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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
Internet Distribution Consent Agreement
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AUTHOR: Hughes, Lawrence
TITLE: Derivatives of piperazine. XIV. (record number: 554227)
PUBLICATION DATE: 1953
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