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 Title Page
 Preface
 Table of Contents
 Review of literature and intro...
 Objectives, methods, and resul...
 Experimental procedures and...
 Summary
 Bibliography
 Acknowledgement
 Biographical items
 Copyright














Title: Derivatives of piperazine. XIV.
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Table of Contents
    Title Page
        Page i
    Preface
        Page ii
    Table of Contents
        Page iii
        Page iv
        Page v
    Review of literature and introduction
        Page 1
        Page 2
        Page 3
        Page 4
        Page 5
        Page 6
        Page 7
        Page 8
    Objectives, methods, and results
        Page 9
        Page 10
        Page 11
    Experimental procedures and tables
        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
        Page 37
        Page 38
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        Page 67
        Page 68
        Page 69
        Page 70
        Page 71
        Page 72
        Page 73
        Page 74
        Page 75
        Page 76
    Summary
        Page 77
        Page 78
        Page 79
        Page 80
        Page 81
        Page 82
    Bibliography
        Page 83
    Acknowledgement
        Page 84
    Biographical items
        Page 85
        Page 86
    Copyright
        Copyright
Full Text










DERIVATIVES OF PIPERAZINE. XIV.


A MODIFIED STRECKER


SYNTHESIS


UTILIZING 1-ARYLPIPERAZINES










By
LAWRENCE J. HUGHES


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









UNIVERSITY OF FLORIDA
August, 1953














PREFACE


The presentation of this dissertation material is

purposely given in detail to facilitate duplication of this work

by future investigators. Every synthesis is reported in detailed

form even though the procedure in a given, homologous series is

basically the same.

Throughout this dissertation all temperatures reported

are corrected values. The thermometers used were calibrated

against a set of thermometers standerlized by the Bureau of

Standards.

In conformity with. present practice in preparing reports

,of this kind, all temperatures are of the centigrade scale.

The percentage yields of nitriles, syntheses of which

are reported in this dissertation, are based upon molar quantity

of 1-arylpiperazine used. Similarly, the percentage yields of the

amide and acids are based on the molar quantity of the nitrile used.

The manner of listing references is the customary one for

technical reports* Journal abbreviations are the official ones

of Chemical Abstracts*














TABLE OF CO!iiTlTS


Chapter Page

PREFACE . . . . . . . . . ii

I REVIEW OF LITERATURE AND INTRODUCTION . . 1

II OBJECTIVES, METHODS, Al-D RESULTS . . . 9

,III EXP:ERI:.ETAL PROCEDURES AND TABLES' . . 12

2-(I-Phenylpiperazino)-ethanonitrile 15

2-(4-Phenylpiperazino)-ethanamide . 15

2-(4-Phonylpiperazino)-propanonitrile 16

2-(4-Phenylpiperazino)-propanaraide . 16

2-(4-Phenylpiperazino)-propanoic Acid 17

2-(4-Phenylpiperazino)-2-methyl-
propanonitrile . . . . 21

2-(4-Phenylpiperazino)-2-methyl-
propanamide . # . . . 21

2-1 4-(2-Methylphenyl)-piperazino ]-
propanonitrile . . . . 24

2- r4-(2-Methylphenyl)-piperazino ]-
propanamide . . . . . 24

2- l4-(2-Methylphenyl )-piperazino J]-
2-methylpropanonitrile . . .. 27

2-1~4-(2-IMethylphenyl)-piperazino ]-
2-methylpropanamide . . . . 27

2-r4-(5-MLethylphenyl)-piperazino J-
propanonitrile . . .... 50

2- 1-4-(5-Methylphenyl)-piperazino ]-
propanamide s . .. . 50












2-r4-(5-Methylphenyl )-piperazino ]-
2-methylpropanonitrile . . . 55
2-- 4- (-MetIhylphenyl)-piperazino ]-
2-methylpropanaride . . . . 55

2- j4-(4-Methylphenyl)-piperazino J-
propanonitrile . . . . .. 56
2- C4- (4-Methylphcnyl)-piperazino -
propanamide . . . . . 56

2- r4-(4-Methylphenyl)-piperazino -
propanoic Acid . . . . .. 57

2- "4-(4-Methylphenyl)-piperazino -
2-methylpropanonitrile . .. . 41
2-j 4-(4-Methylphenyl)-piperazino 1-
2-methylpropanamide . . . . 41

2- 4-(2-Chlorophenyl)-piperazino -
ethanonitrile . . .. . 44
2- 4- (2-Chlorophenyl)-piperazino ]-
ethanamide . . . . . . 44
2- -4-(2-Chlorophen 1 )-piperazino :-
ethanoic Acid . . . . . 45
2- 4-(2-Chlorophenyl)-piperazino ]-
propanonitrile . . . . . 49
2- 4-(2-Chloropheny1l)-piperazino J-
propanamide . . . . . 49
2-C4-(2-Chlorophenyl )-piperazino J-
propanoic Acid . . . . . 50
2-r4-(2-Chlorophenyl)-piperazino I-
2-methylpropanonitrile . . . 54

2-F4-(2-Chlorophenyl)-piporazino ]-
2-methkylpropanamide . . . . 54
iv













2- 4-(2-Chlorophonyl)-piperazino ]-
2-methylpropanoic Acid . . 55
2- 4-(5-Chlorophonyl)-piperazino ]-
propanonitrile . . . . . 59

2-F4-(5-Chlorophenyl)-piporazino ]-
propanamiide. . . . . . 59

2- F4-(5-Chlorophenyl)-piperazino J-
propanoic Acid . . . 60

2-C4-(5-Chlorophenyl)-piperazino J-
2-methylpropanonitrile . . .. 64

2-F4-(5-Chlorophenyl)-piperazino -
2-methylpropanaimide . . . . 64
2-j 4-(4-Chlorophenyl)-piperazino -
propanonitrile . . . . . 67

2- 4-(4-Chlorophenyl)-piperazino ]-
propanamide . . . .. . 67

2- 4-(4-Chlorophenyl)-piperazino ]-
propanoic Acid . . . . . 68

2- 4-(4-Chlorophenyl)-piperazino J-
2-methylpropanonitrile . . . 72
2- C4-(4-Chlorophenyl )-piperazino ] -
2-methylpropanamide . . . . 72
2- r4-(4-Chlorophenyl)-piperazino ]-
2-methylpropanoic Acid . . . 7

IV SU2,iARY' . . . . .. . . . . 77

BIBLIOGRAPHY . . . . . . . 85

ACi-'OULED'L' r "'S- . . . . . . . 84
BIOGRAPHICAL ITEm-S . . . . . . .. 65

GO1.1ITTEE REPORT . .















CHAPTER I


REVIEW OF LITERATURE AND INTRODUCTION



The Strecker SynthesisIs is defined as the reaction of

an aldehyde or ketone with ammonia and hydrocyanic acid to produce

an alpha-amino nitrile which on hydrolysis yields an al-ha-amino

acid. In the present modification the ammonia has been replaced

by a secondary amino group contained in a heterocyclic system,

specifically a piperazine with the 1-position occupied by an

aryl group.

Earlier work on this type of modification goes back to

A. Klages,9 who reacted diethyl amine with lactonitrile to obtain

2-diethyaminopropanenitrile, and T. St. Warcenis and F. Sachs,12

who reacted I?-methylaniline with aldehyde cyanohydrins to obtain

2-(N-methyl-N-phenylamino)-allkynitriles. One instance of

preparation of a 2-(4-arylpiperazino)-alkylnitrile has been

found1 in which 1-phenylpiperazine was reacted with formaldehyde

cyanohydrin to yield 2-(4-phenylpiperazino)-ethanonitrile. Another

heterocycle which has been used is piperidine.7'10

In addition to the use of cyanohydrins for the preparation

of g-aminoalkylnitriles there are several methods of combining the

amine and aldehyde or ketone with hydrocyanic acid. H. Zelinsky














and G. Stadnikoff17 reacted aldehydes with ammonium cyanide to

obtain the 2-aminoalkylnitriles. E. Knovenagel and E. 1Mercklin9

treated l-(lN,N-dialkylaniino)-l-alkylmethanesulfonic acid sodium

salts obtained from the aldehyde, amine and sodium bisulfite,

with potassium cyanide to obtain the 2-aminoalkylnitriles.

Betts3 treated a solution of 2-toluidine and cyclohexanone in

glacial acetic acid with a concentrated aqueous solution of

potassium cyanide to obtain 2-(4-methyphenyl-aaino)-2-cyclo-

hexylethanonitrile. Reaction of the aldehyde or ketone with the

amine and potassium cyanide in dilute aqueous or alcoholic

hydrochloric acid yields the 2-aminoalkylnitrile. Treatment of

the addition .product from aldehydes or methylketones with.the

amine and potassium cyanide gives the desired 2-aminoalkynitriles.

The hydrochloride salts of amines react with potassium cyanide

and aldehydes or ketones to give 2-aminoalkylnitriles.

The kInetics and mechanism of formation of 2-dialkyl-

amino-2-methylpropanonitriles has been studied by T. D. Stewart

and C. Li.1- These workers found that the rate of the reaction



(CuH) OR + R' NH (CHa)sN
\Gl? 2C














follows the law


Ek [ (cHi)g
NR,-'


] [ R'N1e ] in alcohol or


= k [ RIm ] [ (CH3)8CK ] in acetone
nd tht the echnis is



and that the mechanism is


RC T



R2I
0CN


R20 = 0




RSC/




Re .rT


+ B RS2c + HB




SRg C = 0 + CNI


OH
RAiH E= Re
NRA


/CN
+ HCN I R2C0
\112


/1OH

\)i


+ 1120


+ R, C


!CN
+ R'2 C\A
\ITR2














A single mechanism is suggested since it seems improbable

that the reaction would proceed differently in alcohol and acetone.

This mechanism may be verified by deriving the empirically found

Rate Laws from the proposed mechanism,

If we assume the existence of the reaction,


ka. /OH
R2C = 0 + RUi k1 Rg11 (A)
2 \NR



and that the mechanism of aminonitrile formation may be expressed




a = k Re [ HON ] (I)




the concentration of hydrocyanic acid is determined by



R2 0 RC =0 + HOTIT (D)



.It is assumed that with acetone as solvent the equilibrium

between amino alcohol, acetone and amine (equation A) is maintained

as the reaction proceeds, whereas with alcohol as solvent the

amino alcohol is.not at equilibrium but at a low, steady-state

value. In the latter case a low concentration of acetone permits













higher concentration of hydrocyanic acid.and decreases the
probability that any amino alcohol will dissociate into its
original constituents. Therefore equation (A) becomes


=o+ a kim k O
R2C = 0 + RjqHH R9C


(c)


Equations (B) and (0) may be combined:


R H
Rs0( *


gRsO = 0 + R*TH


,0\ + H20


From this the rate
amino alcohol may be found:.


of appearance and disappearance of


d R2 a/dt = kg. [ RZC = 0 R R1NM ]


[R ROH t = k R H + k RaCH GN
dt = kg R2C= + k HRMT
I[R.< /3













When*a steady state is reached the concentration of
Eamino alcohol is



[R2 Sk\ HCN .1 + k1


and


dP kk, [ RO
dt
k


SHON
[Hal'


SR+H HC
+ Ike


if k2 is small compared to k [ HON ] then



=k' [ Rc = 0 ] [ RNH ]


which corresponds to the empirical equation where alcohol is
solvent.
In acetone asosolvent the amino alcohol concentration
is maintained at or near equilibrium:


R2= Rs = o ] [ /::,I ]
\ImR' k2














From equations (I) and (B)


dP= dkg [ R2 0 [ RjiH [ H 3



which,: combined with equation D gives



dP ku R2 IRN


which corresponds to the empirical rate law where acetone is

solvent.

Thus it is possible to use a single reaction mechanism

over the entire range of nixed solvents and still account for

the second order reaction in acetone and the pseudo-first order

reaction in alcohol.

The values of the ionization constants of 2-diethylamino-

ethanonitrile, 2-diethylamino-2-phenylethanonitrile, 2-diethyl-

maminopropanonitrile and 2-diethylamino-2-methylpropanonitrile,

and their hydrochloride salts have been determined by Stewart

and Cook.13 Their values of the Kb, of the order of 10-tl to

10-11, and of the Ka, of the order of 10" to 10"6, were deter-

mined in both alcohol and water.

The hydrolysis of the nitriles to the amides has been

done usually by dissolving in cold concentrated sulfuric acid














followed by dilution and neutralization with anmonia or xanonium

hydroxide. s,

The acids have been formed by hydrolysis of the nitrilos

with: (1) concentrated hydrochloric acid,e (2) concentrated

sulfuric acid,4 hydrobronic acid, anmd (4) bartya water. -C:y

have also boen forced by hydrolysis of the corresponding, aides

with: (1) concentrated hydrochloric acid,3 (2) alcoholic hydro-

chloric acid,s and (5) bartya water or sodium hydroxide solution.

The isolation of the free acid from the salt is usually

carried out by converting the salt to the sodium salt and treating

the latter with glacial acetic acid.5














CHAPTER II


OBJECTIVES, METHODS, A:D RESULTS



The object of this investigation has been the study of

the use of l-arylpiperazines in the Strecker type synthesis.

The investigation is limited to the following adenda: 1-phenyl-

piperazine, 1-(2-methylphenyl)-piperazine, l-(5-methylphenyl)-

piperazine, 1-(4-methylphenyl)-piperazine, 1-(2-chlorophenyl)-

piperazine, 1-(5-chlorophenyl)-piperazine and 1-(4-chlorophenyl)-

piperazine. The cyanohydrins used were lactonitrile and acetone

cyanohydrin; chloroacetonitrile was substituted for glycolonitrile

since it gives higher yields and purer products. The reactions

of these compounds, with the exception of 1-phenylpiperazine and

chloroacetonitrile,' are not recorded in the literature. These

syntheses represent a continuation of work performed in these

laboratories in an effort to produce organic molecules which

possess physiological activity.

The cyanohydrins listed above are available on the

commercial market. The 1-arylpiperazines, which could not be

purchased, were prepared in this laboratory as intermediates for

this investigation.















The reaction of the 1-arylpiperazines with cyanohydrins

was found to proceed sontaneously when the pure reactants were

mixed, and in only a few instances was it necessary to heat the

mixture (on a stean bath) to complete the reaction. The products

solidified readily as the reaction mixtures cooled. The solid

was dissolved in hot 95 per cent ethanol and allowed to crys-

tallize; it was then recrystallized from an appropriate solvent

until a constant melting point was obtained, usually after three

to four recrystallizations.

The products were all stable when dry, but in alcoholic

solution :, the odor of hydrocyanic acid was strong, particular

with the products obtained from acetone cyanohydrin.

The amide derivatives were prepared by hydration of the

nitriles in concentrated sulfuric acid. In general the nitrile

was added slowly to the acid while the temperature was maintained

below 25C. The solution was allowed to stand at room temperature

for 24 hours then it was poured onto ice and neutrallized with

concentrated ammonium hydroxide. The product was extracted from

the resulting precipitate with hot 95 per cent ethanol. The

ethanol solution was then concentrated and the product allowed

to crystallize. The crystalline solids were recrystallized from

an appropriate solvent until a constant melting point was obtained.













The amino acid derivatives were prepared by acid

hydrolysis of the nitriles or aides. The usual procedure was

to dissolve the nitrile or amide in concentrated hydrochloric

acid and roflux: the solution for 6 to S hours. The solution

was then transferred to a beaker and concentrated until crystals

began to form in the hot solution. After the solution had

cooled for 4 to 12 hours theo crystals were filtered off and

recrystallized from water. In most cases treatment with carbon

was needed to remove the color from the product. Considerable

loss occurred in purification.

In seven cases; 2-(4-phenylpiperazino)-2-methylpropanonitrile,

2- 1-4-(2-methylphonyl )-piperazino J-propanonitrile, 2-! |4-(2-methyl-

phenyl )-p iperazino ]-2-methylpropanonitrile, 2- fI4-(- (Eet1hylphonyl)-

piporazino -propanonitrile, 2-1I4-(5-methylphenyl)-piperazino J-

2-methylpropanonitrile, 2-] '- (4-methylphenyl)-piperazino -2-methyl-

propanonitrile, 2-jF4-(5-chlorop'-enyl)-piperazino ]J-2-methylpropano-

nitrile, hydrolysis yielded ;H.I0C1.

Analysis of all compounds synthesized was confined to

micro-Dumas determinations of nitrogen. Niitrogen analysis were

done either by Schwarzkoff Microanalytical Laboratories or by Gellor

Laboratories. In those cases where results of nitrogen determination

required confirmation of molecular foruala, neutral equivalents were

obtained by macro titration procedures with acid or base.

11














CHAPTER III


EXPERIMENTAL PROCEDURES AID TABLES.


Intermediates


Chloroacetonitrile was purchased from Eastnan Chemical

Corporation.

Lactonitrile and acetone cyanohydrin were obtained from

both American Cyanamid Company and M1athoson, Coleman and Bell,

Inc.

1-phenylpiperazine was prepared by themethod of Pollard

and 1acDowell. 1-(2-chlorophenyl)-piperazine, 1-(5-chloro-

phenyl)-piperazine, 1-(4-chlorophonyl)-piperazine, 1-(2-methyl-

phenyl)-piperazine, 2-(m-nethylphonyl )-piperazine, and 1-(4-methyl-

phenyl)-piperazine were prepared by the method of Vicker and

Pollard.16

Reaction Products

In the pages which follow the method of preparation of,

each compound is'described individually. Following each descrip-

tion is a page on which pertinent data are tabulated.














2-(4-Phenylpiperazino)-ethanonitrile


To 0.5 mole (81.1g) of 1-phenylpiperazine in 200 ml. of

benzene was added 0.5 mole C57.8g.) of chloroacetonitrile and

0.25 mole (26.5g.) of anhydrous sodium carbonate. The mixture was

refluxed for two days. The solids were filtered off and the benzene

was removed on a steam bath. The cooled liquid crystallized .readily.

Three recrystallizations from n-hoptane yielded a product of corre-

sponding to that obtained by Adelson and Pollard.1 However, the m

melting point was found to be 75-760C. which is 10 0C. higher than

that reported by these authors. This melting point has been verified

by two .other workers in these laboratories working independently.



2-(4-PhonylpiDerazino)-ethanamide



To 200 ml. of concentrated sulfuric acid was added

0.175 mole (58.4g.) of 2-(4-phenylpiperazino)-ethanonitrile with

stirring and cooling. The resulting mixture was allowed to stand

at room temperature for 24 hours and then was poured onto 1 kg. of

cracked ice. The solution was then made basic with concentrated

ar-ionium hydroxide and the precipitated product filtered off. Three

recrystallizations from Toluene gave 5l1/ of pure product. The

melting point was 169-170, corresponding to that of Adelson and

Pollard.*














2- (4-Phenyl Iiperazino )-ethanonitrile



Chemical Equation:

S CGHg-CH\


OH + 01Ha
-CH -Cl!e








Molecular Formula . . . . . .

Molecular 'eight . . . . .

Melting Point . .* .

Recrystallizing Solvent . . . . .

Solubilities:


Water .

Ethanol

Acetone

Benzene

Toluene


QA20111 03

. 201.26

. 75-76

n-Hoptane


* .*. . Insoluble

* * * * Soluble

. . . . Soluble

. . . . Soluble

* . Slightly Soluble















2- (4-Phenylpiperazino)-ethanamide


Chemical Equation:


Q( CHs-0He H-SO"
}-!H< )N-CH.CIH + 1120 -0--



G \Ch2 CHs-CH


Molecular Formula . . . .

Molecular Weight . . . .

Melting Point . . . . .

Recrystallizing Solvent . . .

Solubilities:

Water . .

Ethanol . .

Acetone . .

Benzene o

Toluene . .


* .* .C '181,00

. . .219.28

* . . 169-170

* . Toluene



.Slightly Soluble

Slightly Soluble

. . Soluble

Slightly Soluble

Slightly Soluble














2-(4-?henylpiperazino)-prooanonitrile


To 0.2 mole (52.4 g.) of 1-phenylpiperazino was

added 0.2 nole (14.2 c.) of lactonitrile. An e::othermic

reaction set in immediately, When cool the two-phase mixture

was solid; it gave a quanititative yield of product. Four

recrystallizations from (c, ethanol gave 80.5% of pure product.

The coma.ound was dried at 500C. (2 Em.) before analysis.

Physical and analytical data are on pagCe 18,



2-(4-Phenylhniperazino)-propanaride



To 200 ml. of concentrated sulfuric acid was added

0.175 mole (57.6 g.) of 2-(4-phenylpiperazino)-propnanoitrile

The mixture was stirred and cooled dUring the addition and was

then allowed to stand at room temperature for 2ji hours. It was

poured onto 1 kr. of cracked ice and the solution was made basic

with concentrated anzonium hydroxide. The precipitated product

was filtered off and after three recrystallizations from 9."

ethanol there was a 705 yield of pure product. The compound

was dried at 5000C. (2 rmm.) before analysis. Physical and

analytical data are on page 19.


16 -














2-(4-Phenylpiperazino)--ropionic Acid'Dihydrochloride

Monohydrate



The amide fron 0.175 mole (57.6 g.) of 2-(4-phenyl-

piperazino)-propanonitrile was dissolved in-150 ml. of con-

centrated hydrochloric acid and the solution refluxed for

8 hours. The solution was poured into a beaker and evaporated

until crystals appeared. heon cool the solid was filtered off

and recrystallized from water. The compound was dried at

100C. ( 2 'mI.). Physical and analytical data are on page 20%
















2-(01-Phen;,lpiperazino )-pronanonitrile



Chemical Equation:




i 2 ) -H H + CHI H MON
tCH12-CH0 2 |
OH


CHO

( ) Ha-( )H-GCIc + HaO
" CH\ e-CH\ I
\1eCH2 ICio;i + 1I20


Molecular Rorula . .

Molecular Ueight . .

Melting Point . .*

Recrystallizing Solvent .

Analysis

Nitrogen, t

Calculated .

Found * *

Neutral Equivalent:

Calculated .

Found .*


* a a a *

* 0 0 0 0 0

* S 0 0 *

* 0 0 0 0


* a a a a a a

a a a a 0 0 0



* 00 a ~ SO

* a .oa*.


. 215.29

87.5-88.10

95% Ethanol





. . 19.52

. . 19.16



. 215.29

. . 212.7


Solubilities:


a 0 0. 0 0

* a.~.


S* 0
. O .


. Insoluble

. Soluble

. Soluble

* Soluble


Water .

Ethanol

Acetone

Benzene
18















2-(4-Ph.enrlpiperazino)-oropananide


Chemical Equation:


C H3
1CH2-CH2\ I
S CN-CHCT + 10 IISO
CY12Hg-CH/


/-'1 0 0


Molecular Formula . .

I.Molecular Weight. .

Melting Point . . .

Recrystallizing Solvent .

Analysis t

Nitrogen, %0

Calculated .

Found ,* *A


* 0


* 0


* . C0,isN2a

S. . . 235.50

. . . 145-145.8

* * 95% Ethanol


* *.

* 0 *


. 18.01
* 18.05


Solubilities:


* Slightly

*00Slig;htly



*a0 slightly


lVtor .

Ethanol

Acetone

Benzone


Soluble

Soluble

Soluble

Soluble













2- (4-Pheny1piperazi-no)-prop ionic Acid-Dihydrochloride*

IMonohydrate

Chemical Equation:



S1N-CH-O/ + 2H,0 + HO1 -
OHa-CIi 2


CHI /G-Cl/ 0
\ ) ;,,-i-cH-/ *21011*H20 + .,Cl


Molecular Formula . . CIH1sNO*2'O

Molecular Weight . . . . . . . 2.20

Melting Point . .. . . . . . 200dec.

Recrystallizing Solvent . . .. . . . . Water

Analysis

iTitro :on, %:

Calculated for O Ii80TsO.*2C1i . . 9.12

Found . . . . . . 8.90

ITeutral Equivalent:

Calculated for CGL3ieU,02*2HC1*HO . 161.6

Found . . . . . ... . 15.1

Solubilitiest

Water . . . . . Soluble

Ethanol . . . . . Soluble

Acetone . . . .. . Insoluble

Benzene . . . . . Insoluble-

20













2-(4-Phenylpinerazino )-2-nethylpro'ianonitri e


To 0.2 mole (52.4 g.) of 1-phenylpiperazine was added

0.2 mole (17.0 g.) of acetone cyanohydrin. An exotherraic re-

action set in immediately. '.'hen cool the two-phase mixture

was solid; it gave a quantitative yield of product. Four re-

crystallization from 95; ethanol gave 87.2, of pure product.

The compound was dried at 50+C. (2 am.) before analysis. Phy-

sical and analytical data are on page 22.


2- (4-Phenylp iperazino )-2-metliylpropanonamide



To 200 ml. of concentrated sulfuric acid was added,

with stirring and cooling, 0.175 mole (40.0 g.) of 2-(4-phenyl-

piperazino)-2-methylpropanonit il The resulting mixture Was

allowed to stand at room temcpeat re for 24 hours and then was

poured onto 1 kg. of crIcked ice. This solution was made basic

with concentrated ammonium hydroxide and the precipitated .product

filtered off. Three recrystallizations from 951 ethanol gave

7
before -analysis. Physical and analytical date are on page 25.















2- (4-Phenryl -iperazino)-2-methylprop.anonitri le

Chemical Equation:

CE0
S (CH2 /CH-CH, +
C-1K I-H + CHIG-CN -
^ \CH,-CH2
OH



0 /CIl-C\h, 1
-1IT )lT-C-C:i + H0O

GCii-


Molecular Formila . a

Molecular Voi'cht .

Molting Point . . .

Rocrystallizing Solvent ,

Analysis :

Nitrogen, j:

Calculated *

Found . .

Neutral Equivalent:

Calculated..

Pound .


Solubilities:


Venter .

Ethanol

Acetone

Benzono
22


. . . . 0~,~ii i

. . . 229.51

*. .* 111.8-112.5

. . . . 93 Ethanol


* a a a a a a a

a a a a a a a .



* a a a a C a a

eq a a a a a a


. 18.75

. 18.15



229.51

. 229.8


. . Involuble

* a Slishtly Soluble

. . a a a Soluble

. . . . Soluble















2- (4-Phenrypiperazino)-2-methylpromanamide

Chemical Equationt

QOH
N )HN-0-0! + H20 .S"

CCH



oi -0112 1 so
C/- / -CH CHj
( I-I{ ,-C-C "
CHO


Molecular Formula . o

Molecular Weight . . . .

Melting Point . . . . . .

Recrystallizing Solvent .* .* * *

Analysis:

Nitrogen, %:

Calculated . . .

Found . . . .*


.* C3H 31-s0

. . 247.5

. 162.8-165.5

* 95% Ethanol





. . 16.99

. . 16,74


Solubilities:


Water .

Ethanol

Acetone

Benzene


C

S

S


. Slightly Soluble

, Slightly Soluble

.*. * Soluble

. Slightly Soluble













2- 4-(2-E ethylphenyl )-nieraino -roranonitrile


To 0.2 mole (p5.2 g.) of l-(2-methylphenyl)-piperazine

was added 0.2 mole (14.2 g.) of lactonitrile. An exothermic

reaction set in inmodiately. When cool the two-phase. mixture

was solid, it gave a quantitative yield of product. Four re-

crystallizations from 95 ethanol gave 48.4% of pure product.

The product was dried at 5000. (2 nu.) before analysis. Physical

and analytical data are on page 25..



2- 4-(2-Metlylhonyl )-piperazino ] -propana.idoe



To 200 il. of concentrated sulfuric acid was added,

with cooling and stirring, 0.175 mole (40.0 g.) of 2-[4-mothyl-

phenyl)-piperazino ]-propanitrile. The resulting nixturoe as

allowed to stand at roon temperature for 24 hours and then was

poured onto 1 kg. of cracked ice. This solution vwas made basic

with concentrated ammonium hydroxide, and the precipitated product

was filtered off. hi-hre recrystallizations from toluene 'and one

from 95; ethanol gave 25.1% of pure product. The compound was

dried at 5000. (2 an.) before analysis. Physical and waalytical

data are on page 26 .
















2- F 4-.(2-M:ethylrhenl )-~pipoerazino 3 -orouanonitrile


Chemical Equationt

CH3 OH
/ -CH-CH + I
-( -;I + C03CullCi
0 Cg12-01s2


CHu
/H -CH2\
-N N-COC + 10
\CH2-CHe


Molecular Formula . .

Molecular Weight .

Melting Point . .

Recrystallizing Solvent

Analysis:

Nitrogen, %:

Calculated

Found *


*. .


S.* *


. . . C^HzHe

. . . . 229.51

. . . 105.5-o106.5

* . . 95 Ethanol


* 9 9 a 9 S a

* 9 0 9 0 5 S


. . 18.59

. . 18.75


Solubilities:


Water ,

Ethanol

Acetone

Benzene


S. . . Insoluble

. . .Slightly Soluble

. . . . Soluble

* . Soluble
















2-r l- (2-.lethyluhenyl)-piTnerazino 1 -propanenide


Chemical Equation:


+ H,0 SO9


Molecular Formula .

Molecular Weight . .

Ilelting Point

Recrystallizing Solvent .

Analysis:

iTitrogen, e:

Calculated .

Found * *


. . . . GEthno!

. . . . 247.55



. . . . 953 Ethanol


* 0 4 B

. . 4 4


. . 16.99

* 17.01


Solubilities:


Water .

Ethanol *

Acetone .

'Denzone


* 0

* 4


Sl igt ly


* B B B B 4

* 0 4 4 4 S


Soluble

Soluble

Soluble

Soluble













2- [ 4- (2-Eoth^-1Dhen:1 )pinerazino ]-2-riethylprooanonjtrile


To 0.2 mole (55.2 g.) of 1-(2-methylphenyl)-piporazine

was added 0.2 mole ("7.0 g.) of acetone cyanohydrine. An

exothermic reaction set in tmnediately, When cool the two phase,

mixture was solid it gave a quantitative yield of product.

Four recrystallizations from 95? ethanol gave 84.2, of pure

'product. The compound was dried at 50C0 (2=m.) before analysis,

Physical and analytical data are on page 28,


2- [4- (2--Hethylrhenyl )-r iperazino ] -2-methylp ro'anamide


To 200 nml of concentrated sulfuric acid was added, with

cooling and stirring, 0.175 nole 140.0 g.) of 2-[ 4-(2-miethyl-

phonyl)-piperazino ]-2-methylproptnonitrile. The resulting mixture

was allowed to stand for 24 hours and then was poured onto 1 kg.

of cracked ice. This solution uiad made basic with concentrated

asmonium hydroxide and the precipitate filtered off* The product

was extracted from the filter cakq wuth 957% ethanol then re-

crystallized three times from third siveont. The pure compound

(60,' yield) was dried at 50C. (2 mm.) before analysis. Physical

and analytical data are on page ?-29














2-E -(2-Metlhlphenyl )-iperazino ]-2-methylpropanonitrile


Chemical Equationt


CH3

OH
+ CY13 Coll

OH


+ H20


Molecular Formula . .

Molecular Weight . .

Melting Point . .

Recrystallizing Solvent ,

Analysis:

Nitrogen, %:

Calculated *

Found . .


. . . . . 245.54

. . . . 122.5-124

. . . 95% Ethanol




*1727
. . . . 17.27

. . . . . 17.22


Solubilities:


Water * *

Ethanol *

Acetone . o

Benzone . .


S. Insoluble

Slightly Soluble

* . Soluble

. *. Soluble














2-j 4--(2-Methylphenyl)-piperatzino ] -2-methylproianaride


Chemical Equation:

CH0113 CH

C )0H N-0-C) + HO Sic
\C Hg-CH/
OH


Molecular Formula . .

Molecular eightt .* .

Ilelting Point . . .

Recrystallizing Solvent .

Analysis

Nitrogen, %:

Calculated .

Found . .


. . . . CzaHgaaB 0
. . . . 2 .55

. . . . 174.-175.5

. . . . 915 Ethanol





. . . . .. 16.08

. . . . . 16.12


Solubilities:


Water *. . Insoluble

Ethanol . Slightly Soluble

Acetone . . . Soluble

Benzene . . . . Soluble














2- F4(--Q4ethy'lbhenyl)-niperazinQ ]-pro-anonitrile


To 0.2 mole (55.2 g.) of 1-(5-methylphenyl)-piper-

azine was added 0.2 mole (14.2 g.) of lactonitrile. An exO-

thermic reaction set in immediately. 11hen cool the two-phaseo

mixture was solid it gave a quantitative yield of product.

Four recrystallization from 951 ethanol gave 51i of pure product.

The compound was dried at 500.' (2 m..)'before analysis. Physical

and analytical data are on par e 5)I


2- 4- (-eth:,honyl )-piperazinoj -nronaneide



To 200 ml. of concentrated sulfuric acid was added,

0.175 role (40.0 g.) of 2-[ 4-(5-MetShylphenyl)-piperazino ]-

propanonitrile. The resulting mixture was allowed to stand

at room temperature for 24 hours, and then was poured onto

1 kg. of cracked ice. This solution was made basic with con-

centrated ammoniums hydroxide, and the precipitated product was

filtered off. Three recrystallizations from 95g ethanol gave

48% of pure product. The compound was dried at 500C. (2 rin.)

before analysis. Physical and analytical data are on pare 524


50















2-[ 4- (f5-'ethlylphenyl)-piporazino ]-propanonitrile


Chemical Equation:


OH

+ CH3 CHCN >


+ H10


Molecular Formula . .

Molecular !eight . .

Melting Point . .. .

Recrystallizing Solvent *

Analysis:

Nitrogen, %:

Calculated .

Found .*


* * *

* * *

* * .

* .* * *


* Ca4H.,Ns

. . 229.51 l

. 62.8-64

* 95% Ethanol


. . .. . 18.59

. .. . . 18.41


Solubilities:


Water .

Ethanol

Acetone

Benzene


* . . . Insoluble

. . Slightly Soluble

. . . . Soluble

. . .. . Soluble















2- [ 4-(5-Methylphenyl)- iperazino 1-pronananide


Chemical Equation:




SCCHH -CH N


Molecular Formula

Molecular Weight

Melting Point .

Recrystallizing Sc

Analysis$

Nitrogen, %:

Calct

Founc


\ ,O-OH), | He


. . . . . Cz4H2,NsO

. . . . . 247.53

. . . . . 126.5-127.5

lvent . . . . 95% Ethanol


. 0 0 0 a 0

4 0 9 . 0 * 0


I


Solubilities:


Water .

Ethanol

Acetone

Benzene


. . Slightly

.* Slightly



. Slightly


16.99

16.91


Soluble

Soluble

Soluble

Soluble














2-r 4-(3-.Chlorop:-iebyl) -niperatino 1-2-raethylropanonitrile


To 0*2 mole (p9.5 g.) of l-(5-chlorophenyl)-piper-

azine u.a added 0.2 mole (17.0 g.) of acetone cyanohdrin. An

exother:ic reaction set in L-ia.diatcly,. When cool the two-phase

mixture was solid; it gave a quantitative yield of product.

Four recrystallizations from 95% ethanol gave 89.00 of pure

product. The compound was dried at 50C. (2 rn.n) pressure before

,analyoia. Physical and analytical data are on page 52.


2-[ 4-(5-Chloropheny l)-piperaziro 1-2-methypropeanmide


To 200 ml. of concentrated sulfuric acid was added,

with cooling and stirring, 0.175 mole (49.5 g.) of 2-[ 4-(5-chloro-

phenyl)-piperazino ]-2-4ethylpropanonitriloe. The resulting

solution was allovod to stand at room temperature for 24 hours

and then was poured onto 1 kg. of cracked ice. This solution

was then made basic with aumoniun hydroxide and the precipite

filtered off. The product was e::tractod from the filter cake

with 99 ethanol and recrystallized from the same solvent. Three

recrystallizations gave 8$6 of pure product. The compound Wras

dried at 500C. (2 rtn.) before analysis. Physical and analytical

data are on page 55.














2- 4-(3-Methylphenyl)-pinerazino ]-2-mcthylpropanonitrile


Chemical Equation:



1 Hg-CHg2 I

OH

CH3 OH
/}CHa-2\ I1
-! ; )H-ON-CN + H10
CHs-CH2 ]
C03

Molecular Formila . . . . Ci9HEtIh a

Molecular Weight . . . . .. . 24,5.54
Melting Point . . . . . . . 81-2.1

Recrystallizing Solvent . . . . 959 Ethanol


Analysis:

Nitrogen, ,:t

Calculated .

Found *.


. . . 17.27

. . . 17.20


Solubilities$


Water .

Ethanol

Acetone

Benzene


* . Slightly Soluble

. . Slightly Soluble

. . . Soluble

. . . . Soluble















2- 4-(5-Methylohenyl)-piperazino ]-2-methylpropanamide



Chemical Equation:


-/CII-C N-C + 20 O

b/ 0CH2-CH12
CHs



S H1-OH2 CH 0


CH, NH2
Molecular Formula . . . . . C CiOH2INO

l.olecular Leight . . . . . 261.55

Melting Point . . . . . . 1525-155.5

Recrystallizing Solvent . . . . 95% Ethanol


Analysis:

Nitrogen, %:

Calculated

Found .


.~* 4

* 4 4


Water *

Ethanol .

Acetone .

Benzene ,


. . 16.08

. . 16.06


Slightly Soluble

Slightly Soluble

* . . Soluble

. . Insoluble


Solubilities:













2- 4-(4-Methylvphenyl )-piperazino J-propanonitrile


To 0.2 mole (55.2 g.) of 1-(4-methylphenyl)-piperazine

was added 0.2 mole (14.2 g.) of lactonitrile. An exothermic

reaction set immediately. When cool the two-phase mixture was

solidjit gave a quanititative yield of product. Four recrys-

tallizations from 95% ethanol gave 80.5% of pure product. The

compound was dried at 500C. (2 Em.) before analysis. Physical

and analytical data are on parc- 58.


2- [ 4-(4-Metlyophenyl)-piperazino ]-propanamide


To 200 ml. of concentrated sulfuric acid was added,

with cooling and stirring, 0.175 mole (40.0 g.) of 2-[4-Methyl-

phenyl)-piperazino J-propanonitrile. The resulting mixture was

allowed to stand at room temperature for 24 hours and then was

poured onto one kg. of cracked ice* This solution was then

made basic with concentrated anmonium hydroxide and the

precipitated product filtered off. Three recrystallizations from

95% ethanol gave 70% of pure product. The compound was dried

at 50o0. (2 rna.) before analysis. Physical and analytical

data are on page 59














2- [4-(4-Meth'lph.enyl_)-pierazino J-propanoic Acid*Dihydrochloride*

Monohydrate



The crude aide from 0.175 mole of 2-[4-(k-methyl-

phenyl)-piperazino 3-propanonitrile was dissolved in 150 ml.

of concentrated hydrochloric acid and the mixture refluxed for

8 hours. The .solution was then poured into a beaker, concentrated

to one half of its volume and allowed to cool. The product

crystallized out in 77T yield. Three recrystallizations from

distilled water gave a pure product. The compound was dried

at 5000. (2 a.) before analysis. Physical and analytical data

are on page 46.















2-[ 4- (4-MIethylnhenyl)-piperazino 1-propanonitrile


Chemical Equation:

/-\ IC 2-CH\,
CH,\ /"2\ )I-\ + CHOHOCI -

OH


C rl +CH )H-CO 1
COI- -0I1
C113 UECi f. nZ


M-olecular Fornula .. ,

Molecular Weight . .

Melting Point . . .

Recrystallizing Solvent *

Analysis

Nitrogen, p:

Calculated ,

Found .

Neutral Equivalents

Calculated ,

Found .


4 9 9 9 9 9 .


* 6 9 6 0 6

* a a 6

* 9 0 0 4


a a * a *

60 066 99e
w


* 0

* 6


. . 229.51

. 126-127.2

* 955 Ethanol


. 18.75

. 13.26



. 229.51

. 250.5


Solubilitiest


Water ,

Ethanol

Acetone

Benzene


* . . . Incoluble

* . Slightly Soluble

* . . Soluble

. . . . Soluble














2- [ 4-(4-Methylphenyl )-piperazino 3-propane&ide


Chemical Equation:

013
1,^0 1110






Holecular Foriila . . . . . i CzUHllO0


Molecular Weight . . . .. . . 247.5

Helting Point . . . . . . 152.8-1l4

Recrystallizin; Solvent . . 95% Ethanol


Analysis:

Nitrogen, %:

Calculated . .

Found . . .


. ... . . 16.99

. . . . 6.8


Solubilitiest


Water .

Ethanol

Acetone

Benzene


0 0 Slightly Soluble

* . Slightly Soluble

. . . . Soluble

* Slightly Soluble















2- 4- (4- _~othyl-henyl )-n)iverazino ] -propanoic Acid- Dihydrochlorido*

:.henodmicr.. Nation

Chemicc.l Equationt


C113 0
O y C._-CHg ,\IM
^CI3^ -OIl /n


+ 21120 + ,1 HC-
0


0 0

3 r-" -00 *2\IICC1*20

+ UH41Cl


Molecular For.:''- 4 .

Molecular Weight a .

Melting Point .a.

Recrystallizing Solvont a

Analysis:

Nitrogen, 6:

Calculated .

Found .a

Neutral Equivalentt

Calculated .

Found . .


a

a


*. C G.sooIs0 02HO01*H0O

* . . 55?.24

. . . 202-203dec.

. . . .. . Water


* a a a

* a a *


* a a

* S a S


. . . 8.26





. . 1608.62

. . . 171.5


Solubilitiest


Water . . *

Ethanol O .

Acetone a

40e:cne
40


* . Soluble

Slightly Soluble

Slightly Soluble

a Insoluble














2-[L 4- 4-Mlothylphenyl )- porazino -2- ethylpropanonitrile


To 0.2 mole (05.2 g.) of l-(4-nethylphenyl)-?iperazine

vas added 0.2 mole (17.0 g.) of acetone cyanohydrin. An exo-

thermic reaction set in immediately. When cool the two-phase

mix%-ure was solid; ~t gave a quantitative yield of product.

Four recrystallizations from 95% ethanol gave 37,2% of pure

product. The compound was dried at 50C. (2 'm.) before analysis,.

Physical and analytical data are on page 42:.



2- 4- j-Mcthylthonyl)-vi'nerazino l-2-mOt jylpropanatide


To 200 nl, of concentrated sulfuric acid was added,
with cooling and stirring, 0.025 mole (6.1 g.) of 2-[4-(4-Methyl-

phenyl)-piperazino 3-2-methylpropanonitrile. The resulting

mixture w.as allowed to stand at room temperature for 24 hours

and then was poured onto 1 kg. of cracked ice. This solution

was then made basic with concentrated aeronium hydroxide and

the precipitated product filtered off. Three recrystallizations

from 95% ethanol gave 76% of pure product. The compound was

dried at 50C. (2 m,.)before anal ysiical and analytical

data are on page 45,















2-[ L-((-Ioethylphenyl)--iperanino 2-notlroanntrile


CheL1_ical Equationt
Cl i

c )I + c1:30-c: -


Molecular Forrula .

Molecular Weight .

Molting Point . .

.Recrystallizinj Solv

SAnalysis:

Nitrogen, ,.

Calcula

Found


\C12g-CII/ I I


S. . . . C a no

. . . . . . 24.54

. . . . . . 156-157.5

,ont . . . . 9, Ethanol


ted .

* >'


. S * S S 0 S S

a a a a a a ~


. 17.27

. 17.09


Ilat-Or a *

Eth4nol a

Ace one . .

Ben4ene .


Sl eight ly

Slightly



Slightly


Soluble

Soluble

Soluble

Soluble


Solubilities:















2-[ 4- (4-Mothylheny.l)-iperazino 1-2-methylpropanamide


Chemical Equationt

01%


1Molocular Formula. .,

Molecular Weight *.

Melting Point . . .

Recrystalliizig Solvent

Analysis%

Nitrogen, %:

Calculated

Found .


* a a.. a

* aow a. a

* a a a 4 0

as 9~**#


. CaGHaSQ0

. .. 261.35

S. 1. 70-171

S95< Ethan6l


* a a a 4 * * *

* a a a a a 0 a a


. 16.08

. 16.42


Solubilities:


Water . ,

Ethanol .

Acetone ..

B3enzOene .


Slightly

Slightly



Slightly


Soluble

Soluble

Soluble

Soluble













2- C 4l-(2-Chlorophe-inyl)-piperazino I-ethanonitrile


To 0.*5 mole (98.5 3.) of l-(2-chlorophenyl)-

piperazine in 200 ml. of benzene was added 0.5 mole

(57.3 g.) of chloroethanonitrile and 0.25 mole (28 g.) of
sodium carbonate. The mixture iwas refluxed for two days. The

solids were filtered off and the benzene renovod on a stoam

bath. The residue was recrystallized from n-heptane to yield

45, of puro product. The compound was dried at 5000. (2 nm.).

Physical and anal'-tical data are on page 46.



2-[4-(2-Chl.oronhenyl )-piperazino ]-ethanalide



To 200 ml. of concentrated sulfuric acid was added,

with cooling and stirring, 0.175 mole (04.5 g.) of 2-[4-(2-chloro-

phenyl)-piperazino I-ethanonitrile. The resulting mixture was

allowed to stand at room temperature for 24 hours and then was

poured onto 1 1:g. of cracked ice. This solution was then made

basic with concentrated aimonium hydroxide and the precipitated

product filtered off. Two rocrystallizations from 95% ethanol

followed by two recrystallizations from toluene :ave 5% yield

of pure product. The compound was dried at 500C. before analysis.

Physical and analytical data are on page 47,














2- t4-(2-ChloroIhenyl )-ni'erazino ]-ethanoic Acid.

nionohydrochlori de .monohydrate


2- 4A-(2-Chlorophenyl)-piperazino J-ethanonitrilc,

0.175 mole (44.5 g.), was dissolved in 150 ml. of concentrated

hydrochloric acid and the solution refluxed for 24 hours. The

solution was transferred to a beaker and evaporated to 1/5 of

its volume, 'hlen cool a solid had formed. This solid was

filtered off and recrystallized four times from water, The

yield of pure product was 27?. The compound was dried at 100C0.

(2 mm.). Physical and analytical data are on page 4..

















2- [ 4-(2-Chlorophenyl )-piperazino 1-ethanonitrile


Chemical Equationt
l01

C1I2Hg-CH ,
)N-H +
CMe-2 CH2


CICH.CNH --


Cl

16 / C11-H1 +
-N' )N-CHsOI + 0


Molecular Formuila . .

i:Molecular eight t * *

I-Molting Point . .

Recrystallizing Solvent .

Analysis:

Nitrogen, %t

Calculated .

Found .


* 0 0 *

* a a


* a a 0

* ** *0


* 0 0 0 0 0

* a a a *


. 255.71

112.2-115.5

* n-IIHoeptane






* . 17,85

. . 18.00


Solubilities:


* 0 0 0 0 0

* 0 0 0 0

* a a * *

* a a a *


Water .*

Ethanol ,

Acetone ,

Benzene a


Insoluble

. Soluble

* Soluble

. Soluble














2- l-(2-Chlorophenyl )-piperazino I-ethanamide



Chemical Equations

C1

-( )-CHsCli + I4O Hy
~C CH2-CH
Cl
01
61- 0N-CH
C CHI ICH'N/


Molecular Formula . . . . . 0H2.6N30C

Molecular Ueight . . . .. . . 255.75

Melting Point . . . . . . 169.70

Recrystallizing Solvent . . . . Toluene

Analysis:

Nitrogen, %;

Calculated . . . e . 16.56

Found . . . . . . 16.44

Solubilitiess

Water . . Slightly Soluble

Ethanol . . . . Soluble

Acetone . .* . Soluble

Benzene . Slightly Soluble












2- r -(2-Chlorophenyl )-piperazino -othanoic Acid-

Monohydrochl oride .monohydrate

Chemical Equation:

-Cl

6 )-IK )N-GCigCN + 5H20 + 2HC1 -

01

/CH2-CH\ /H
-GH~l-Hso + I i1Cl



Molecular Formula . . . . . Czg 00eOl'HCl-Hg0

Molecular Weight . . . . . . . . 508.18

Melting Point . . . . . . . 200 dec.

Recrystallizing Solvent . . . . .. . . Water

Analysis:

Nitrogen, %:

Calculated for CII aOC-H01ClH01* .0 9.65

Found . . . . . . . . 9.54

Neutral Equivalent:

Calculated for CzHN202ClI*HOCl . 508.2

Found . . . . . . . . 505.1

Solubilities:


Water . . . .. . . Soluble

Ethanol . . . .. . Soluble

Acetone . . . . .. Insoluble

Benzene . . . . .. -Insoluble

48













2- E 4-(2-Chloropheyl )-piperazino J-propanonitrile


To 0.2 mole (55.9 g.) of l-(2-Chlorophenyl)-piperazine

was added 0-.2 mole (14.2 g.) of lactonitrile. An exothermic

reaction set in immediately, 'ihen cool the tuo-phase mixture

solidified, on seeding with a few crystals of the three chloro-

analog of the product, to give a quantitative yield. Four

reocrystallizations from 95; ethanol gave 92,5 of pure product.

The compound was dried at 50C. (2 rmn.) before analysis. Physical

and analytical data are on page 51.



2- 4-(2-Chlorophenyl )-piperazino l-propanamide



To 200 ml. of concentrated sulfuric acid was added,

with cooling and stirring, 0.175 mole (46.8 g.) of 1-[ 4-(2-Chloro-

phenyl)-piperazine 1-propionitrile. The resulting mixture was

allowed to stand at room temperature for 24 hours and then was

poured onto 1 kg. of cracked ico. This solution was then made

basic with concentrated anmonium hydroxide and the precipitated

product.filtered off. Three recrystallizations from 95/ ethanol

gave 70" of pure product. The compound was dried at 500C. (2 Ln.)

before analysis. Physical and analytical data are on pae 52.














2- 4-(2-Chlorophenyl)-piporazino -propanoic Acid

*Monohydrochlori de* Monohydrate



The crude anide from 0.175 mole of 1-[ -(2-chlorophenyl)

-piperazine ]-propionitrile was dissolved in 150 ml. of con-

centrated hydrochloric acid and the mixture refluxed for

8 hours. The solution was then poured into a beaker, concentrated

to one half of its volume and allowed to cool, The product

crystallized out in 70% yield. Three recrystallizations from

distilled water gave a pure product. The compound was dried

at 50WC* (2 Ea.) before analysis. Physical and analytical

data are on page 55*
















2- L 4-(2-Chloropheniyl)-piperazino J -propanonxitrile


Chemical Equation:

Cl

S /CH1-CH C
TH + CCHOCU -

Oil


+ IT0


Molecular Formula . .

Molecular Weight . .

Melting Point . .

Recrystal lizing Solvent

Analysis:

Nitrogen, 5:

Calculated

Found. *


* 0 0 0 0

* 0 S 0

* 0 0 0

* 0* 00


* SO@

* 0 0 0


* . 131 1T Cl

. . . 249.17

. .. 84-84.8

. . 9. Ethanol


. . 16.85

. . . 16.77


Solubilitiess


Water . . . Insoluble

Ethanol Slightly Soluble

Acetone . . . . Soluble

Benzene 0 . . . Soluble















2-F 4-(2-Cnloroohenvl)-niperazino J-nrowanamiide


Chemical Equations


Ci- \ I ,so
.- /CHe-,Hg _C T0
2 ),- C )N-CHO, H+ -0
v*- OHg-CHs


Molecular Formula . .

Molecular Weight , ,

Melting Point .

Recrystallizing Solvent

Analysis:

Nitrogen, %:

Calculated

Found .*


. 0 0 a A


* 1 0 .


* CO.Hiou1301

. . 267.75

. . 165-165

* 95% Ethanol


* 4 5 5 9 S S

* '0 0 * 0 0 0


* 15.69

. 15.95


. Slightly

. Slightly



. Slightly


Uater .

Ethanol

Acetone

Benzene


Soluble

Soluble

Soluble

Soluble


SSolubilities:














2- r.4- (2-Chloro.ev;l)-picerazino J -propano:ic Acid

*ionohydrochlorideo Monohydrate

.Chemical Equation:

Cl
001
+-21 /H+-1201, O/
-\ I-CI + 2I0O + 2H01


*HIIO'Hic + ::L 01


Molecular Formula . .

Molecular ..ei .

Melting Point .

Recrystallizing Solvent .

Analysis:

Nitrogen, j:

Calculated .

Found .

Teutral Equivalont:

Calculated for

Found , .


. . . C21Is 03eCl'Kl*1O0

. . . . f f f 4 25.21

. . . . . 205-212dec,

* . . . . . UWater


* ft ft ft ft ft ft ft ft

* ft ft ft ft ft ft ft ft ft ft ft


ft ft ft ft ft ft ft 4


. 8.67

. 9.17



. 525.2

. 522.2


Solubilities:


ft ft ft ft ft ft I

ft ft 4 ft ft ft ft

ft ft 4 ft ft ft ft

ft ft ft ft ft ft ft


. . . Soluble

Slightly Soluble

Slightly Soluble

. . Inooluble


Water .

Ethanol

Acetone

Benzene

55














2-L 4- (2-Chlloroohenryl)-piperazino ]-2-raethylpronanonitrile



To 0.2 nole (59.5 S.) of l-(2-Chlorophenyl)-piperazine

was added 0.2 nole (17,0 g.) of acetone cyanohydrin. An exo-

the mic reaction sot in immediately. h.1len cool the two-phase

mnituro was solidly it gave a quantitative yield of product.

Four recrystallizations from 955 ethanol gave 1.8^ of pure

product. The co.-ouan was tried 5at 000C (2 ni.) before analysis.

Physical and analytical data are on pvge 56.



2-I 4-(2-ChlorohenylJ )-ninerazino -2-z iet ylro ana.i de



To 200 nli of concentrated sulfuric acid was added,

with cooling and stirring, 0.175 mole (A19.5 g.) of 2-[14-(Chloro-

phenyl)-piperazino ]-2-motlhylpropanonitrile. The resultinI

rnixture was allowed t. stand at room- temperature for 24 hours

and then was poured orto 1 :g,. of cracked ice. Thi. solution

was then made basic wvJth concentrated amroniun hydroxide and the

precipitated product flitterod off. Three recrystallizations from

95- ethanol .gave 70,- ofL pure product. The compound was dried

at 500C. (2 mn.) before analysis. Physical and analytical

data are on ',"g, 57.













2--4-(2--Chlorophenyl)-piporazino 1-2-methylpropanoic Acid*

M.onohydro chloride


2'- 4-(2-Chlorophenyl )-piperazino J-2-nethylpropanonitrile,

0.175 mole (49.5 z.), was dissolved in 150 al. of concentrated

hydrochloric acid and the solution refluxed for 241 hours. The

solution was transferred to a beaker and evaporated to 1/5 of its

volume. r When cool a solid had formed. This solid was filtered off and

recrystallized four times front water The compound was dried at

100lO' ( 2 nm.). Physical and analytical data arc on page 58















2- 4- (2-Ch1oro'hcr~cT1 )-pi~erazLo I -2-mcthy1pro~anonitr ile


Chemical Foru 1.


1 1

+ CH3CCN -

OH


0113

-n O M,-C-ON + 720

CHi


Molecular Formula .

I.olecular Weight . .

Melting Point 0 t .

Rocrystallizing Solvent

Analysis:

Nitrogen, ']:

Calculated .

FoUld .* *


. . . 0 CIi18KIOC1

* . . . . 265.76

. . . . 115-11#.5

. . . . o ] Ethanol





. . . . . I.95

. . . . 9 15.71


Solubilities:


Water . . . Insoluble

Ethanol . Slightly Soluble

Acetone . . . Soluble

Denzene . . . Soluble















2- F 4-(2-Chilorophenyl)-piberazino ] -2-ot.hypro':anwide


Chemical Equation:


+ 110 to


Molecular Formula,, . . .

Molecular T'oiUiJt . . . .

1ielting Point . * .

Recrystallizing Solvent . .

Analysis:

Nitrogen, #:

Calculated.

Found . . .


* C:12HsuIOOl

. . 0 261.7G

. . . 166-186

. . 95% Ethanol





. . . 14.91

. . 14.34


Solubilities:


!Water *

Ethanol

Acetone

Bonzeno


* 0 Slightly Soluble

* . Slightly Soluble

* . . . Soluble

, . Slightly Soluble













2- 4-(2-Chlorophenyl)-piperazino ]-2-merthylpropanoic Acid-

Monohydrochlori de

Chemical Equations

CCH

-I + 0 + 21 01
C C-Ci


Clio

"- C-c-' *H01 + :7:.. 1l



Molecular Formula . . . . . .CO

Molecular Weight . 0 . . . . a. 19.24

Melting Point . . . . . . . 200 dec.

Recrystallizing Solvent . . .. . . . . Water

Analysis

Nitrogen, I-

Calculated for Ca,1 1O'HCl. . . 8.78

Found . . . . . . . 892

:ocutral Equivalent:

Calculated for C1HjiO*20*I2iC1 . . 519.2

Found . . . . . . . .

Solubilities

Water . . . . . Soluble

Ethanol . . . . Soluble

Acetone . . . . . Insoluble

Benzeno . . . . . Insoluble
58














2-r 4--(5-Chlorothonyvl)-piorazino 1-propanonitrile


To 0.2 nole (59.5 g.) of 1-(5-chlorophenyl)-piper-

azine was added 0.2 mole (14.2 g.) o"' lactonitrile. An

exothemic reaction sot in immediately. ".:he cool the two-phase

mixture was solid; it gave a quantitave yield of product. Four

recrystallizations from 95% ethanol gave 84.270 of pure product.

The compound was dried at 5000. (2 iz) before analysis. Phys-

ical and analytical data are on page 61.



2-r 4-((5-Chlorophcnyl )-piperazino 1-pro)anamaide



To 200 nl. of concentrated sulfuric acid was added,
4
with cooling and stirring, 0.175 nole (4i*.2 j.) of 2-C 4-(Chloro-

phonyl)-piporazino J-propanonitrile. The resulting mixture was

allowed to stand for 24 hours and than was poured onto 1 kg. of

cracked ice. This solution was made basic with concentrated

a:m-oniun hydroxide and the precipitate filtered off. The product

was extracted from the filter cake with 95% ethanol then recrys-

tallized three times from this solvent. The pure compound

(60,' yield) was dried at 500, (2 rm.) before analysis. Physical

and analytical data are on page 62.


59-













2- 4-(5-Chlorophenyl )-,piperazino I-pronionic Acid


2- 4-(5-Chlorophenyl)-piperazino J-propanonitrile,
0.175 mole (45.6 g.), was dissolved in 150 ml. of concentrated
hydrochloric acid and the solution refluxed for 6 hours. The
solution was transferred to a beaker and evaporated to 1/5 of its

volume. ;ehen cool a solid had formed. This solid was filtered

off and recrystallized four times from water. The compound was

dried at 100C. (2 mm.). Physical and analytical data are on

page 65.















2- 4-(5-Chloropheoiyl )-npierazino 7-propanonitrile


Chemical Forulat

cl


-H + CHOICI >

OH


C1 CI13

1-CHICH1 + iI,0
He/ \S CHs


I-Iolecular Forfaula . . .

Molecular '..ci;;. . .

Melting Point .w, . .

Recrystallizing Solvent .

Analysis:

Nitrogen, %:

Calculated ,

Found . .


. . . CisHigisC1

. . . . 249.17

. . . 98.5-99.5

. . . 95% Ethanol


* 0 0

* 0*


. . . 16.5

. . . 16.68


Solubilities:


Water *..* . . Insoluble

Ethanol . Slightly Soluble

Acetone *. * . * Soluble

Benzene *. . . Soluble















2-[ F-((-Chlorophenyl)-ninerazino -1-pronanamide


Chemical Equation:


/C1H2- I ,so,
d -. C iN o + 0 .
v- Ceg-CII,/


Molecular Formula . .

Molecular Weight . .

iIelting Point . . .

Recrystallizing Solvent

Analysis

Nitrogen, %1

Calculated

Found .


* . S S

* S S S S S

* 5 9 * S S S

* S S S S S 9 5


* 9 . . S 9

* S S S S S S S


. 267.75

. 151.5-2.6

955 Ethanol


. 15.69

. 15.65


* Slightly Soluble

*. Slightly Soluble

. . . . Soluble

S. . . Insoluble


Wator .

Ethanol

Acetone

Denz one


Solubilities:















2- .4-(5-Chlorophenyl)-piperazino .-propionic Acid

Chemical Equationt

l 01
ClC

/ +H-.CHN I
N CF)1 )N-CH-CN-+ .l240 + HC1 -
'CHg-CI


,,H s .0 '
/.s-CH,\ I /
-/ N-0H- + NHCl
3OHi -CHI) ")H


Molecular Formula . . .. . . . .

1.olecular Weight . . .... . . .

Melting Point . . . . . .

Recrystallizing Solvent . . . . .

Analysis:

Nitrogen; 5:

Calculated for C1HIyNeO1cl

Found . . . . . .


CS1H17N20eC1

. . 263.74

. 200 dec.

* a . Water





. .. 10.42

S. . 10.50


Solubilities:


Water . . .

Ethanol . . .

Acetone . . .

Benzone . . .


. a. Soluble

. . .. Soluble

* . Insoluble

. . Insoluble


65














2- [ 4-(5-Ohlorophenyl) -niperartzino 1-2-mnthy1nronanonitrile



To 0*2 mole (}9.5 c.) of l-(5-chlorophonyl)-piper-

c.zine was added 0.2 nole (17.0 go) of acetone cyanohdrin. 'An

exotheric reaction set in ir:i1odiately. When cool the two-phase

n.ix;ture was solid; it gave a quantitative yield of product.

Four recrystallizations from 955 ethanol gave 009.0 of pure

product. The compound was dried at 50C00. (2 ranm) pressure before

analysis. Physical and analytical data are on page 65.



2-r O-(5-Chlorophenl)-piocrazi-o 1-2-mcthylprogananide



To 200 ral. of concentrated sulfuric acid was added,

with cooling and stirring, 0.175 mole (49.5 g,) of 2-[ 4-(5-chloro-

phonyl )-piperazino ]-2-n-et4lproaoanonitrilo. The resulting

solution was allowed to stand at room tounerature for 24 hours

and then uas poured onto 1 kg. of cracked ice. This solution

was thon raarde basic with aErz.ionitu hydroxide and the precipite

filtered off. The product was extracted from the filter cakc

with 95, ethanol and recrystallized froi the saac solvent. Three

recrystallizations gave 86, of pure product. The compound was

dried at 5000. (2 r;.) before analysis. Physical and analytical

data aro on page 66,














2-F 4-(5-Oh1orophen~r). )-pircr~z~no 1 -2--th-1prov2ano~itrilc


Chermical Equation:

01

)-n NI-H + CHaCN C ----

OH


.-( )N--CH+ eIO
\ C~i -CHa I
CH3

IIolocular Forzila . . . . C13IIU103C

Molecular Voight . o . ... . . 265,76

Melting Point . . . . . . . L. 89-90

Recryctallizing Solvent . . . . 95* Ethanol

Analysis:

Hitrogen, cs:

Calculated .. . . . . 15.95

Found *. . . . . . 15.&2


".ater .

Ethanol .

Acetone *,

Benzene .


. . . Insoluble

. Slightly Soluble

S. *. Soluble

. . . Soluble


Solubilitieo:















2-[ 4-(5-Chlorophenyl )-piperazino 1-2-methylpropanamide


Chemical Equations

0113

0 )N-C-CN + 1 13 -

04a


13 0

0 'HH.


Molecular Formula . ..

Molecular Weight . .

Ielting Point ... . .

Recrystallizing Solvent .

Analysis.

Nitrogen, %:

Calculated .

Found . .

Solubilities:


*

*


* .* C2UH2oNQOC1

. . . .. 2" .50

. . . 157.2-158.5

. . . 95) Ethanol


* 0 S 0 0 0 0 0

* 0 5 0 5 0 5 0


. 14.91

* 14.76


Water . . Slightly Soluble

Ethanol . Slightly Soluble

Acetone . . Soluble

Benzene . . . Insoluble













2-F 4--(4-Chlorophernyl)-piperazino ]-propanonitrile


To 0.2 mole (59.5 c.) of l-(4-chlorophenyl)-piper-

azine was added 0.2 mole (14.2 8.) of lactonitrile. The

mixture was heated on a steam bath for fifteen minutes and alloiw-

ed to cool. The two-phase mixture was then solid and gave a

quantitative yield of product. Four recryttallizations from

95'5 ethanol gave 95% of pure product. The compound was dried

at 5000.C (2 ::m.) before analysis. Physical and analytical data

are on pago 69.



2-r 4-(4-Chlorophenyl)-piperazino -propananide



To 200 ml. of concentrated sulfuric acid was added,

with cooling and stirring, 0.175 mole (40.8 g.) of 2-E4-(4-chlorc

phenyl)-piperazino I-propanonitrile. The resulting mixture was

allowed to stand at room temperature for 24 hours and then was

poured onto 1 kg. of cracked ice. This solution was then made

basic with concentrated ammonium hydroxide and the precipitated

product filtered off. Three recrystallizations from 9";;, ethanol

gave 88.5% of pure product. The compound was dried at 50C. (2 mn.)

before analysis. Physical and analytical data are on page 70,











2- r4-(4-Chlorophenyl )-piperazino I-propanoic Acid*

Dihydrochloride*


2- r 4- (4-Chlorophonyl )-piperazino ]-propanonitrile,

0.175 mole (45.6 g.), was dissolved in 150 ml. of concentrated

hydrochloric acid and the solution refluxed for 24 hours. The

solution was transferred to a beaker and evaporated to 1/5 of its

volume. When cool a solid had formed. This solid was filtered off

and recrystallized four times fror wator. The compound was dried

at 100C. (2 tm.). Physical and analytical data are on page 71.














2-[ 4-(4-ChloroDhenyl )-piperazino .-propanonitrile


Chemical Equation:

-_ /CHs-CHl,

C( )) r 1+ CHcCHNC -
C12-CH0I


CHs

Cl .N )HN-CHCT + 110
molecular Formula CHCH . .

Molecular Formula . . . . . CiBHigN3(


Molecular Weight . . . . .

Ielting Point . .

Recrystallizing Solvent . . ,

Analysis:

Nitrogen, /%:

Calculated . . .

Found . . . .

Solubilitiest


Water .

Ethanol

Acetone .

Benzene .


. . 249.17



. 955 Ethanol





. . . 16.85

. . . 16.89


. . . nsoluble

. Slightly Soluble

. . .. . Soluble

. . . Soluble


1














2- (4-(4-Chlorophenyl)-piperazino ]-propanaiide



Chemical Equation:

OH3
_/\ /CH2-CH2 112 SO4
G1 j-N c M -CHOI + H20 -
^- CIg-GHs7


N CHg-CH -C
/-!'I N--C\ 1O
CIIg-CH7 N1

. . . . C1sHoNH30C

. . . . ... 267.75

. . . . 171-172.2

. . . . 950 Ethanol


o1<


Molecular Formula .

Molecular lieight .

Melting Point . . .

Recrystallizing Solvent

Analysis:

Nitrogen, %/

Calculated *

Found . .

Solubilitiest


Water . .

Ethanol . .

Acetone .

Benzene . .


* 0 S 0

* S S S


Slightly Soluble

Slightly Soluble

* . Soluble

. . Insoluble


.:15.69

. 15.65













2- r4-(4-Chlorophenyl)-piperatino J-oropanoic Acid*

Dihydrochloride

Chemical Equationt


CH3

01 -1/ C-GC1 I CH- + 21120 + 501 ----
CH-CH~I2


CHS 0
Cl/-\ C0-CH I-CH-
1CH -CHi 1


Molecular Formula . . . .

Molecular Weight. . . . . .

melting Point . . . . .

Recrystallizing Solvent . ..

Analysis:

Nitrogen, 5:

Calculated for CzsHjy

Found . . .


,2H01 +! 41Cl


. . C3sHyN12O*Cl'2HCl

. . . . 541.67

. . . . 200 -dec.

. . . Water


,gO2Cl*2HCl


Solubilities:


Water .

Ethanol

Acetone

Benzene


* V * V * *

* * * *

* * . . *

* * * .


. Soluble

. Soluble

Insoluble

Insoluble


* 6.57

S .71













2- F 4-(4-Chloro.he'ny.l).-iperazino 1-2-methylpropanonitrile


To 0.2 mole (59.5 g.) of l-(4-chlorophenyl)-piperazine

was added 0.2 mole (17.0 g.) of acetone cyanohydrin. An exothermic

reaction set in immediately. Uhen cool the two-phase mixture was

solid; it gave a quantitative yield of product. Four recrystal-

lizations. from 951 ethanol gave 90.0% of pure product. The

compound was dried at 500C. (2 mnm.) before analysis. Physical

and analytical data are on page 74.


2- [ 4-(4-Chlorophenyl )-piperazino 1-2-methylpropanamnide


To 200 ml. of concentrated sulfuric acid was added,

with cooling and stirring, 0.175 mole (49.5 g.) of 2-[ 4-(4-chloro-

phenyl)-piperazino J-2-methylpropanonitrile. The resulting mixture

was allowed to stand at room temperature for 24 hours and then was

poured onto 1 kg. of cradled ice. This solution was then made

basic with concentrated anmonium hydroxide and the precipitated

product filtered off. Three recrystallizations front 95% ethanol

gave 840 of pure product. The compound was driedat 50oC. (2 ran.)

before analysis. Physical and analytical data are on page 75*













2- 14-(4-Chlorophenyl )-piperazino J-2-methylpropanoic Acid


2- 4--(4-Chlorophenyl )-piperazino ]-2-methylpropano-

nitrile, 0.175 mole (45.7 g.), was dissolved in 150 ml. of

concentrated hydrochloric acid and the solution refluxed for

8 hours. The solution was transferred to a beaker and evaporated

to 1/5 of its volume. Uien cool a solid had formed. This solid

was filtered off and recrystallized four times from water. The

compound was dried at 100C. (2 mm.). Physical and analytical

data are on page 76.















2- f 4- (4-Chliorophenyl)-piperazino 1-2-rmethylprooanonitrile


Chemical Equationt




OH


Molecular Formula .

Molecular Weight .

Melting Point . .

Recrystallizing Sol

Analysis

Nitrogen, Os

Calcult

Found


/"T /oQ12 -L) + 1120
OH3


. . . . . .0G^~0IIiCl

S. . . . ...265.76

. . . .. . .126.5-127.2

vent *. . 95% Ethanol


ated

& v


* a a a a

* a a a a


. . 15.95

. . . 15*6?


Solubilitiest


V'ater . . . . Insoluble

Ethanol * Slightly Soluble

Acetone * . a Soluble

Benzene . . . Soluble















2-r 4-(4-Chlorophenyl)-piperazino 1-2-methyloropanoanae


Chemical Equations



01 ICH -i + O -0
^CHs-CIHg'


MIolecular Formula .

Molecular Weight .

Melting Point . .

Recrystallizing Solv

Analysis:

Nitrogen, %s

Calcula

Found


C1HC-CHs\ O

1io-Gl-' 'Of i

. . . .. O1411Ho0ToOC

. . . . . 281.76

. . . . . 180,2-181.2

rent . . . . 95% Ethanol


oted

* 9


* S 0 0 0 0 6

* 0 0 0 *


. 14.91

. . 14.S5


Water . .

Ethanol . .

Acetone . .

Benzene .


Slightly Soluble

Slightly Soluble

*. . Soluble

Slightly Soluble


Solubili'.ios:'














2- r4-(4-Chlorophenyl)-piperazino ]-2-nethylpro-anoic Acid



Chemical Equation:

CHo
S/OFg-CII
01 -C-CH + 2H10 + HC1 >
CH-Chi2 1
CHs


O /CHg-CHg\ 1 //
01 -N )N-C-G-' + NHACl
0CHg-CH 2 I H .'OH
CHs

Molecular Formula . . . . . . ..CiH~,N202C

Molecular Weight . . . . . . . 282.76

iMelting Point . . . . . . . . 200 dec.

Recrystallizing Solvent .. . . . . . . Water

Analysis:

Nitrogen, %:

Calculated for C4l19gNC021 . . . 9.95

Found . . . . . . . 10.02


Water . . . ..

Ethanol . . . .

Acetone . . . .

Benzene . . . ..


. . Soluble

. . Soluble

. . Insoluble

. . Insoluble


Solubilities:












CHAPTER IV


SUI-MARY



Thirty-seven newv nitriles, aides and acids have been

prepared from l-phenylpiperazine, 1-(2-chlorophenyl)-piperazine,

1-(5-chlorophenyl)-piperazine, 1-(4-chlorophenyl)-piperazine,

1-(2-methylphenyl )-piperazine, 1-(5-methylphenyl)-piperazine,

or 1-(4-nethylphenyl)-piperazine with chloroacetonitrile, lact-

onitrile or acetone cyanohydrin and described. Data on these

compounds are summarized in Tables I, II, and III.






TABLE I

Physical and Analytical Data of 2-(Arylpiperazino)-alkanonitriles


cag-CH2
ArA .
Molecular Molecular Melting Point, Yield, Nitrogen, %
Ar T Formula Weight %C. % Cale. Found


0605

%H5
065

o-H3C6H5

_-CH3065

mG-C6H

-CHC6H5

27-cg0o5
2-cac6n5
r-ClC6H5
o-ClC6H5
o-Cl1gH-


012"155N
014W3







014H19N

C15H2113





C13H16N3cC
C14n18301


201.26
215.29
229.31
229.31
243.34
229.31
243.34
229.31
243.34
235.71
249.17
263.76


75 76
87.3- 88.1
111.8-112.5
105.5-106.5
122.5-124
62.8- 64
81 82.1
126 -127.2
136 -137.5
112.2-113.5
84 84.8
113 -115.5


80.5
87.2
48.4
84.2
51.0
75.0
80.5
87.2
43.0
92.5
81.8


19.52
18.74
18.39
17.27
18.39
17.27
18.39
17.27
17.83
16.83
15.93


19.16'
18.15b
18.75
17.22
18.41
17.20
18.26c
17.09
18.00
16.77
15.74


a.N.M. Calc., 215.29;
Found, 230.5.


Found, 212.7.


N.E.t Calc.,


229.31; Found, 229.8. cN.E.: Calc., 229.31;


CH%


(C)20



CR3CH

(CH)20
(c03)2C






(C3)20
GH) 2C














TABLE I (Continued)
Ar y Molecular Molecular Melting point, Yield, Nitrogen, %
I Formula Weight 00. % Calc. Found


c13 16 3

C 1316 301
c1418 3e1


249.17
263.76
249.17
263.76


98.5- 99.3
89 90 .
120 -121.5
126.5-127.2


84.2
89.0

93.0
90.0


16.83

15.93
16.83

15.93


16.68

15.82
16.89

15.83


1. 1.


_m-ClC6H5
-dcl6 H
- 65


-CieH5
L- clc6 5


CH3 CH
(cH3)2o


(cH3)2c







TABIS II
Physical and Analytical Data of 2-(4-Arylpiperazino)-alkanamides
0
Ar- -N CH -H NY)-C


Molecular Molecular Melting Point, Yield, Nitrogen, %
Ar Y Formula Weight oC. % Calc. Found


c> 06 5
C605


o-CH3C6"5

c3c6H5

m-C0RC6H5


-C .3C65


2-CC06H5
o-ClC6H5


%2"17530


C H* O0
14 215 30
014'21 30o
c15'233 0
C 14H21N30



C15H2350

012H16N3001
C13185 30Cl

SC14H2o053Ocl


219.28
233.30
247.33
247.33,
261.35
247.33

261.35
247.33
261.35

253.73
267.75
281.78


169 -170
143 -143.8
162.8-163.5
122.3-123.4

174.5-175.5
126.5-127.3
132.5-133.3'
152.8-154

170 -171
169 -170
163 -165
186 -188


31.0
70.0
76.0
23.1
60.0
48.o
66.0
70.0
76.0
54.0
70.0
76.0


18.01
16.99
16.99
16.08
16.99
16.08
16.99
16.08
16.56

15.69
14.91


18.03
16.74

17.01
16.12
16.91
16.o6
16.83
16.42
16.44

15.93
14.84


CH3CH

(0c3)2c6
CH3CH

(C5)2;
CESCH

(CR3)2 a


(cH3)2c
CH2
CH3CH

(c3) 20C
















TABLE II (Continued)
Molecular Molecular Melting Point, Yield, Nitrogen,%
A Formula Weight oC. % I ale. I Found


C13H1853001
014o20 3001

c13H183001

C14N203001O


267.75
281.78

267.75

281.78


151.3-152.6

157.2-158.3

171 -172.2

180.2-181.2


60.0

86.0

88.5

84.0


15.69

14.91

15.69

14.91


15.65

14.76

15.63

14.85


m-C106C H5
a0106"5

CD E-C1C6H5

k-ClC6H5


CH3CH


C73CH
(C3)2c








TABLU III
Physical and Analytical Data of 2-[4-Arylpiperazino]-alkanoic Acids




Molecular orMolecular Nitrogen, % Neutral Equivalent
Ar Y Molecular Forsmla
Weight Cale. Found Calc. Found

C6"5 CH3CH 013 H18T202 2H01*20 323.20 9.12a 8.90 161.6 158.1
-CH 36AH Cc3CH CH 20N202o2H1*" H20 339.24 8.26 8.33 168.6 171.3
o-01cC65 oH C12H15 N20201 'Hco120 308.18 9.63b 9.54 308.2 305.1
o-C016H5 0CH H C 13H1720201lHCl'H20 323.21 8.67 9.17 323,2 322.2
-201005 (cE3)2C C 14H19202ClHO.1 319.24 8.78 8.92
m-ClC6H5 CCH C013 17o202C1 268.74 10.42 10.50
2-ClC6H5 CH3CH C13 H 202Cl*2H01 341.67 8.37 8.71

L-010C65 (c0~)2c C14H19N20201 282.76 9.93 10.02


bCale. for 012 15"20201* OI *H20.


aCalc. for C13 H18N2022HC.11*20.


c0alc. for 0C13 91772o201-H1Ho20.













BIBLIOGRAPHY


I. D. E. Adelson and C. B. Pollard, J. Am. Chem. Soc.
Ly, 140 (1955).
2. G. Barger and F. P. Ooyne, Biochem. J. 22, 1417 (1923).
5. R. L. Betts and S. P. G. Plant, J. Chema. Soc., (1928) 2075*
4. F. Bradkorb, et. al., German Patent No. 6. 5 (1958).
5. 1. . Bukhsh, et. al., J. Chem.Soc., (1956) 1159.
6. H. T. Clarke and H. J. Bean, Orfg. Syntheses, Coll,'Vol. II,.
29 (1945).
7. R. A. Jacobson, J. Am. Chenm. 67, 1996 (1949).
8. A. Klages, J. Pralt. Chmo., (2) _, 188 (1902).
9. E. Knovenagel and E. 1iercklin, Ber, _t, 4087 (1904).
10. 0. Nicoderns, H. Lange and H. Kranz,.U. S. Patent 2,211,152.
(1940).
11. 0. B. Pollard and L. G. 1IacDowell, J. Am. Chem. Soc., 56,
2199 '(1954).
12. T. St. Warcenis and F. Sachs, Ber., 2[, 26 (1904).
13. T. D. Stewart and V. Cook, J. Am. Chem. Soc., 5g, 1975 (1923).
14. T. D. Stewart and C. Li., J. Am. Chem. Soc., 60, 2782 (1953).
15. A. Strecker, Ann., 75, 27 (1850).
16. T. H. Wicker and C. B. Pollard, unpublished work.
17. N. Zelinsky and G. Stadniikoff, Der.41, 2061 (1908).



















Tlie author wishes to express his sincere appreciation

to Dr. C. . Pollard, Chaiman of the candidate's Special

Supervisory Committee. Dr. Pollard's patience, assistance,

advice and encouragement have helped the author i~aeasurably.

This work was done under a Parke, Davis and Company

research grant. The author extends his thanks for financial

assistance, chemicals and supplies.

Finally, the author wishes to thank his follow students

for nakin- this work as pleasant as possible.














BIOGRAPHICAL ITEMS0


Laroence J. Huehes was born in Quincy, Illinois on

October 11, 1924'

Mr. Ilughes entered the University of Louisville,

Kentucky, in Ilarch, 191A4b In Novenber, 1944, he entered Duko

University and -ias awarded the degree of Dachelor of Arts in

Juno, 1946. 11He then pursued graduate i-tork at Dal:e until August,

1947. He entered the University of Florida in Septem-ber, 1950.

From 1 hny, 1942 to July, 1945s 1r. .uChes :as employed

by the C. F. Durgoss Laboratories, Inc. as e control and junior

research chemist., In July, 1945, he enlisted in the U. S. iTavy

where he remained until June, 1946, lie began his e:_ploymont by

the Anerican Cyanamid Conpany as a research chemist in September,

1947, and remained with that corapny until August, 1950.

.Mr Huihes is a member of Kappa Si:'a, a social fraternity;

a senior member of the American Chemical Societyl a Lt.(jg.) in

the Volunteer. iaval Research Reservej and a nemober of Pi Mu Epsilon,

an honorary mathematics society, He hold a) U, S. Army Fellowship

at Duke University and has hold, in succession, a Gnrrduate

Assistantship and h; Parke-pairis Fellowship at the University of

Florida.















Committee Report


This dissertation was

the Chairman of the candidate's

been approved by all members of

to the Graduate Council and was

the requirements for the degree


prepared under the direction of

Supervisory Committee and has

the Committee. It was submitted

approved as partial fulfilment of

of Doctor of Philosophy.


Date


SUPERVISORY Ci0-MITTEE:




Chairman


Dean,
College of Arts and Sciences







Dean,
Graduate School











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TITLE: Derivatives of piperazine. XIV. (record number: 554227)
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