H26N2S
276.43
160-160.5/0.170mm.
1.5501


Analytical Data:


Nitrogen, %:


Calculated: 69.53


Found:


Hydrogen, %:


Calculated:

Found:


69.31



8.75

9.18


Calculated: 10.14


Found:


10.15


Sulfur, %:


Calculated: 11.60


Found:


11.8


Solubilities:


Ethanol..
Methanol .
Benzene.
Ether. ..
Water. .
5 % HC1l .
5 % NaOH .
Chloroform


. 9 . 9

. . .

9 9 . 9
9 . 9 .
9 9 9 .
9 9 9


* 9


Soluble
Soluble
Soluble
Soluble
Decomposes very slowly
Reacts
Decomposes slowly
Soluble


Carbon, %:














1- ( 3-Methylphenvl) -4-n-butvlthiomethvlPoierazine

Equation for Synthesis:



N S N-H + CH20 + C4H9-SH >


3


SS -CH2-S-C4H9
CH 3


Purification Method .
Yield . . ..
Molecular Formula . .
Molecular Weight. . .
Boiling Point . . .
Refractive Index (25) .


* S
* 9
9 9
S


9 5 9
S S S
9 5 5 9
* 9 5
* 9 9 9
9 9 9 5


Distilled at 0.2mm.
46%
C16H26N2S
276.43
167.5-168/0.2mm.
1.5590


Analytical Data:


Carbon, %:


Calculated:

Found:


Nitrogen, %:


69.53

69.21


Hydrogen, %:


Calculated: 10.14


Found:


10.13


Sulfur, %:


Calculated:

Found:


8.75

9.01


Calculated: 11.60


Found:


11.5


Solubilities:


Ethanol.
Methanol .
Benzene. *
Ether. ..
Water. .
5 % HCl. .
5 % NaOH .
Chloroform


* . *
. 9 .
* * *
* * *
* 9 0 5 5
* *
9 9

. . .
* *
* * *


* 9
* 9
* .

* 9 @

* .
* 9


Soluble
Soluble
Soluble
Soluble
Decomposes very slowly
Reacts
Decomposes slowly
Soluble














1- (4-Methyvlhenvl)-4-n-butvlthiomethvlDiPerazine

Equation for Synthesis:



CH3 N S N-H + CH20 + C4H9-SH >




CH S -CH2-S-C4H9


Purification Method .
Yield . . . . .
Molecular Formula . .
Molecular Weight. . .
Melting Point . .


* .
* .

* .
* .


* *
* .
* *
* .
* .


Recry.---Ether
54%
C16H26N2S
276.43
28.3-30.6


Analytical Data:


Nitrogen, %:


Calculated: 69.53


Found:


Hydrogen, %:


Calculated:

Found:


69.31



8.75

9.04


Calculated: 10.14


Found:


9.98


Sulfur, %:


Calculated: 11.60


Found:


11.3


Solubilities:


Ethanol. .
Methanol .
Benzene. .
Ether. .
Water. .
5 % HCl. .
5 % NaOH .
Chloroform


* ..
* .


. .


* .
* . .
. . .
* . .
. * *
. .
. . .
. . .


Soluble
Soluble
Soluble
Soluble
Decomposes very slowly
Reacts
Decomposes slowly
Soluble


Carbon, %:













1-(2-ChloroThenvl)-4-n-butvlthiomethylpioerazine


Equation for Synthesis:


+ CH20 + C4H9-SH -


C1N -CH2-S-C4H9
Cl


Purification Method .
Yield . . . . .
Molecular Formula . .
Molecular Weight. . .
Boiling Point . . .
Refractive Index (25)


* .
* .


* .


* . *
* 0 *
* . .
* 0 5
* S St S
* * *


Distilled at 0.150mm.
48%
C15H23ClN2S
298.867
178-178.5/0.150mm.
1.5634


Analytical Data:


Carbon, %:


Nitrogen, %:


Calculated: 60.27


Found:


60.44


Hydrogen, %:


Calculated:

Found:


Sulfur, %:


Calculated:

Found:


7.75

7.68


Calculated:

Found:


Solubilities:


Ethanol. . . .
Methanol . . .
Benzene. . . .
Ether. . . . .
Water. . . . .
5 % HCl. . . .
5 % NaOH . . .
Chloroform . . .


* S S
* 0 5

S 0 5
S S S
* .
S S S


Soluble
Soluble
Soluble
Soluble
Decomposes very slowly
Reacts
Decomposes slowly
Soluble


9.38

9.41


10.73

10.4













1-(3-Chlorophenyl)-4-n-butvlthiomethvlpierazine

Equation for Synthesis:



OS -H + CH20 + C4H9-SH ---

Cl


NI S\-CH2-S-C4H9

Cl


Purification Method .
Yield . . . . .
Molecular Formula . .
Molecular Weight. . .
Boiling Point .. .
Refractive Index (25) .


* S S
* 9 9
* S
* . 9
* 9 .
* . S


Distilled at 0.15mm.
72%
C15H23ClN2S
298.867
179.5-180/0.15mm.
1.5721


Analytical Data:


Carbon, %:


Calculated:

Found:


Nitrogen, %:


60.27

60.11


Hydrogen, %:


Calculated:


Found:


Sulfur, %:


Calculated:

Found:


Calculated:


7.75

7.79


Found:


Solubilities:


Ethanol. .
Methanol .
Benzene. .
Ether. .
Water. . .
5 % HCl. .
5 % NaOH .
Chloroform .


. S 9 ~

. S ~ S S
* S ~ ~
* 9 9 9 *
9 S S ~ S
* S 9 9 5


Soluble
Soluble
Soluble
Soluble
Decomposes very slowly
Reacts
Decomposes slowly
Soluble


9.38

9.68


10.73

10.65














1- (4-Chloroohenvl) -4-n-butvlthiomethvloiperazin.e

Equation for Synthesist



Cl-c\ N-H + CH20 + C4H9-SH >




Cl N S N-CH2-S-C4H9


Purification Method .
Yield . . . . .
Molecular Formula . .
Molecular Weight. . .
Melting Point . . .


* .
* .


* . .
* . .
* . .
* . .
* .


Recry.---Ether
47%
C15H23ClN2S
298.867
47.2-51.1


Analytical Data:


Carbon, %:


Nitrogen, %:


Calculated: 60.27


Found:

Hydrogen, %:


60.09


Calculated:

Found:


Sulfur, %:


Calculated: 7.75


Found:


7.76


Calculated:

Found:


Solubilities:


Ethanol. .
Methanol .
Benzene. .
Ether. .
Water. .
5 % HCl. .
5 % NaOH .
Chloroform


* . .
* * .
* . .
. . .
* . *
* . *
. . .
. . .


. *
* .
. a
. .

. .
* .


Soluble
Soluble
Soluble
Soluble
Decomposes very slowly
Reacts
Decomposes slowly
Soluble


9.38

9.73


10.73

10.35














1-(2-Methoxvphenvl)-4-n-butvlthiomethvlplDerazine


Equation for Synthesis:


*H + CH20 + C4H9-SH -


o CH2-S-C4H9

OCH3


Purification Method .
Yield . . . . .
Molecular Formula . .
Molecular Weight. . .
Boiling Point . . .
Refractive Index (25) *


. .


* *

* .


* . .
* . .

* 0 ~ 0
* 0
* 0


Distilled at 0.20mm.
57%
C16H26N20S
294.45
180-180.5/0.20mm.
1.5583


Analytical Data:


Carbon, %:


Nitrogen, %:


Calculated 65.28


Found:

Hydrogen, %:


65.21


Calculated: 9.52


Found:


9.06


Sulfur, %:


Calculated: 10.89


8.90

8.65


Found:


10.57


Solubilities:


Ethanol. .
Methanol .
Benzene. .
Ether. . .
Water. . .
5 % HCl. .
5 % NaOH .
Chloroform .


. 0 .
. 0 *
* @
. .

. . .
. . .
. . .


* 0 ~

. 0 0


. 0
. 0 *


Soluble
Soluble
Soluble
Soluble
Decomposes very slowly
Reacts
Decomposes slowly
Soluble


Calculated:

Found:













1-Methvl-4-n-butvlthiomethvlpierazilne


Equation for Synthesis:



CH3- -H + CH20 + C4H9-SH -




CH3- S -CH2-S-C4H9


Purification Method . .
Yield . . . . .
Molecular Formula .
Molecular Weight. . .
Boiling Point . . .
Refractive Index (25) *


. . .
. . .
. . .
. . .
. . .
. . .


Distilled at 0.18mm.
62%
C10H22N2S
202.36
89-90/0.18mm.
1.4933


Analytical Data:


Carbon, %:


Nitrogen, %:


Calculated: 59.34


Found:


Hydrogen, %:


Calculated:

Found:


59.30



10.96

10.79


Calculated:

Found:


Sulfur, %:


Calculated:


Found:


Solubilities:


Ethanol. . . .
Methanol . . .
Benzene. . . .
Ether. . . . .
Water. . . . .
5 % HC1. . . .
5 % NaOH . . .
Chloroform . ..


. .
. .


* .
. .

. .


Soluble
Soluble
Soluble
Soluble
Decomposes very slowly
Reacts
Decomposes slowly
Soluble


13.85

14.01


15.84

15.9














CHAPTER IV


THE STRUCTURE OF THE PRODUCTS OF THE REACTION
OF ARYLTHIOLS WITH FORMALDEHYDE AND PIPERAZINES


A. General Discussion


As previously mentioned, McLeod and Robinson13 were

the first workers to use thiols in the Mannich reaction.

They were followed by Renshaw and Searle,14 who used the

reaction as an intermediary step in a different investi-

gation.

In 1954, Grillot, et al.,16 reported the use of

arylthiols in place of the alkylthiols used by McLeod

and Robinson.13 The resulting products had no absorption

peak in the 2690-2550 cm.-1 region of the infra-red

spectrum, could not react to add a second dialkylamino-

methyl group, and were unstable to dilute acids as are

alkylthiomethylamines. These workers assumed that the

products have an arylthiomethylamine structure rather than

a structure comparable to that of the product obtained

when phenol is reacted with formaldehyde and a secondary

amine.

The Mannich reaction using phenols has been extensively

applied. The ortho andpara hydrogens of phenol are

sufficiently active to undergo the Mannich reaction.

Ordinarily, the first substitution product has the

37









aminomethyl group in the ortho position. The work of
Decombe17 and of Bruson18 furnished examples of the type
of reaction typical of phenol:

OH OH

O + (CH3)2NH + CH20 1CH2-N-(CH3)2
OH
O CH2-N-(CH3)2 + (CH3)2NH + CH20

OH
O CH2-N-(CH3)2

CH2-N-(CH3)2

It was found that a third substituted aminomethyl group
could be introduced into phenol if large enough excesses
of amine and formalin were used.
There were two possible structures for the product
of the reaction of an arylthiol and formaldehyde with a
piperazine. The two proposed structures (piperazine being
represented as NR2) are:

S-CH2-NR2 SH
Sa CH2-NR2












B. Proposed Methods of Attack


1. Infra-red Analysis

Bell19 found an absorption peak between 2690-2550 cm.-1

in the infra-red spectrum of thiophenol which was absent in

the spectrum of diphenyl sulfide. Thus the infra-red

spectra of the compounds in question would help to determine

their general structure. The absence of any absorption in

the 2690-2550 cm.-1 region would show the absence of an -SH

group indicating that the substances were thioethers rather

than orthosubstituted arylthiols.

Furthermore, in the infra-red spectra of numerous mono-

substituted benzenes Young, DuVall, and Wright20 found a

series of four bands of gradually diminishing intensity in

the 2000-1650 cm.-1 region. The presence of four weak

bands of diminishing intensity in this region would be

strongly indicative of a monosubstituted benzene ring.

Since structure II has to contain a disubstituted benzene

ring, such bands would indicate that the compounds were

arylthiomethylamines (thioethers) corresponding to structure

I.

Whiffen and Thompson21 have described a band indicating

monosubstitution which appears between 760-740 cm.-1

This range has been broadened by Colthup22 to limits of 770-

730 cm.-1 Undortunately an ortho-disubstituted benzene ring

also absorbs near 760 cm.-1 so another band is needed for












absolute identification of a monosubstituted benzene ring.

Bellamy23 gives an absorption band at approximately 690

om.-1 that appears in the spectra of almost all monosub-

stituted benzenes. Randall, et al.,24 gave 690 L 10 cm.-1

as the range in which this absorption appears. The pres-

ence of strong bands in these two regions would strongly

indicate the thioether structure (I).

2. Ultraviolet Studies

It has already been established that any compound

containing the ( S structure has absorption peaks in

the ultraviolet region of the electromagnetic spectrum.25

If the compound in question contained a free thiol group,

the addition of alkali would cause a reversible shift in

the absorption maximum. However, if in the case of an

arylthiomethylamine, nucleophilic attack of the hydroxyl

ion produced the thiophenolate ion, acidification would

result in free thiophenol. This free thiophenol would not

show an absorption maximum at exactly the same wave length

as the untreated compound.


3. Oxidation Studies

Oxidation of the product from the reaction of thio-

phenol, formaldehyde, and a piperazine would be expected

to yield benzene sulfonic acid or diphenyl disulfide if

structure I is the true structure, indicating reaction at

the thiol sulfur atom. If on the other hand structure II












were correct, nuclear condensation having taken place,

the oxidation would be expected to produce 2-carboxy-

benzene sulfonic acid or di-2-carboxyphenyl disulfide.

It was decided to investigate also the oxidation of

the product from the reaction of p-thiocresol, form-

aldehyde, and a piperazine. The methyl group provides

a means of distinguishing the various positions on the

benzene ring. If structure I were correct, oxidation

would be likely to yield p-tolylbenzene sulfonic acid or

di-p-tolyl disulfide. If structure II were correct,

oxidation would be expected to yield 2-carboxy-4-methyl-

phenyl sulfonic acid or the corresponding disulfide.

4. Reduction Studies

Hydrogenation of a compound containing a benzyl
group attached to a nitrogen atom has been found to

result in the fission of the CH2--N bond.26 Thus

toluene or substituted toluenes ave been isolated as the

major products of hydrogenation along with an amine with

at least one hydrogen attached to the nitrogen atom. The

following equation may be used as an example:



2 CH2-N(R')2 H > CH3 + H-N(R')2

R1 R1

Birkofer,26 because of the value of the preparative method












available through the catalytic removal of the benzyl

group attached to a nitrogen atom, found numerous

examples of the hydrogenative fission of N-benzyl compounds.

Birkofer26 found that the hydrogenation of, 1,4-dibenzyl-

piperazine in acetic acid, using a palladium oxide catalyst

at.room temperature and atmospheric pressure, gave a 92%

yield of the piperazinium diacetate.

The reduction of a compound of structure I would

result in either thiophenol and the N-methylpiperazine or

thioanisole and the free piperazine. The reduction of a

compound of structure II would be expected to give only

o-thiocresol and the free piperazine as products.


5. Mass Spectroscopic Analysis

Up to the present time investigators had not applied

the technique of mass spectroscopy to the problem of

distinguishing between compounds corresponding to

structures I and II:


S-CH2-NR2 SH




I II


The presence in the mass spectrum of a peak

corresponding to the fragment shown next would confirm

structure I:












-S-CH2-NR2+


Also a compound with structure I would be expected to give

a large peak corresponding to a m/e ratio of 110. This

fragment can only be:


GS-H +


Besides this, a smaller peak corresponding to a m/e ratio

of 124 would be expected. This could correspond to either

III or IV:


-S-CH + S-H

CH 3


III IV


Fragment III would be derived from structure I and fragment

IV would be derived from structure II. If the peak for
124 is smaller than the peak for 110, the correct structure

would have to be I. A compound with structure II would be

expected to give a very large peak corresponding to a m/e

ratio of 124 and a small or non-existent 110 peak.


C. Discussion of Results


1. Infra-red Analysis

Infra-red spectra were prepared for diethylamino-

methyl isopropyl sulfide and the reaction products of

piperazine and trans-2,5-dimethylpiperazine and formaldehyde












with thiophenol. A reaction with the thiol group would

lead to compounds having a sulfide structure similar to

that of diethylaminomethyl isopropyl sulfide, i.e.,

similar to structure I, where the phenyl group is replaced

by the isopropyl group. However, a nuclear reaction would

lead to compounds having an -SH group on the phenyl ring.

Examination of the spectra showed that in no case was

there any absorption peak in the 2690-2550 cm.-1 region.

Since this region has been assigned to absorptions due to

the -SH group,19, 24 and barring a shift in such a peak,

it must be assumed that none of the compounds analyzed

contained an -SH group.

Further examination of the spectra obtained from the

products involving thiophenol, in all cases, shows a

strong band between 750-730 cm.-1 and a second strong band

at 690 cm.-1 Also a series of four weak bands of gradually

,diminishing intensity appears between 2000-1650 cm.-1

Since absorptions in these three regions have been assigned

to a monosubstituted benzene ring21,22,23,24 and since the

intensity variation on the four weak bands has been given

as characteristic of a monosubstituted benzene ring, it

must once again be assumed that none of the compounds con-

tained a free -SH group on a benzene ring. If the compound

contained a free -SH group, the molecule would necessarily

have contained an ortho-disubstituted benzene ring and












would not have shown the infra-red absorption bands

characteristic of monosubstitution. Thus all of the infra-

red evidence points to structure I as the true structure.

See Table 1.


2. Ultraviolet Studies

The results of the ultraviolet studies on the products

of the condensation in neutral and basic media were not as

useful as might have been hoped. If the molecule contained

a free -SH group, the spectrum resulting from addition of

first base and then acid should have been totally reversible

to exactly the same ultraviolet absorption peak as shown

by the untreated compound. If the molecule was decomposed

by alkali, the spectrum obtained after acidification should

show a shift in the maximum absorption.

The results show a definite although very slight shift

in the absorption peak upon acidification. This shift

although small must be assumed to mean that the reaction

between alkali and the compound in question is not a

reversible salt formation but is a nucleophilic decomposition.

This ultraviolet evidence points to structure I as the true

structure. See Table 2.


3. Oxidation Studies

It has been proposed that the structure of the conden-

sation product of thiophenol or p-thiocresol, formaldehyde,










TABLE 1


INFRA-RED PEAKS OF THE CONDENSATION PRODUCTS


-SH Band Monosubstitution Bands
Condensation Product 2690-2625 2000-1650 770-730 700-680
cm.-1 cm.-1 cm.-1 cm.-1


Isopropyl diethylamino- NO PEAK NO PEAK NO PEAK NO PEAK
methyl Sulfide


Bis-1,4-phenylthiomethyl- NO PEAK 1950 743-740 688-680
piperazine 1880
1810
1730


Bis-1,4-phenylthiomethyl- NO PEAK 1945 745-738 692-690
2,5-dimethylpiperazine 1880
1810
1735












TABLE 2

ULTRAVIOLET DATA


Compound*


Thiophenol


p-Thiocresol


Bis-1,4-phenyl-
thiomethyl-2,5-
dimethylpiper-
azine


Absorption in the 220-340 mu, Region
Initial After Add. After Add. of
of Alkali Excess Acid


239.4


238.3


239.5


266.2


264.2


265.0


239.4


238.3


238.5


*Solvent System -- 95% Methanol-Water.


and a piperazine corresponds either to that of an arylthio-

methylamine (I) or an orthosubstituted thiol (II):


RI( S-CH2-NR2



I

R1 = (H-,CH3-).


R1 SH
CH2NR2


II


Oxidation of a compound of structure I would lead to either

a disulfide or a sulfonic acid. Oxidation of a compound

of structure II would lead to either an ortho-disubstituted












disulfide or an orthosubstituted sulfonic acid.

Oxidation of the condensation product of thiophenol,

formaldehyde, and trans-2,5-dimethylpiperazine led to a

solid product. No depression of the melting point was

observed when this solid product was mixed with an

authentic sample of diphenyl disulfide, prepared by the

reaction of atmospheric oxygen with thiophenol.27 Oxi-

dation of the condensation product of p-thiocresol,

formaldehyde, and trans-2,5-dimethylpiperazine led to a

solid product whose melting point was not depressed by

admixture with an authentic sample of di-p-tolyl disulfide,

prepared by the reaction of bromine upon p-thiocresol.28

These oxidations were carried out with both alkaline

permanganate and with hydrogen peroxide in ethyl acetate.

A quantity of the di-p-tolylsulfonic acid salt of the

piperazine was isolated from the water layer.

If it is assumed that no decomposition of the starting

material took place prior to oxidation, the results indicate

that the products of the Mannich condensation with thio-

phenol and p-thiocresol are actually arylthiomethylpiper-

azines (structure I).

Carbon atoms attached to a benzene nucleus are

particularly resistant to cleavage, remaining attached to

the ring under most conditions. An exception may be found

in the reversibility of the Friedel-Crafts reaction whereby

an alkyl benzene may be converted to higher and lower













substitution products under the action of anhydrous

aluminum chloride. However, no such conditions were

present in the oxidation of the arylthiol condensation

products with either alkaline permanganate or hydrogen

peroxide. Thus oxidation evidence points to structure I

as the true structure.


4. Reduction Studies

When a benzyl group attached to a nitrogen atom,

particularly a tertiary nitrogen atom, is subjected to

hydrogenation the result is usually fission of the benzyl

to nitrogen bond producing a secondary amine and a toluene.

The hydrogenation of a compound of structure I could have

produced either the free thiol and a methyl substituted

piperazine or a methyl aryl thioether and the free piper-

azine. Hydrogenation of a compound of structure II could

have produced only the free thiocresol and the free piper-

azine.

Reduction of the condensation product of thiophenol,

formaldehyde, and trans-2,5-dimethylpiperazine led to a

product whose melting point was not depressed by admixture

with an authentic sample of trithiophenylmethane (the

orthoester of thiophenol and formic acid). The production

of this orthoester should have been expected as the reduc-

tion was carried out in a large excess of 88% formic acid.

The 88% formic acid was used to carry out the reduction to













avoid possible desulfurization which might have occurred

if reduction had been attempted catalytically.

Since thiophenol must have been present to form the

orthoester, it must be assumed that structure I is

correct and that these hydrogenation conditions resulted

in splitting the arylthiomethylamine.

5. Mass Spectroscooic Analysis

The compound whose structure was to be determined

was subjected to mass spectrograph through the kindness

and cooperation of the Shell Oil Company, Houston, Texas.

The two possible structures of the particular compound are:
CH3

I S-CH2- ( N-CH2-S

CH3
CH3

II < CHg-N S N-CH2

SH CH3 HS

The presence in the mass spectrum of a peak corresponding

to a sulfur atom attached to a methylenepiperazine would

definitely confirm structure I. The presence of a large

peak representing a m/e ratio of 110 and a smaller peak

representing a m/e ratio of 124 would also confirm

structure I.

The results of the mass spectrographic analysis show










a very small peak at a m/e ratio of 172. This peak can
be attributed to the following fragment:
CH3
-S-CH2-N S N-CH2-


The largest peak in the spectrum has a m/e ratio of 110
and must correspond to the following fragment:


OSH+


A somewhat smaller peak has a m/e ratio of 124 and could
represent either of the following structures:


( S-CH3 + or CH3+
SH
The presence of the peak at m/e ratio of 172
absolutely confirms that structure I is correct. This is
further confirmed by the presence.of such an extremely
large peak at a m/e ratio of 110. Therefore, the structure
of the condensation product of an arylthiol, formaldehyde,
and a piperazine must be that of an arylthiomethylamine.

6. Theoretical Reason the Exerimental Results
It has been shown in the preceding sections that
thiophenol does not react in the same manner as phenol
when subjected to the Mannich reaction. This experimental












fact can be explained and might have been predicted on

the basis of work done by Robertson and Matsen.30 These

investigators obtained the near ultraviolet absorption

spectrum of thiophenol in both the vapor phase and in

solution. Upon comparing this spectrum with those of

phenol and aniline, they found that this spectrum does

not occupy the position relative to phenol and aniline

expected from the ionization energies of the substituent

group. They suggested that this may be due to a relatively

smaller resonance integral between the ring and the sub-

stituent for thiophenol.

Our experimental results are in accordance with their

suggestion. If the resonance integral between the ring

and the substituent for thiophenol had been comparable to

that for phenol, the Mannich reaction would have proceeded

with nuclear condensation as in the case of phenol. Since

the Mannich reaction in the case of thiophenol does not

involve nuclear condensation, the resonance integral between

the ring and the substituent must be smaller than that for

phenol.


D. Experimental


1. Preparation of Isopropyl Diethylaminomethvl Sulfide13

To an aqueous solution of approximately 35% form-

aldehyde (13 g., 0.12 mole) was slowly added 8.5 g. (0.12

mole) of diethylamine. The mixture was cooled and swirled













in an ice bath during this addition. Thirteen grams (0.12

mole) of isopropyl mercaptan was then introduced in one

portion. The solution was saturated with anhydrous potas-

sium carbonate. The non-aqueous layer was separated and

allowed to remain in contact with an excess of anhydrous

potassium carbonate for 24 hours. The product was isolated

by fractionation as a colorless oil boiling between 183-

1850. A yield of 9.0 g. was obtained; 46% based upon the

amount of diethylamine.


2. Preparation ol Bis-1.4-phenvlthiomethvl-trans-2.5-
dimethylpiperazine

One tenth mole (11.4 g.) of trans-2,5-dimethylpiper-

azine was placed in a modified Erlenmeyer flask. The

Erlenmeyer flask was equipped with an addition side arm

and a ground glass joint to connect to an efficient con-

denser. .Two tenths mole (22.0 g.) of thiophenol was added

through the addition side arm slowly with stirring and then

in one portion, formalin equivalent to 0.20 mole of form-

aldehyde, was added. The mixture was stirred and refluxed

on a combination magnetic stirrer-hot plate for four to

six hours. After cooling to room temperature, the mixture

was extracted with three 50 ml. portions of ether. The

ether extracts were combined and dried over anhydrous

potassium carbonate for 24 hours. The ether solvent was

removed at reduced pressure and the product crystallized.

The product was recrystallized from ethanol as white












crystals with a melting point of 97-980. A yield of

18.5 g., 51.5% of theoretical, was obtained. More data

on this compound may be found in Chapter V.


3. Preparation of Bis-1.4-phenvlthiomethyloiperazine

One tenth mole (8.6 g.) of piperazine was placed in

a modified Erlenmeyer flask. Two tenths mole (22.0 g.)

thiophenol was added slowly through the addition side arm

with stirring and then, in one portion, formalin, equivalent

to 0.20 mole of formaldehyde, was added. The mixture

was stirred and refluxed on a combination magnetic stirrer-

hot plate for four to six hours. After cooling to room

temperature, the mixture was extracted with three 50 ml.

portions of ether. The ether solution from combination

of the extracts was dried over anhydrous potassium car-

bonate for 24 hours. The ether solvent was removed at

reduced pressure and the product crystallized. The

product was recrystallized from ether as white crystals

with a melting point of 101-1030. A yield of 18.0 g., 54%

of theoretical, was obtained. More data on this compound

may be found in Chapter V.

4. Preparation o. Bis-1.4-(4-methylphenvl)thiomethyl-
trans-2. -dimethyloioerazine

One tenth mole of trans-2,5-dimethylpiperazine was

placed in a modified Erlenmeyer flask. Two tenths mole

(24.8 g.) of p-thiocresol was added through the condenser












with stirring and then, in one portion, formalin, equiva-

lent to 0.20 mole of formaldehyde, was added. The mixture

was stirred and refluxed for four to six hours. After

cooling to room temperature, the mixture was extracted with

three 50 ml. portions of ether. The ether extracts were

combined and dried over anhydrous potassium carbonate.

The ether was removed at reduced pressure and the product

crystallized. The product was recrystallized as white

crystals with a melting point of 136-1380. A yield of

20.5 g., 53% of theoretical, was obtained. More data on

this compound may be found in Chapter V.


5. Infra-red Spectra

The infra-red spectra were obtained in the laboratory

set up for that purpose at the University of Florida. The

samples were run as mulls andc in KBr pellets on a Perkin-

Elmer Model 21 Recording Infra-red Spectrophotometer. Peaks

are listed in Table 1, page 46.


6. Ultraviolet Spectra

The ultraviolet spectra were run on a Beckman Model

DK Ratio Recording Spectrophotometer. The peaks for thio-

phenol, p-thiocresol and the compound whose structure was

to be determined in neutral and basic media are compiled

in Table 2, page 4?.












7. Oxidation of Bis-1.4-phenylthiomethyl-trans-2.5-
dimethvlopierazine

a. Oxidation Using Potassium Permanganate

Three and six-tenths grams (0.10 mole) of the

piperazine was added to a solution of 0.02 mole of potas-

sium permanganate in 200 ml. of water to which 5 ml. of

10% sodium hydroxide had been added. An immediate reaction

was noted; the mixture became warm. The reaction mixture

was refluxed for one-hour and allowed to cool. After
acidification with sulfuric acid, a saturated solution of

sodium hydrogen sulfite was added to reduce the manganese

dioxide to a soluble sulfate. White crystals were noted

floating on the top of the solution. These crystals were

filtered and recrystallized from ethanol. They gave a

positive test for sulfur. The melting point of this

compound was 59-61o. The melting point of diphenyl di-

sulfide recorded in the Handbook Chemistrynd Physics

is 610. A mixed melting point showed no depression with a

known sample of diphenyl disulfide, showing the two to be

identical.

b. Oxidation Using Hydrogen Peroxide

One hundredth mole (3.6 g.) of the piperazine

derivative and 9 ml. of 30% hydrogen peroxide solution

(approximately 0.08 mole) were shaken together for 5 minutes.

The mixture became warm almost immediately. After addition

of 50 ml. of water, the mixture was shaken for 15 minutes












and the organic layer separated. The solvent was evaporated

in a stream of air and the product crystallized. The

resulting crystals were recrystallized from ethanol. They

melted at 59-610 and a mixed melting point of this compound

and diphenyl disulfide showed the two to be identical.

8. Oxidation of Bis-1.4-(4-methylrhenvl)thiomethyl-trans-
2.5-dimethylpoierazine

a. Oxidation Using Potassium Permanganate

One hundredth mole (3.9 g-.) of the piperazine

derivative was added to a solution of potassium permanganate

in 200 ml. of water to which 5 ml. of 10% sodium hydroxide

had been added. An immediate reaction was noted; the

mixture became warm. The reaction mixture was refluxed

for one hour and allowed to cool. After acidification with

sulfuric acid, a saturated solution of sodium hydrogen

sulfite was added to reduce the manganese dioxide to a

soluble sulfate. White crystals floating on top of the

solution were noted. These crystals were filtered and then

recrystallized from ethanol. They gave a positive test for

sulfur. The melting point of this compound was 46-48.
The melting point of di-p-tolyl disulfide is reported as

45.60.28 A mixed melting point of the compound melting at

46 with a known sample of di-p-tolyl disulfide showed the

two to be identical.

b. Oxidation Using Hydrogen Peroxide

One hundredth mole (3.9 g.) of the piperazine












derivative and 9 ml. of 30% hydrogen peroxide solution

(approximately 0.08 mole) were shaken together for 15

minutes. The mixture became warm almost immediately.

A volume (50 ml.) of water was added. The mixture was

shaken for 15 minutes and the organic layer separated.

The solvent was evaporated in a stream of air, leaving

a yellow oil. The oil was taken up in ether. The ether

was allowed to evaporate and the resulting crystals were

recrystallized from ethanol. The white crystals obtained

from this recrystallization melted at 45-470 and a mixed

melting point of this compound and di-p-tolyl disulfide

showed the two to be identical. A yield of 1.75 g. of

the disulfide, 71% of theoretical, was obtained.

Upon partial evaporation of the aqueous layer a

compound was isolated, which was shown by analysis to be

the bis-p-toluene sulfonic acid salt of trans-2,5-dimethyl-

piperazine. A yield of 0.48 g., 11% of theoretical, was

obtained.

Analysis: Calc: C = 52.39% H = 6.59%
Found: C = 52.41% H = 6.56%
Calc: N = 6.11% S = 13.98%
Found: N = 6.10% S = 13.79%

9. Preparation of DiDhenvl Disulfide27
In a 250 ml. flask was placed 0.05 mole (5.5 g.) of

thiophenol and 50 ml. of very dilute ammonia solution. Air

was bubbled through this solution for five to six hours.













White crystals were noted floating upon the surface of the

solution. The crystals were filtered and then recrystal-

lized from ethanol. The melting point of this diphenyl di-

sulfide was 60-610. The melting point recorded in the

Handbook of Chemistry and Physics is 610.

10. Preparation of Di-p-tolvl Disulfide

In a 250 ml. Erlenmeyer flask fitted with a dropping

funnel side arm, a reflux condenser, and a magnetic bar

stirrer were placed 6.2 g. (0.05 mole) of p-thiocresol and

200 ml. of ether. The solution was cooled to 0 and 3.20

g. (0.20 mole) of bromine was added. The mixture was

stirred for half an hour and washed twice with a saturated

sodium hydrogen sulfite solution. The ether was evaporated

on a steam bath leaving a yellow oil which solidified upon

cooling. This solid was recrystallized from ethanol as

white crystals. The melting point of this di-p-tolyl di-

sulfide was 45-470. The reported melting point is 45.60.28

11. Reduction of Bis-1.4-phenylthiomethvl-trans-2.5-
dimethvlpiperazine

Two hundredths mole (7.2 g.) of the piperazine deriv-

ative was placed in a 100 ml. round bottom flask equipped

with a reflux condenser. A very large excess of 88% formic
acid (35 ml. = approximately 0.60 mole) was added through

the condenser. The resulting solution was refluxed for

three hours. Two liquid layers were formed. After cooling












to room temperature, the two layers were separated. The

organic layer was washed twice with 20 ml. portions of a

40% potassium hydroxide solution and once with distilled

water. The resulting oil crystallized upon standing over-

night. The crystals were recrystallized from ethanol.

The crystals melted at 39-40 and a mixed melting point of

this compound and trithiophenylmethane showed the two to be

identical.

12. Preparation of Trithiophenylmethane

Thirty-one hundredths mole (33.3 g.) of thiophenol

was mixed with 0.10 mole (5.3 g.) of approximately 88%

formic acid. Two liquid layers resulted. Into these

liquid layers, anhydrous hydrogen chloride gas was passed

for two hours. After standing for three days, the organic

layer was separated. This layer was washed with water,

twice with 40% potassium hydroxide solution, and finally

with distilled water. The product recrystallized upon

standing overnight and was recrystallized with some diffi-

culty from ethanol. The melting point of this trithio-

phenylmethane was 39-40. The reported melting point is

39.50.29

13. Masg Spectrograph

The mass spectrum of the compound shown below was








61



prepared through the courtesy of the Shell Oil Company,

Houston, Texas.














CHAPTER V


SYNTHESIS OF ARYLTHIOMETHYLPIPERAZINES


A. General Discussion


The only workers who previously have prepared aryl-

thiomethylamines are Grillot, et al.16 These investigators,

on the basis of infra-red spectra, instability in dilute

acids, and inability to introduce more than one dialkyl-

aminomethyl group into thiophenol, assumed that the pro-

ducts of the reaction between thiophenol, formaldehyde, and

a secondary amine were arylthiomethylamines.

As proved in Chapter IV, the reaction between aryl-

thiols, formaldehyde, and a piperazine produces an arylthio-

methylpiperazine.


B. Experimental


The general procedure employed for the synthesis of

the arylthiomethylpiperazines is subsequently described.

This procedure is followed by individual data sheets which

tabulate the equations for synthesis, purification method,

yield, molecular formula, molecular weight, melting or

boiling point, refractive index (if liquid), analytical

data, and some solubilities.

There are two general equations for the synthesis of

62












these compounds. The only difference in these equations
lies in the fact that some of the piperazines used have

two free amino hydrogens, while others have only one.
Thus when each of the nitrogens in piperazine has an avail-

able hydrogen, the reaction requires twice as many moles of
formaldehyde and arylthiol as would be required for a
single available hydrogen. The two general equations are:
B1

I H- -H + 2CH20 + 2R2 Q SH >
R1
R1

R2 S-CH2- S N-CH2-S TR2


R1 = (H-, CH3-)
R2 = (H-, CH3-),

II 3- S -H + CH20 +


R3-N S CH2-S R2


R2 SH )


R2 = (H-, CH3-)














R3 = (CH3-, Cl ,
OCH3 Cl




CH3 CH3


In all cases 0.10 mole of the particular piperazine
was placed in a 250 ml. modified Erlenmeyer flask. This

flask was equipped with an addition side arm and a ground

glass joint as a neck. A reflux condenser was fitted to
the ground glass neck. The correct amount of arylthiol
was added slowly with stirring. When the piperazine was
a low melting solid heat was applied. The correct amount
of formalin (approximately 35% formaldehyde) was added in

a single portion with continuous stirring. The reaction
mixture was stirred and refluxed for four to six hours.

After allowing it to cool to room temperature, it was

extracted with three 50 ml. portions of ether. The.
ether extracts were combined and dried over anhydrous

potassium carbonate. The dried ether extracts were then

passed over a column of activated alumina. The activated
alumina absorbed any unreacted starting materials. The

alumina used was non-alkaline (almost neutral), activity
grade 1 for chromatographic analysis.












The ether was removed at reduced pressure and

ordinarily the compound crystallized. In a few cases, the

compound was of a glassy consistency. When crystallization

did not occur spontaneously, it was induced either by

scratching the container with a glass rod or by seeding.

Seed was obtained by treating small portions of the non-

crystalline product with crystals of different homologs

until one was found which induced crystallization. In one

case the product was a liquid and was distilled at reduced

pressure. None of the crystallization products could be

distilled at pressures as low as 0.1 mm. All of the

crystalline products were recrystallized.












Bis-1.4-phenvlthiomethvlpoierazine


Equation for Synthesis:


H-N -H + 2CH20 + 2 SH >



0 Q S-CH2- S -CH2-S


Purification Method .
Yield . . . . .
Molecular Formula . .
Molecular Weight. . .
Melting Point . . .


* . .


Recry.---Ether
55%
C18H22N2S2
330.50
100-102.9


Analytical Data:


Carbon, %:


Nitrogen, %:


Calculated: 65.42


Found:

Hydrogen, %:


65.70


Calculated: 8.48


Found:


8.64


Sulfur, %:


Calculated: 19.41


6.71

7.01


Found:


19.4


Solubilities:


Ethanol..
Methanol .
Benzene. .
Ether. .
Water. .
5 % HC1. .
5 % NaOH .
Chloroform


Soluble
Soluble
Soluble
Soluble hot
Decomposes slowly
Reacts
Decomposes
Soluble


Calculated:

Found:













Bis-1.4-phenvlthiomethvl-2-methylpiperazine

Equation for Synthesis:

CH3
H-NS -H + 2CH20 + 2 SH >


Purification Method .
Yield . . . . .
Molecular Formula . .
Molecular Weight. . .
Melting Point . ..


* .. . .
* . . .
* S * *
* p p S
* . S *


Recry.---Ether
52%
C19H24N2S2
344.52
43.5-46.6


Analytical Data:


Carbon, %:


Calculated:

Found:


Nitrogen, %:


Calculated: 8.13


66.23

66.18


Hydrogen, %:


Found:


Calculated:

Found:


7.02

7.12


Calculated: 18.61


Found:


18.35


Solubilitiest


Ethanol..
Methanol .
Benzene..
Ether. ..
Water. .
5 % HC .
5 % NaOH .
Chloroform


* . .
S S S S

* S p .
* S 5 9

p p * *


. . Soluble
. . Soluble
. . Soluble
. . Soluble
. . *Decomposes slowly
. . Reacts
Decomposes
. . Soluble


Sulfur, %:


8.10













Bis-1.4-phenvlthiomethvl-trans-2.-dimethvlipperazine

Equation for Synthesis:

CH3

H- S N-H + 2CH20 + 2 SH --


CHQ


S-CH2- S-CH2-S<


Purification Method .
Yield . . . . .
Molecular Formula . .
Molecular Weight. . .
Melting Point . . .


* . .
* . .
* . *

* . .


Recry.---Ethanol
48%
C20H26N2S2
358.55
97-98


Analytical Data:


Carbon, %:


Calculated:

Found:


Nitrogen, %:


67.00

67.10


Hydrogen, %:


Calculated: 7.82


Found:


7.50


Sulfur, %:


Calculated:

Found:


7.31

7.21


Calculated: 17.88


Found:


17.84


Solubilities:


Ethanol. .
Methanol .
Benzene..
Ether. .
Water. .
5 % HC1. .
5 % NaOH .
Chloroform


*
*
* . .

*
*

*
. . .
. . .
. . .


Soluble hot
Soluble hot
Soluble
Soluble
Decomposes slowly
Reacts
Decomposes
Soluble













1-Phenyl-4-henylthiomethyl-iperazine


Equation for Synthesis:



N S N-H + CH20 + OSH -



O / N-CH2-Sf Q


Purification Method .
Yield . . . . .
Molecular Formula .
Molecular Weight. . .
Melting Point . . .


* . .
* . .
* . .
* . .
* . .


Recry.--Methanol-Ether
76%
C17H20N2S
284.41
75.8-78.3


Analytical Data:


Carbon, %:


Nitrogen, %:


Calculated: 71.80


Found:

Hydrogen, %:


Calculated:

Found:


71.51


Calculated:

Found:


Sulfur, %:


Calculated:


7.09

6.94


Found:


Solubilities:


Ethanol. .
Methanol .
Benzene. .
Ether. .
Water. .
5 % HCl..
5 % NaOH
Chloroform


. . .

* . .
. . .

. . .


Soluble
Soluble hot
Soluble
Soluble
Decomposes slowly
Reacts
Decomposes
Soluble


9.85

9.81



11.28

10.85













1-(2-Methvldhenvl) -4--henylthiomethvlDierazine

Equation for Synthesis:



N S -H + CH20 + SH

CH3


NS N-CH2-S D >
CH 3


Purification Method .
Yield . . . . .
Molecular Formula . .
Molecular Weight. .
Melting Point . ..


* .


* . .
* . .
* a
* . *


Recry.---Ether
49%
C18H22N2S
298.44
55.6-57.7


Analytical Data:


Carbon, %:


Nitrogen, %:


Calculated: 72.45


Found:


Hydrogen, %:


72.40


Calculated:

Found:


Sulfur, %:


Calculated:

Found:


Calculated:


7.43

7.14


Found:


Solubilities:


Ethanol..
Methanol .
Benzene..
Ether. .
Water. .
5 % HCl. .
5 % NaOH .
Chloroform


* 0 a

* . a

* . a

* . a
* a *


* a *
* a *





. a .


Soluble
Soluble
Soluble
Soluble
Decomposes
Reacts
Decomposes
Soluble


9.39

9.65


10.74

10.95












1-(3-Methylphenvl)-4-phenvlthiomethvlplperazine

Equation for Synthesis:



CS N-H + CH20 + Q SH -->
CH3



CH3


Purification Method . .
Yield . . ......
Molecular Formula . . .
Molecular Weight. . . .
Melting Point . . . .


Recry.---Methanol.
82%
C18H22N2S
298.44
84.9-87.1


Analytical Data:


Carbon, %:


Calculated:

Found:


Nitrogen, %:


72.45

72.20


Hydrogen, %:


Calculated: 9.39


Found:


9.41


Sulfur, %:


Calculated:

Found:


Calculated: 10.74


7.43

7.17


Found:


11.15


Solubilities:


Ethanol. .
Methanol .
Benzene. .
Ether. .
Water. .
5 % HC1. .
5 % NaOH .
Chloroform


Soluble
Soluble hot
Soluble
Soluble
Decomposes slowly
Reacts
Decomposes
Soluble


* . .

. . .













1-(4-Methylphenvl) -4-phenvlthiomethvlpiperazine

Equation for Synthesis:


CH3 Q S -H + CH20 + Q SH -




CH3 S -CH2-S Q


Purification Method .
Yield . . . . .
Molecular Formula . .
Molecular Weight . .
Melting Point . ..


. .
* .

* .


Recry.---Methanol
81%
C18H4N2S
298.44
138.9-141.4


Analytical Data:


Nitrogen, %:


Calculated: 72.45


Found:


72.25


Hydrogen, %:


Calculated: 9.39


Found:


9.24


Sulfur, %:


Calculated: 7.43


Found:


7.49


Calculated: 10.74


Solubilities:


Ethanol.. .
Methanol .
Benzene. .
Ether. . .
Water. . .
5 % HC1. .
5 % NaOH .
Chloroform .


Soluble
Soluble hot
Soluble
Soluble
Decomposes slowly
Reacts
Decomposes
Soluble


Carbon, %:


Found:


10.6













1- (2-Chlorophenvl) -4--henvlthiomethvlUi-erazine

Equation for Synthesis:



S N-H + CH20 + SH -





C Ol -CH2-SK
-Cl -


Purification Method .
Yield . . . .
Molecular Formula . .
Molecular Weight. . .
Melting Point . . .


* *


* .
* * .
* .
* . .
* *


Recry.---Ether
63%
C17H19ClN2S
318.857
52.6-56.5


Analytical Data:


Carbon, %:


Nitrogen, %:


Calculated: 64.03


Found:


Hydrogen, %:


64.21


Calculated: 8.79


Found:


Sulfur, %:


Calculated: 6.01


Found:


6.06


Calculated: 10.06


Solubilities:


Ethanol. .
Methanol .
Benzene. .
Ether. .
Water. .
5 % HC1. .
5 % NaOH .
Chloroform


. . S
* . S
* S ~ S S
* . .
* S ~


Soluble
Soluble
Soluble
Soluble
Decomposes slowly
Reacts
Decomposes
Soluble


8.55


Found:


9.85


. .
. .












1-(3-Chlorophenvl)-4-phenvlthiomethvlplerazine


Equation for Synthesis:


+ CH20 + OSH -.


CO -CH2-SO
Ci


Purification Method .
Yield . . . .
Molecular Formula . .
Molecular Weight. . .
Melting Point . . .


* .

* 4 .
* . 4
* . .


Recry.---Ethanol
79%
C17H19ClN2S
318.857
101-103.1


Analytical Data:


Carbon, %:


Nitrogen, %:


Calculated: 64.03


Found:


64.10


Hydrogen, %:


Calculated: 8.79


Found:


8.67


Sulfur, %:


Calculated:

Found:


Calculated: 10.06


6.01

5.65


Found:


10.3


Solubilities:


Ethanol. . . .
Methanol . . .
Benzene. . . .
Ether . . . .
Water. . . . .
5 % HCl. . . .
5 % NaOH . . .
Chloroform . . .


. 4 4


* 4 4


Soluble hot
Soluble hot
Soluble
Soluble
Decomposes slowly
Reacts
Decomposes
Soluble











1-(4-Chlororhenyl)-4-nhenvlthiomethylpiDerazine

Equation for Synthesis:

I--N
Cl Q-NJ MH + CH20 + SH >



Cl Q NQ- -CH2-S< Q


Purification Method . ... . .
Yield . . . . . . . .
Molecular Formula . . . . .
Molecular Weight. . . . . .
Melting Point . . . . . .

Analytical Data:

Carbon, %: Nitrog

Calculated: 64.03 C

Found: 64.00 F

Hydrogen, %: Sulfur
Calculated: 6.01 C

Found: 6.26 F

Solubilities:

Ethanol . . . . .
Methanol . . . . .
Benzene . . .
Ether . . . . . .
Water. . . . . . .
5 % HCl. . . . . .
5 % NaOH . . . . .
Chloroform . . . . .


Recry.---Methanol
75%
C17H19C1N2S
318.857
83.9-85.0


en, %:

alculated: 8.79

ound: 8.82

, %:
alculated: 10.06

found: 10.25


Soluble
Soluble hot
Soluble
Soluble
Decomposes slowly
Reacts
Decomposes
Soluble













1- (2-Methoxyhenvyl) -4-phenylthiom ethvlpiperazine

Equation for Synthesis:



N S N H + CH20 + SH
OCH3



6o -CH2-So
OCH3


Purification Method .
Yield . . . . .
Molecular Formula . .
Molecular Weight. . .
Melting Point . . .


* . .
* . .
* 0 0

* . .


Recry.---Ether
50%
C18H22N20S
314.44
67.2-71.1


Analytical Data:


Carbon, %:


Nitrogen, %:


Calculated: 68.75


Found:


Hydrogen, %:


Calculated:

Found:


68.70



7.,06

7.13


Calculated:

Found:


Sulfur, %:


Calculated:

Found:


Solubilities:


Ethanol..
Methanol .
Benzene..
Ether. .
Water. .
5 % HCl. .
5 % NaOH .
Chloroform


* 0 0 0
. 0 0 ~
O 0 0 0 0
. 0 0 ~ 0
. 0 0 0 .

0 0 0 0 ~
0 ~ 0 0 *


Soluble
Soluble
Soluble
Soluble
Decomposes slowly
Reacts
Decomposes
Soluble


8.91

9.09


10.20

10.25












1-Methyl-4-phenvlthiomethvlPiDerazine


Equation for Synthesis:


CH3- -S N-H + CH20 +




CH3- -CH2-S(


Purification Method .
Yield . . . . .
Molecular Formula . .
Molecular Weight. . .
Boiling Point . . .
Refractive Index (25)


* 9 9
* 9 *

* 9 9
* . .
* 9 9


Q SH >


Distilled at 0.15mm.
48%
C12H18N2S
222.34
112-113/0.15mm.
1.5734


Analytical Data:


Carbon, %:


Calculated:

Found:


Hydrogen, %:


64.80

64.91


Nitrogen, %:


Calculated: 10.24


Found:


10.15


Sulfur, %:


Calculated:

Found:


Calculated: 14.42


8.16

8.02


Found:


14.34


Solubilities:


Ethanol. .
Methanol .
Benzene. .
Ether. .
Water. .
5 % HC1. .
5 % NaOH .
Chloroform


* . 9 9

* 9 9


. 9 9 .


Soluble
Soluble
Soluble
Soluble
Decomposes slowly
Reacts
Decomposes
Soluble


. .t












Bis-1.4- (4-methyvlhenvlthiomethvl) pierazine


Equation for Synthesis:



H-Q S -H + 2CH20 + 2CH3- SH >




CH3 OS-CH2-N S -CH2-S -CH


Purification Method .
Yield . . . . .
Molecular Formula . .
Molecular Weight. . .
Melting Point . . .


* . .
* . .

* 9 9 .


Recry.---Ethanol
84%
C20H26N2S2
358.55
127.3-130.4


Analytical Data:


Nitrogen, %:


Calculated: 67.00


Found:


67.30


Hydrogen, %:


Calculated: 7.82


Found:


Sulfur, %:


Calculated:

Found:


7.31

7.68


Calculated: 17.88


Found:


17.48


;olubilities:


Ethanol. . . ..
Methanol . . .
Benzene. . . .
Ether. . . . .
Water. . . . .
5 % HC1. . . .
5 % NaOH . . .
Chloroform . . .


. 9 .


* .


. 9 9


Soluble hot
Soluble hot
Soluble
Soluble
Decomposes slowly
Reacts
Decomposes
Soluble


Carbon, %:


. 7.53













Bis-1.4-(4-methylphenvlthiomethyl) -2-methylpiperazlne

Equation for Synthesis:

CH3

H- -H + 2CH20 + 2CH3 -SH -


CH3

CH3/ -S-CH2-N S -CH2-S CH3


Purification Method .
Yield . . . . .
Molecular Formula . .
Molecular Weight. . .
Melting Point . . .


* . . .
* . . .


Recry.---Methanol
69%
C21H28N2S2
372.57
68.7-70.8


Analytical Data:


Carbon, %:


Nitrogen, %:


Calculated: 67.72


Found:


Hydrogen, %:


Calculated: 7.52


Found:


7.40


Sulfur, %:


Calculated:

Found:


Calculated: 17.22


7.58

7.55


Found:


17.05


Solubilities:


Ethanol. .
Methanol .
Benzene. .
Ether. .
Water. .
5 % HCl..
5 % NaOH .
Chloroform


* . *
* . .
. .


Soluble
Soluble hot
Soluble
Soluble
Decomposes slowly
Reacts
Decomposes
Soluble













Bis-1.4-(4-methvlDhenvlthiomethyl)-trans-2. -dimethyl-


Equation for Synthesis:


CH3


-H + 2CH20 + 2CH3 -SH -


CHI3

S S-CH2- S N-CH2-S. )CH3


Purification Method .
Yield . . . . .
Molecular Formula . .
Molecular Weight. . .
Melting Point . . .


Analytical Data:

Carbon, %:


Calculated: 68.35


Found:

Hydrogen, %:


68.36


* . .
* . .
* . .
* .
* . .


Recry.---Ethanol
62%
C22H30N2S2
386.60
135.3-137.4


Nitrogen, %:


Calculated: 7.25


Found:


7.15


Sulfur, %:


Calculated:

Found:


7.82

7.78


Calculated: 16.58


Found:


16.60


Solubilities:


Ethanol. .
Methanol .
Benzene. ..
Ether. . .
Water. . .
5 % HCl. .
5 % NaOH .
Chloroform .


* . .






* *


* *


Soluble hot
Soluble hot
Soluble
Soluble
Decomposes slowly
Reacts
Decomposes
Soluble













1-Phenyl-4-(4-methvlphenylthiomethvl) pi'erazlne

Equation for Synthesis:



KII iS -H + CH20 + CH3. SH




NS -CCH2-S CH3
\--^/ 0


Purification Method .
Yield . . . . .
Molecular Formula . .
Molecular Weight. . .
Melting Point . . .


* . .
* . .


Recry.---Methanol
85%
C18H22N2S
298.44
100-101.1


Analytical Data:


Nitrogen, %:


Calculated: 72.45


Found:


72.45


Hydrogen, %:


Calculated: 9.39


Found:


9.22


Sulfur, %:


Calculated:

Found:


7.43

7.46


Calculated: 10.74


Found:


10.28


Solubilities:


Ethanol. .
Methanol .
Benzene. .
Ether. .
Water. .
5 % HC1. .
5 % NaOH .
Chloroform


* .
. .
. . .

. .
* S S *



* S S *


Soluble
Soluble hot
Soluble
Soluble
Decomposes slowly
Reacts
Decomposes
Soluble


Carbon, %:












1-(2-Methyl henyl)-4-(4-methylphenvylthiomethyl)-


Equation for Synthesis:


+ CH20 + CH3Q SH --->


OS-CH2-SO CH3
CH3


Purification Method .
Yield . . . . .
Molecular Formula . .
Molecular Weight. . .
Melting Point . . .


* . .


Recry.---Methanol
73/
C19H24N2S
312.46
56.6-58.7


Analytical Data:


Carbon, %:


Nitrogen, %:


Calculated: 73.02


Found:

Hydrogen, %:


Calculated:

Found:


73.00


7.74

7.54


Calculated: 8.97


Found:


8.80


Sulfur, %:


Calculated: 10.26


Found:


9.92


Solubilities:


Ethanol. .
Methanol .
Benzene. .
Ether. .
Water. .
5 % HC1. .
5 % NaOH .
Chloroform


. . Soluble
. . Soluble hot
. . Soluble
. . Soluble
. . Decomposes
* . Reacts
* . Decomposes
* . Soluble












1-(3-Nethylohenyl) -4-(4-methylphenvlthiomethvl)-
Piperazine

Equation for Synthesis:



\-H + CH20 + CH3. SH -

3

f- N-CH2-S-(f--m CH3


Purification Method .
Yield . . . . .
Molecular Formula . .
Molecular Weight .
Melting Point . . .


Recry. ---Ether
72%
C19H24N2S
312.46
63-64.5


Analytical Data:


Carbon, %:


Nitrogen, %:


Calculated: 73.02


Found:


Hydrogen, %:


Calculated:

Found:


73.11


7.74

7.89


Calculated:

Found:


Sulfur, %:


Calculated:

Found:


Solubilities:


Ethanol..
Methanol .
Benzene. .
Ether. .
Water. .
5 % HC1. .
5 % NaOH .
Chloroform


*. . *


* @ "
. .


Soluble
Soluble
Soluble
Soluble
Decomposes slowly
Reacts
Decomposes
Soluble


8.97

9.03


10.26

10.3












1-(4-MethvlDhenyl)-4-(4-methyl-helnv1thiomethYv)-


Equation for Synthesis:



CH3 S N-H + CH20 + CH -SH



CH3 -CH2-S CH3


Purification Method .
Yield .. . . .
Molecular Formula . .
Molecular Weight. . .
Melting Point . . .


* .


Recry.---Ethanol
68%
C19H24N2S
312.46
138.4-139.9


Analytical Data:


Carbon, %:


Nitrogen, %:


Calculated: 73.02


Found:


Hydrogen, %:


Calculated:

Found:


72.65


7.74


7.54


Calculated: 8.97


Found:


9.25


Sulfur, %:


Calculated: 10.26


Found:


10.5


Solubilities:


Ethanol. .
Methanol .
Benzene. .
Ether. .
Water. .
5 % HC1. .
5 % NaOH .
Chloroform


Soluble hot
Soluble hot
Soluble
Soluble
Decomposes slowly
Reacts
Decomposes
Soluble











1- (2-Chlorophenvl) -4-(4-methvlphenylthiomethvl) -
Diverazine

Equation for Synthesis:


S N-H + CH20 + CH3 SH -
Cl



S1 S -CH2-S CH3
C-,^ -- '--


Purification Method . .
Yield . . . ...
Molecular Formula . .
Molecular Weight. . .
Melting Point . . .


Recry.---Ether
78%
C18H21CIN2S
332.89
66-68


Analytical Data:


Carbon, %:


I Nitrogen, %:


Calculated: 64.95


Found:


Hydrogen, %:


Calculated:
Found:


Calculated:
Found:


64.96


Sulfur, %:


6.36
6.36


Calculated:

Found:


Solubilities:


Ethanol..
Methanol .
Benzene..
Ether. .
Water.* .
5 % HC1..
5 % NaOH .
Chloroform


* S * ~


Soluble
Soluble
Soluble
Soluble
Decomposes slowly
Reacts
Decomposes
Soluble


8.42
8.65


9.63
9.42












1-(3-Chlorophenvl)-4-(4-methvylhenvlthiomethyl)-
piperazine

Equation for Synthesis:



-N -H + CH20 + CH3 SH -

Cl



C OS -CH2-S CH3
Cl


Purification Method .
Yield . . . .
Molecular Formula .
Molecular Weight. .
Melting Point . .


Recry.---Ether
81%
C18H2lClN2S
332.89
67.7-69.8


Analytical Data:


Carbon, %:


Nitrogen, %:


Calculated: 64.95


Found:


Hydrogen, %:


Calculated:

Found:


64.98



6.36

6.53


Calculated:

Found:


Sulfur, %:


Calculated:

Found:


Solubilities:


Ethanol. .
Methanol .
Benzene..
Ether. .
Water. .
5 % HC1. .
5 % NaOH .
Chloroform


Soluble
Soluble
Soluble
Soluble
Decomposes slowly
Reacts
Decomposes
Soluble


8.42

8.40


9.63

9.50


. .
.
. .












1- (4-Chlorohenvyl) -4-(4-methyvlhenvlthiomethyl)-
pioerazine

Equation for Synthesis:



Cl N-\H + CH20 + CHYH3 SH --->



Cl Q- Q -CH2-S CH3


Purification Method .
Yield . . . . .
Molecular Formula . .
Molecular Weight. . .
Melting Point . . .


Recry.---Methanol
81%
C18H21ClN2S
332.89
103.1-105.2


Analytical Data:


Carbon, %:


Nitrogen, %:


Calculated: 64.95


Found:


65.39


Hydrogen, %:


Calculated:

Found:


Sulfur, %:


Calculated: 6.36


Found:


6.25


Calculated:

Found:


Solubilities:


Ethanol. . . .
Methanol . . .
Benzene. . . .
Ether. . . . .
Water. . . ..
5 % HCl. . . .
5 % NaOH . .
Chloroform . . .


Soluble
Soluble hot
Soluble
Soluble
Decomposes slowly
Reacts
Decomposes
Soluble


8.42

8.21


9.63

9.10


. .
. .












1-(2-Methoxvrhenvyl)-4-(4-methvylhenvlthiomethyl) -
piperazine

Equation for Synthesis:



o -H + CH20 + CH3 SH >
OCH3


OS -CH2-S CH3
OCH3


Purification Method .
Yield . . . . .
Molecular Formula . .
Molecular Weight. . .
Melting Point . . .


Recry.---Ether
69%
C19H24N20S
328.46
48.5-51.6


Analytical Data:


Carbon, %:


Nitrogen, %t


Calculated: 69.45


Found:


Hydrogen, %:


Calculated:

Found:


69.30



7.36

7.42


Calculated:

Found:


Sulfur, %:


Calculated:

Found:


Solubilities:


Ethanol..
Methanol .
Benzene..
Ether. .
Water. .
5 % HCl .
5 '% NaOH .
Chloroform


* . .


* S S


* S S S
S S S


Soluble
Soluble
Soluble
Soluble
Decomposes slowly
Reacts
Decomposes
Soluble


8.53

8.30



9.76

9.63


* .












1-Methyl-4-(4-methvl)henvlthiomethvl) piperazine

Equation for Synthesis:


CH3-N S N-H + CH20 + CH3 SH -



CH r- S -CH2-S CH3


Purification Method .
Yield . . . . .
Molecular Formula . .
Molecular Weight. . .
Melting Point . . .


Recry.---Ether
36%
C13H20N2S
236.37
33.4-36.5


* .


Analytical Data:


Carbon, %:


Nitrogen, %:


Calculated: 66.06


Found:

Hydrogen, %:


Calculated:

Found:


66.15


Calculated:

Found:


11.85

12.1


Sulfur, %:


Calculated:


8.53
8.52


Found:


13.56

13.55


Solubilities:


Ethanol. . . .
Methanol . . .
Benzene. . . .
Ether. . . . .
Water. . . . .
5 % HC1. . . .
5 % NaOH . . .
Chloroform . . .


* .


Soluble
Soluble
Soluble
Soluble
Decomposes slowly
Reacts
Decomposes
Soluble














CHAPTER VI


SUMMARY

The condensation of arylthiols, formaldehyde, and a

piperazine has been shown to lead to arylthiomethylpiper-

azines and not to true Mannich bases. In this respect

arylthiols behave like aliphatic mercaptans. Evidence for

the formation of sulfides is listed:

1. The infra-red spectra of the condensation products

show the absence of the peak associated with a thiol group.

2. The infra-red spectra of the condensation products

show bands associated with a monosubstituted benzene ring,

which can only be true of the arylthiomethylpiperazines.

3. The ultraviolet spectra of the condensation pro-

ducts show a non-reversible shift when subjected first to

alkali and then to acid media.

4. The oxidation of the thiophenol condensation pro-

duct leads to diphenyl disulfide.

5. The oxidation of the p-thiocresol condensation
product leads to di-p-tolyl disulfide.

6. The reduction of the thiophenol condensation

product leads to trithiophenylmethane.

7. The mass spectrum shows a peak corresponding to

a fragment which could only be derived from an




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