Title: Derivatives of piperazine, XI
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 Material Information
Title: Derivatives of piperazine, XI addition of 1-Arylpiperazines to alpha, beta-Unsaturated nitriles and esters
Alternate Title: Derivatives of piperazine, XI
Derivatives of piperazine, eleven
Physical Description: 74 leaves. : ; 28 cm.
Language: English
Creator: Robbins, Robert, 1916-
Publication Date: 1951
Copyright Date: 1951
 Subjects
Subject: Piperazine   ( lcsh )
Chemistry, Organic   ( lcsh )
Chemistry thesis Ph. D
Dissertations, Academic -- Chemistry -- UF
Genre: bibliography   ( marcgt )
non-fiction   ( marcgt )
 Notes
Thesis: Thesis -- University of Florida, 1951.
Bibliography: Bibliography: leaves 72-73.
Additional Physical Form: Also available on World Wide Web
General Note: Manuscript copy.
General Note: Vita.
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Bibliographic ID: UF00098042
Volume ID: VID00001
Source Institution: University of Florida
Holding Location: University of Florida
Rights Management: All rights reserved by the source institution and holding location.
Resource Identifier: alephbibnum - 000551219
oclc - 13306142
notis - ACX5686

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Derivatives of Piperazine. XI.


Addition of


1-Arylpiperazines to alpha, beta-


Unsaturated Nitriles


and Esters


BY
ROBERT ROBBINS


A DISSERTATION PRESENTED TO THE GRADUATE COUNCIL OF
THE LINiVFRSIT' OF FI.ORIDA
IN PARTIAL FULFILMENT OF THE RFQUIRFMENTS FOR THE
DEGREE OF DOCTOR OF PHILOSOPHY










UNIVERSITY OF FLORIDA
lune, 1951





















CHEMISTRY
LIBRARY
















PAJNi


The presentation of this disursbation material is purposely

given in detail to facilitate &uplieatien of this work by future

inventigatort. Uvery synthesis is reported in detailed form even

though the procedure in a given, homelege s series is basically the



Throughat this dissertation all temperature reported, both

boiliq points and melting points, are corree4ed vale. The thermo-

m~ers useed were calibrated against a set of theirmeeters standardized

by the Bureau of Standards.

In conformity with present practice in properig reports of

this kind, all teuperatmres are of the centigra&e scale, and its eye-

bel is omitted.

The percentage yields of the nitriles and esters, syntheses

of which are reported in this dissertMtim, are based upne the melar

qentity of l-e rlpiperaine used. Similarly, the peraetage yields

of the amine acids and aides are based uIon the melar quantity of the

nitrile ueed.

The maIer of listing referasoes is the easteary one for teth-

nieal reports. ZeI-rl abbreviatieam are the official o sn of Ch9Mbf

haanate|.












TABLI OF COrTENTS


Chapter Page
PR AC . . . . . . . . . . . . ii

I REVIEW OF LITBRATIRE AND INTRODUCTION . . . . . 1

II OBJECTIVES, METHODS, AND RESULTS. . . . . . . 13

III ZXPIRIM RTAL PROGIDURIS AND TABIS. . . . . . . 19

1-Phenyl-4-(2-cyaeathyl)pipraine . . . .. 20

1-Phenyl-4-(2-carboxyethyl)piperaine . . . .. .22

l-Phenyl-4-(2-carbonamide-ethyl)piperazine ..... .24

l-Phenyl-4- (2-carbethozyethyl)piperazine
dihydrochloride ............ . 26

l-Phemyl-4-(2-carb.e--butoxyethyl)piperazine
monohydrochloride . . . . . . .... 28

Pheylthiourea of 1-Phonyl-4-(3-aminopropyl)-
pinerazine. . . . . . . . ... ... 30

1-(2-Methylpheayl)-4-(2-cyanuethyl)piperazine . . 32

1-(2-Methylpheny]4)--(2-carbeyesthyl)-
piperazine monohydrochloride. . .. . . . 34

l-(2-Methylphenyl)-4-(2-arbonamide-ethyl)piporazine. 36

1-(2-Methy~lnhenyl)-4-(2-carbethoxyethyl)-
piperazine aenohydrochloride. . . . . ... 38

1-(2-Methylphenyl)-4-(2-carbo-a-butoxyethyl)-
piperazine dihydrochloride. . . . . . ... 40

1-(3-Methylphenyl)-4-(2-cyanoethyl)piperazine .... 42

l-(3-Methyl~henyl)-4-(2-carboxyethyl)piperazine . .. 44

1-(3-Methnyphenyl)-4-(2-carbonamide-ethyl)-
piperazine. . . . . . . . ... ... 46












TABLES OF CONTElTS (Coatin aLd)
Chapter Paeg

1-(3-Methylphayl) -4- (2-earketkoarthyl) pipers-
zine dihydreeleri . . . . . . . 48

1-(3-Methylphlnyl)-4-(2-earbel--biatexythyl)-
piperazina menohydrechloride . . . 50

1-(4-e thylphemyl)-4-(2-cyaaoethyl)piperazine . . 52

1-(4-Met hylphenyl) -4- (2-carboxyethyl)piperazine
meaohydrochleride . . . . . . . . 54

1- (4-Mt hylph yl) -4- (2-carboaam ide-ethyl) -
pipera in . . . . . . . . . .. 56

1-(4-Methylphenyl)-4-(2-carbethexyethyl)pipera-
sine dihydrochloride. . . . . . .. ..58

1-(U-Me hylpheayl)-4-(2-carboe-a-butoxyethyl)-
piperazine dihydrochloride. . . . . ... 60

l-(3-hlerophanyl)-4-(2-cyanoethyl)piperazian . .. 62

l-(3-Chloropheeyl)-J-(2-carboxyethyl)piperazine . 64

I-(3-Chlorophneyl)-4-(2-carbeonaide-ethyl)pipera ine. 66

SUWART . . . . . . . . . .. . 68

BIBLIOGRAPR . . . . .. . . . . . 72

ACcKOWI DIfTS . . . . . . . . . . 7

BISRAPRIICAL ITI'S. ................. 75

COMMITT" REPORT












CHAPTER I


RZBITW OF LITfRATTUR AND IWTRODUCTIO


An addition t eameua. ean be defined as a waeitaume that is

formed by a direct embinatioe of tw or wore simpler sunbtaaese.

This definition of addition will, therefore, eliminate from this

oategery all campends that do not contain all the ateme that were

present in the original reactants.

During the early history of organic chemistry abnormalities

were observed in the oeurse of certain of the addition reactions

which involved substanees containing alternate single and multiple

linkages. Suah an unsaturated system is called a Saiaspied au.Yt

It differs frem a simple unsaturated system in that addition takes

place at the ends of the conajuated system rather than acres the

nltlple linkages. Thiele, in 1899, propeed the theory of partial

valeaeo to account for addition oeuring at the ends of a conjuCate4

system 1 He assumed that not all the available affinity is aee& by

a double bond between twe atem. This anmee affinity was called a

JartJial alM; and whenever the multiple linkages oecur in alternate

petitions, the partial valenaes an intermediate atoem aetralise eah

other so that the seat of unsaturatiem is loealised at the to minal

atems in the oenjuated system. This eensepties of partial valeney













is repwueatie byW .ea lie* ia ta feA.1wtE lleaMfteln.


-C-c-c-c- -* -c-c-c-C-
. *
*. .



While Thiele.' theory vwas early aAepj it. priasipal deftt wa

in the vagwemees f the eeasopt of the affinity that every atm is

aseemt to hswo. kNt to be eTverloeet is that the theewy f partial

valeawy requires exluTsive 1,4-additiM, mL may ease are kUaa

where l,2-aaditila takes plane with esejqAted systems.

Planeble elsetresis intorpretatieas kalm bee applied sasw s-

fully in dealing with may type s f resotiemn involvig eajitles.

Lewy ceftlated. ar am eeke of eleotri disrplaremet kaem as the

IaiiMrgu| UM hL This meebamism my operate only is csau. e-

tia with multiple boern anl involves a ohma ia the oe4ut affilia-

tims of am or -me el rem ptirs. Ne does oenitite of the seleule*

seers Ir *g thi11 s diplamnat. Ieffally, the difplaemet is repae-

seabS bW mrred w u*ve whieh g'ab*olis the tantemrti tisplam.t

dr olestw- paips. Tis Aimpi oment i seallA t&he Lg

Mjgf The earlier partial valoas thee7y of Thkiel is emplairnl

in toe of the newer eleetmi theery, as is lai ateM in the ltui-

larity at the fullemtq rep.eertat ism:





--C O G- -- C C-
S *
**


-Cso-C=C- .4 -CO Cm -C-











3
UneaturaM earboayl compeAids poen the properties of

elefias as well as those. of the saturated earbtFyl compeaids. If

the $thyleaic bead is in the ,S-positiea with reoweet to the oatrbyl

gremp, a conjugated system exists, and 1,4-addiftioen a take plane.

Tor example, an s,p-uneaturated ketose has a pelarised structure (II)

ia which the positive center is at the 4-poeitio as well as that i

which it resides on the 2-positiea, or carbenyl ate (I):

+- 4 3 21 +
n-Ca1G-O-0 .. -oH--e : 3-CI-OU.C-O0



(I) (UI)

As a consequeaoe, carbo(yl reagents may attack at peeitiai 4 rather

than at the usual site positione 2). The additisa ef ai uasymerical

reagent, HA, in this manner occurs in at least two stages, the first

being the attackmeat of the negative (A~) or the positive (eN) meiety.

Considering the case in which the first step is the attacheat ef the

negative meiety (A7) at positive 4, the resultet aiuct mW correv-

peeo to either of two resonance structures, III and. IT. As diagramd

belew, the final result is 1,4 -er 3,4-a6ditiea:

-+
1R-Cf-OSO-0O + E -' R-CE-,-G -OE

A R A 2
^ (III) (V) ^
*+
-B-OBH-01- + E -. H-CE-CH -C-0
1k.


(IT)


(VI)












Iewly all enelle eompe ds seh a these pr neod bhr l,4-mMitima (V)

reaurrage mspotaneasjly to the eelMeapea g ea t e.aPueaet" (VI)

whioh woeld be prodtue by 3,4-C1 1itt. 5I-N it Ir4LtauNtly ii i4

pesible t tell whether the addition raetib is of the 1,4- or the

3,4- type. The eseeatial feature of the reseAtla is the attaebmat of

the nogtive iar at position 4.

The present reseah teals mere speelfieally with addition

to a,-vsaturatred aitrileo and esters; however, the swm mrekaim

an peotrraped for addition to a,-arsaturated keteme applies equally

well tl kind, if not in d&gvee of rosetie, to a,-umttmeratod altriles

rand eters.

a,.-U~s atanrted nitlrleI and eaters oideioe bOet 1,4- and 1,2-

additioa. In general, as the activity of the nitrile or earblkary

grwup doere..e*, the salM t of 1,4-additiua increase. The soe of

addition also will depend upeB the umber, kind, aid peeitLion of the

*abetitLeats in the nitrile or ester and upn the graV or grape

present in the addeMidm. The react ionse these umeatwMled system

with alemic esters are typienl of l,4eLitiea:


0 S %oR0 + O%(_211)2 z so%0O

u(oo0x )2


Cc~agmonos I + at'woe )2 .-- aK5 i)
00O )











5

A wide variety of organic and inorganic ~omelds assessingg

labile hydten atems add readily to acrylenitrile with the foraties

of meleealee e.taiing a syaaeethyl e"iping (-CI-2GC2).3 Most

authors have oensiAereo this addities te occur by l,4-addittie with

a subsequent tauteerie shift of the &adt t to the saturated aitrilo.

As already pointed out, it is not orMaarily possible to determine

vetb* r 1,l-additime or 3,4-editiea oecurs. The essential feature

is the attaesasm t of the negative e ty of the adAeAdi in the 4-

positioa of the aseepty. Generalized, the reactisr which is

oioadly called eyasewthylti -- is represented as follows:


RA + CG-G=HCI --o ACI -C-CI --+ A0H20H20G

Typical compounds cetainiag reactive hyirge atems which have besa

aided to aerylonitrile are omplunds having one or more -M-- growe.

such as aammoia, primary an seeotary aiaes, IhyLasize, hydroxyl-

amine, imiles, laefams, sad asides. A wide variety of other ompeurads

containing labile hydrogen atems also have been aMeid e aerylemitrile.

Druses has presented a very there h review of the symneethylation

resetiea.

This reaetien, eapt with certain aulas, unally requires

the presees of an alkaline estalyt. Typeal catalysts vlftl as

useful for this purpose are the oxides, hydroxides, alkelxies, hyrides,

eyaniles, and mumes of the alkali metals sodium aA potassium as well

as the metals themselves. Because of their selability ia osieaic media.

the strongly basic quateomary m ewima hydrexidee are particularly










6

effective as afbalywti for this SA&tIta. Oaly small sam tks of

the eta lrts are re ired. Miay of the rest ies are sesMgly eme-

tenrt ad wmquirt e exilual selling to pre t o*zeX etre pellpwt-

satim *f the aerylamitrile. Inert *elvemtsi eas as bUenew t nii sum ,

pari&its, amteaitrile, aad tertilaf latyl aloehi have %in epla Ad .

The latter, while restive with aeIyleslitrle at temperaturee aove

60*, i relatively inert at or near reem tempeatuwe.

Aummina mat mest mlaes add to awsyleitrile withe t t1ke

aid of a etlyTfI. Ammr ia, havinB three labile hyMdreg amse,

yield. a mixtLuL of ame-, di-, aed tri- eyameethlatrle pres&ute:5


/-+ a12522039
h + neasg -Mf w(aOgRa)



Is a give resette the yield of mmem-, di-, or tri- eyaasethrliumin

deperls "mxe the teiomprtars of the rsetties ait the 1s matloe of

restentme mpleget. Ike trieymieethylaalI, la all eaORs, is ebta i t

in the lowet yield.

Brsea states that, is gasmal, aisxe. adA to aeryloritrile

m re reaetly thel anq eths elas es f eeoo es, but their ese of

imaAtti varies ensiideimbly. With these alMuse vkish rest slvoly,

a met&ie or beA:e catalyst it desirable. While primary amiae my

reast with e r two meles of eryllitrile, seseadary Iad'Sm

ret with aly me male of aerylenitrile. Beesre of the latter










7

definitensus of addition, the temperature at which the reaction eoa

take place may be varied over a wide rrge.

Nothylamine, ethylamine.5 prepylamim, iseprpyllamine,

lrbam lamine, Ag.-butylamine, ad t~grl-butylaomne yield the moae-

eyanoethylated AeriTative. Piperidi.e adds nUadily to aerylenitrile

with the evelutiea of heat.5,10 w~kolime is oaly slightly less

reactive than piperiiine.. Dietkylamime, heweerr, &L&A more slowly

than morpholine, although no diffieulby is neeeatred in obtaining a

near-qujtitative yield of predmet rely by heating the re-Ctetas to-

gether.5

Whitmore ad eellabonrers indiesate that the rate of addition

of the ami e is primarily depetesit epa the iez and complexity of

the aian. Other r*eeaek*ers have indicated that; si.ae the ioniz&-

tiea coostants of diethylamine, piperiline, and morpleline are, respect-

ively, 1.2 x 10"3, 1.6 x 10-3, and 2.4 x 10-6 and all rat quite rapid-

ly: the basicity of the armie is probably net an important facter.11

The e anoethylation resetim has been extended to mazy complex

primary and secondary aines. These are too namr a to include in

this review. At 95* sua mimed meeasary mines as methyl-j-propyl-

anine, ethyliseprapylamine, cyclepentylethylanine, j-buutyl-g-prepyl-

auiae, j-butyl-j-t-butylamie ,12 and beazylaethylaime13 ad readily

to acryleaitrilo. The cyclic bse -- pyrrelidine, 2-aethllpiperidine,

3-methylpiperidina 4-mewhylpiporldine, and 2,6-dimethylpiperidine -

are other ewx les of mines which add roeily.14












htereeyelie bMass coataining two imimto grous -- Mso as

pipe azine, hydregeiated pyraiidines, and hydrelageat perilidines --

react with two meleeules of acryleitrlle:15'16
CTcQ%-0E






Behr and collaborators did not isolate the dicyarnethylation prodoet

obtained from piperaSine but redu.C d it directly to the diamiLn.15

Certain aminas, especially those in the aran tis and heta&-

yelie series, rraet s9ly very slowly with acrylonitrile in the absence

of a catalyst. Methylaniline and 1,2,3,I&-tetrahydreq.auioline do not re-

aet a-npreciably rhon heated in a evalt| tube at 200'. Hewverr, in the

proeeti of glanial aetie acid they react at 120-140* to give geoo

yields of the cyaaoethylated derivativee5

Subatituted aerylenitrilres, such as ma-ethylaerylonitrile an

creb eonitrile, wret loss readily than .eryloaitrile with the variwo

classes of eqolpnds that undergo cyanoethylatiem. Brueon stated that

it had not been possible to add aldehyaes and keooaeM to ao-nethylacryle-

aitrilo, althboeh he rucoeeoed in adding to it the stroully beete anime,

piperitine.3 Crotaeitrile is mReh more reactive thU oeithkylaerylo-

nitrile. Bntrisa enem tered no diffiealtise in adding aines and nitre-

pagaffins to croteAaitrile.3

The addilen of compouads possessing active hydrogen et acrylake

estezt to give P-emabutituted propionates is very similar to the eyane-












ethylatien reaetieo. This addition, which has at times been called

h3xyethfrtlaitia., my be gene alis in the fellovwia way:


NA + 02=CBHOOR -- A-0C20CI20e

As in the cyenoethylatiot, the earbexyethylatiL reaction is presumed

to proceed by 1,4-a*dition and a subsequent tastemeric shift, yielding

a product identical with that which would be obtained by 3,4-adtition.

Kethberylate esters, acrylate eeters hanlag an alkyl Mabstitusem ea

the a-oarba atem, are lose reactive and do not uandACe all of the

addition reaction which ea be esrrft eat with aerylate mate..

A wide variety of inorganic and organic molecules poseessing

labile hydrogen atme react with acrylate enters. Nalegea aids,

aleohols, pheaols, hydrogen sulfide, mereaptane, thiophenols, amonia,

amines, amino alcohol, nitroparaffins, and eompaunds with reactive

methylene groups have been added to acrylate esters.17

The addition ef ammeia to acrylate enters was investigated

as a means of producing P-alanine, K2NCHY2C 000E, for use in the

preparation of pantetlhnic acid. Ammenia has three active hydrogen

and, therefore, forms the secondary and tertiary amino esters as well as

the primary amine ester. Nellvain and Stork have shewa that foratiao

of the primary, secondary, and tertiary amino esters is a reversible

reaction.18

Primary aliphatie anines readily add twe mles of acrylate

esters to give the tertiary amino esters; no catalyst is required for

this addition:
RMEI + 2 C -cCDOR' ---* Mi(C2H C200OK')










10

Nemwthrlmi.ae and oth.* aerwyla*, are Ppt rt to give a yield of the

adsmet of 94 per esat:19 sIst 'I amim and ethyl srylo e mthyl

r'ylate &ar repsartd to ive a yisld of 8" per eaJ.20S21 Althogh

unian trate esters are less ooetivn tnema the addties of mrime

that the aerylate estese, asthIy nmthoeaw- te and tamm-thylamine wice

a 7? per eat yield of the tertiay aami eastr.21

In his work with amines rewettE disevered. that yields Ae-

erease as b~reacia of chain in a seoenaary amine increases. Tkis

effeet of structure and the lesser resetivity ef metheryllate esters,

a Mopedl with aerylate *Otwe, result in greatly red se yields. Ne

observed that piperid&ae a l e4hyl aerylate reacted t give a 9 paw

seat yield of the tertiary amis sac Bnraeking f the aehal of the

seoaAe"y amst redned the yield ef the ateiot. The yield of the

adtsiet obtained frsm ethyl-j -b7tylmia and etyl aserylate was 69

per seat vwh the reetti es as arted& out at 85-120*. 1Di tprepyl-

sata and eh3rl aerylate did set reset t th boili f patat. The re-

ioeties of yield with sesmmiar anine of this type ad aerylate *estep

em e ow e dmti a to a siarir reLustim in yield wiv these same asies

and aeryle trile is the eyasethylaties resetim. Weisel aa se-

wo:here related piporidim with ebhl awtherylate tad obtained an

83 per east yield of the tertiafr amse ester by heating the eter

with an recess of piperidise at 1000.3 Deepite this sucees, other

vesie have fed the nmelaerylate eate to be praetisally uresetiv

with allphatise eeeda6 y am*es.21.34 The high order of resetivity ef











11

the heterseyelie M-nh is s*ow by the 97 per smet yield In the carbexy-

thy dhta of the fellowin pyrrelidin derivative:25



+ C=0jcUOOC 5 --b t ; C.HOOoC5


CemparM& to the parent mubetanee, pipoertie, the l-aryl-

piperasines have been sadied isa aly a limited. y. The synthesis

of 1-phoeylpiperaziae was rlqpmrt slimltmeusly Ly different investi-

gators: Pellard and NoeDvll prepared this srubtanee by heating aniline
26
hydrochleride at 240* for six to eiht hurs;26 Prleg aaA Drisa heated

na etfluzx ,p'-dichlorodiethylamiam with a mthaselic solution of

aniline for 16 hoaw.27 Prolog andl Blank extenrad this resetio of

P,01-dihalodiethylamine mslts to other arylarles, father than aniline,

to obtain l-(2-methylphenyl)piperaziae, 1-(4-nethylphe.rl)pipera2ine,

and other 1-arylpiperazines. 8 Mre recently Wieker and Pollard have

synthesised 1-(2-methylphemyl)piperazine, 1-(3-aethylphemyl)piperasino,

l-(4-lethylpheoyl)piperazinm, l-(3-chlorophenyl)piperazine, and other

1-arylpiperazines by heating the appropriate arylaiae hydrochloride

and tie. a elamiie ader the sam eearitieas that Pollard and Mae-

Dowell utilised in making l-pheaylpiperaszin.29

In prepiring synthetic analogs of oxytocie drcgs, Phillips

prepared the dihydrochloride of methyl 4-b.nzy-l--piperasiaylpropiemato

by the addition of l-benzy1piporazie to methyl acrylate.0 AMdele

ad Pollard synthesized alkyl 4-pheayl-l-piperasiaMlaeetates by the

action of l-phoaylpiperauine and chloroaoetie esters; 4-phanyl-l-











1l

piporauiLseirlme ammiie by the aetioa of amMeti hydrea.Ae s ebtyl

l-plahenyl--piper aitaylactate and fx l 1-ph*Mylpiperatcin, ehlereethan-

amite, and sdilm earboate; na d -pemay-l-l-piperaziFia lt~ t lmnibuile

firm 1--phnylpiperailae, metheal, aad. hydroge cpaAhLo anm ale fr e

l-pheaiypiperamine, ohlew ethl saitrile, and sodim oarb ste.31













CHAPlR II


OBJ.CTIITC KITEBS, AID RESULTS


The object of this investigation has been the study of the

addition of 1-arylpiperazines to a,f-unsaturated nitriles and eaters.

The investigated is limited to the following addeada: l-phenyl-

piperazine, l-(2-methylpheayl)piperaziae, l-(3-methylphenyl)piperazine,

l-(4-m~dipheayl)piperaxlme, and l-(3-ehlorophanyl)piperauine. The

accepters used were acryleaitrile, cretenemitrile, metblcrylonitrile,

ethyl acrylate, butyl aerylate, methyl methacrylate, and ethyl meth-

aerylate. The additions of these cemperond are not reeeried in the

literature; they represent a continuation of the work performed in

this laboratory in an effort to synthesize organic molecules which

peoess ph eielegieal activity.

The acceptors outlined abeve, except cretenenitrile, are

available on the commercial market. The 1-arylpiperazines, which

ceuld not be purchased, and the crotoaeaitrile were prepared in the

laboratory as intermediates for this iaveetigatiea.

The additiea of 1 erylpiperazines to acrylemitrile was found

to be effected easily by the addition of a slight excess of the nitrile

to the l-arylpiperazine, with stirring, at a temperature higher than

room temperature. No catalyst was needed to effect the addition when

acrylenitrile was the acceptor molecule. In general, the procedure was:












A fraetioaml melee of the l-artlpiperastim was hotel to 50-55';

wkile this temoraturn Yugoe aad stirring wre maintain seoatirm-

eusly, a sl1&t eoaoe (0.02 mole, usually) of the nitrile wee slowly

a&te* te the amine. Oersimae l external cooling was neeseary to maim-

tala this temperature range. Stirring aad the temperature roeeoded

above sveo maintain frea 1.5 to 4 heors after the addition of the

mitrile was completed. The resetiosi aitare wa allowed to etand

for snTral hours to determine the state of the roeetiem reoduet.

If the mixture was a slid, the solid mes was washed well with water

to rermee any asemeted aitrile or l-arylpiperasiie. The aomponaM

was them air-dried to obtain the eraie yield. If the reoatiea mixture

was a visseLm oil, the Eatire sente i were purified by distillatioa

iA"er vaan.

The yields of the purified eyimeathylatiem reactie pradust

raised fram 48.7 per eent te 86 per mat. The solid prodetrs were

recrystallised. from 95 ?*r oat othasel; generally it was nenemsary

to reerystallize from two to fa r times before a pre@di t vhisk ve

ae chance ia melting point was obtained.

Addities of 1-arylpiperasmlne to aerylaeitrile probably oceuzn

in the eual maeser of additiems to ca,f-muoturated. nitriles. 1-Aryl-

piperazi a adds i the 1- and the 4- positiams to produe the imie

fer (I) of the additi-a seameelm, whear A is an aryl gre p:



A1 -- --z + -* Ar-C 2 2)-9h(O) W
2 F. (I)











15

The mine form is unstable and is rapidly nraverted to the stable

nitrile fora (II), with which it exists in revereible equilibrium



CH2-CH'2 C-2IC\2

(I) (II)

The equilibrium favors the formation of the nitrile, and the major

portion of the oompouad probably exists iR this form. As pointed

out in the previous chapter, the compound formed is, in effect, a

eewpeund obtained by 3,4-aMitiem.

The cases in which additional have been aceomplished are enam-

erated in Chapter III. Crotemeaitrile and or-methylaerylonitrile did net

yield addition pdo&aets with l-phenylpiperaziae under the experimental

conditional which were successful with acrylonitrile; however, it is

known that these compounds are vey mach less reactive than acrylo-

nitrile.

The cyanoethylation products of 1-arylpiperazines are all

stable under ordinary conditions. They are readily converted to the

aside and amino acid derivatives. In one case, l-phenyl-(2-cyane-

ethyl)piperaziae, the primary amine was formed by reduction with sodium

and ethanol and identified as the phenylthiourea of the amine.

The aide derivatives were prepared by hydration of the nitrile

in concentrated sulfuric acid; the iminosulfate formed by the addition











16

of the aid to the aitrile was thae hydrolysed. The resetioln are

diagramed below:



R"y N 5 ac r -?---+ B-- U* -W
1 1 11 2
L 0


The asid s were purified by recrystallizatien fero water or from very

dilute eth]iael. They were obtained in yields ranging between 37 and

66.6 per oa*t.

The amine acid derivatives were prepared by alkaline hydroauis

in dilute ethamol solution. The usual procedure was to reflux me-teat

mele of the cyaneathylation reaction product with a 50 per sent exess

of potlaslim hydroxile in 60 per sest ethamel. After removal of eth~.-

o1 and some water by distillation the amino acid wae presipitatel by

eemfal neatralizatiea with dilute hydrochloric acid. Two oeaie re.

tuired the addition of xe*4ee hydrochloric acid; thee aiaaae~dds

were isolated as the hydrochloride mlts. These derivatives were

purified by reerystallieatioa free water and were obtained in yields

betwa 4 0.4 a d 63.4 per cent. Coemiderable loss was experimed in

purification.

The redeutieo of 1-phM-il.(2-eyma*etl)piperatise by sedifl

and ethuml was meeesplished in a meaer that is generally knlwn and

sanfs nI diseu aie9. Nlwever, teo l-pheayl-4-(3-einoprepyl)piperazine

was set obtained in a pure soadition a portion of it was isolated and

identified ae the pheylthicurea derivatYUe.










17

The additions of 1-arylpiperasiMe to the acrylate eaters

were effected by refluxlag an excess of the aerylate ester with the

piperazine derivative in anhydrous benzene. The mode of addition is

analegeas to the 1,4-additisa which was outlined for kstonee and ni-

trilesS A mixture of one-tenth mole of l-arylpiperasine and two-

tenths mole of the acrylate ester in 25 al. anhydreus benzene was

heated under reflux for 18-19 hours. After the solution had cooled

it was extracted three times with 3][hydrochloric acid. The acid

solution was made basic with petmestom carbonate solution, and the free

ester was extracted with ether. An excess of nethanolic hydrogen chlor-

ide wras added to the ether solution, after drying over anhydrous po-

tassilu carbonate, to precipitate the hydrochlloride of the ester.

Purifioatien was accomplished by recrystallization from anhydrous neth-

anol or from a methao l-ether mixture. The crude yields ranged from

71.6 per cent to 98 per cent, while the yields of the purified com-

pounds were between 25 and 72 per event. hie oases in which additions

were effected are enumerated in Chapter III.

Under the conditions that yielded addition products with

acrylate esters, methyl methacrylate and ethyl methacrylate did not

add to 1-phenylpiperazine or l-(2-methylphenyl)piperazine in yields

great enough to permit separation of the hydroohloridea of the enters

from the unreacted vaines.

From electronic concepts it would appear that the meMhacrylate

esters and methacrylonitrile uould not reaet as readily as the acrylate











18

e otre or acrylonitrile. The methlt greup, with refermnee to hydrogen,

release elee taen (-. I offset) so that the direction of elmoti dis-

placemat idu to the methyl grreu prwmeate or deereaese the eleetro-

erie shift of oleetieas in the a, -umaatkra osytem. This, therefore,

reudnes the possibility of 1,4-cadition.

Analyses of all the addition copounds synthesized were coaf ias

to semi-micro Kjeldahl aeteminatioan of nitrogen. In those casms in

which reeults of nitrogen determination required confirmation of molecu-

lar fornla, chlori s asalys, were made by eacre, grarimetric precipi-

tation of silver chloride.










CHAPTP. III


EXPRIMIRfAL PRO CB7JR AND TAJMS


Intetniad t


Acrylonitrile was purchased from American Cyasamid Coripany.

That portion of the nitrile which boiled at 77.30 was used.

Ethyl acrylate was purchased from Carbide and Carbon Chemicals

Division of Union Carbide and Carbon Corporation. Methyl methacrylate,

ethyl methaerylate, and a-butyl aerylate were purchased from RohI and

Haas Company. Purificatien of these monomers was not necessary.

Methacrylonitrile, which needed no further purification, was obtained

from the Shell Development Company.

1-hoaylpiperazine ee prepared by the method of Pollard

and MacDowell.26 l-(2-Methylphe*l)piperazine, l-(3-methylphenyl)-

piperasine, l-(l-methylpheyl)piperasi:ie, and 1-(3-chlorophenyl)pipera-
29
zine were prepared by the method of \icker and Pollrd..

Crotononitrile was prepared by the Isemerization of allyl
32
cyanide, utilizing the procedure of Brudo. That portion of the

distillate boiling at 105-117.5 which BrMson states is a mixture

of the cis- and tr nsl- forms, was used.


Addition CoMpuaajd

In the pntes which follow the method of preparation of each

co-pound is describe'. individial3y. Following each description is a

paCe on which pertinent data We tabulated.













1. PFeparatiea of 1-~9hr .-4-(2-qpmet* 1)V)pipe meti



Oe mole (162 C.) of l-p-healpiperazine uas plaseL ia

a 1-litor, 3-am&W flask eqmtppe with thermmeter, iamaer l

stirrer, and idrepi~ J fbmel. The l-pswaylpiperasine was heated

ta 550, ad 1.2 male (63.5 .) ef aeyloeitrile wax flowly md&-

ed. With oeoseioaal external coeling the temperature weA maia-

tained at 559. Stirring was eontiinu for one awd oae-halt houw

after the additiea of aeryleoitrile was eMleed. When Geel the

re etioa mixtuoe was a solid. The solid mes vae tratElerred to

a Buehber ftasel and washed well with water. The eoapousM was

air-Aried and reerystalliise there tie fea 95 per Met ethamml,

yielding pure white erysals. The yield of thi erate ppoenst was

qsrntitative, ads the yield aftor tWk reerystallizatios was

86 pye we t of theeortieal. The purified proetet was dried i

3gI over ea-mcrqn ated sulftric asd4 before it was aalysed.

Analysis gave 19.44 1; eeltlalted, 19.52% I1. the -ltian point

of the pure empeami is 71.3-72.10.














1. l-Phl yl-4-(2-cyaneethyl)piperaine


Chuemial equation:

S- -5 + CN2aKCEI -




CK2 2-C=


Molecular Formala. . .

Moleeular Weight . . .

Melting Point. . . .

Yield of Crude Produet. .

Tield of Pare Product. .

Analysis -- Nitrogen, %:


S . . C13 7

. . . 215.29

S. . 71.3-72.1*

. . Quantitative

..s


Calculated . . . ... .19.52

Feund. . . . . . . .19.44

Peerystallizing Solvent. . . . . 95% ethmaol

Solubilitie :

Water ........... .Insoluble

Ethanol. ..... Fairly Soluble

Mother . . . . .... .Soluble

Aetoe. . . . ... .Soluble

Bensem . . . . .Solible


....

rr














2. Prepaation of 1-Phecal-J-(2-earboi e thyl) pip er-sie



One-tnth mole (21.5 g.) of l-phrnyl-4-(2-cymnethyl)-

piperasine was heated under reflux with 0.15 Mole (8.4 g.) of

potssriu hydroxide ia 250 al. of 60 per oent ethanol for 4 hours.

The condenser was set for distillation, and volatile materials were

remwred by heating on the steam bath. The residual solution was

cooled and extracted meo with ether, and the aqueoum solution

wae heated on the stem bath to remove dissolved ether. The

cool aqueous solution was carefully neutralized with dilute hydro-

chloric acid to preeipitate the amiam acid. The compound wae

filtered with suction ind washed well with water. The produet

was air-dried aad reerystallized two tian from water, yielding

pure white platelets. The yield of the crude product was 60 per

sent of theoretical, and the yield after twe reerystallisatone

wae 56.4 per eoat of theoretical. The lrMifia prodtet wer &ried

IS. vM over e*aesmtrated sulfuric acid before it wae anlysed.

Analysis gave 12.05 : eanlelated, 11.9I N. The melting point

of the pure eospeqia was 187.6-188.6'.











23

2. l-Phenyl-4-(2-oarboxyethyl)piperasiae

Chemical Iquatiea:


(- 2 -cx I2 CH2-C)E -1


C.


Molecular Forml. . .

Molecular Weight . . .

Melting Point . . .

Yield of Crued Product .

Yield of Pure Product. .

Aaalysis Nitrogen, %:


0

CK -CI 2



. . . . .013 18202

. . . . . .234.29

. . . . 187.6-188.6*

. . . . . . 60%

. . . . . . 56.14


Calculated, .

ouand. . .


Reerystallizing Solvent . . . . .

Solubilities:


Water . ..

Ithanol . .


Either . . . .

Acetone . . . .

Be e e . . . .


. . . . 11.96

. . ... .12.05


. . Water


. . eoluble
. . Insoluble


. Insoluble

. Insoluble

. Insoluble














3. Pnrpawatiom of 1he.ysl--l4..(arbnrWemiit-e tyl)pipeatsiae


lerty-thro thwaadthu mole (10 g.) of 1-phegal-4-(2-

cyalmetvl1)pipcrsiae wee dissolvl in 40 ra. of conceBatatsd

su flrie at This mixts e heated spean~mnewly. After tatt-

ing feI f the elamte at approximately 90 the renactiae mixtaos

wae eoele and peered into 300 al. of ioc-cold water. The aque-

ew aelutiea was made besie to litMn with a eslution of sodiv

1piruxide. The oseralem was filtered with uentin and wvahed

well with water. It was air-risd and reerystallisd be times

fren water, yielding silky, whites needles. The yieli after two

esFryutallisaties wva 55.7 per set. The purified prodmet was

iried I& v over Osneeo tratye sulfuric acid before it was

analyzed. Amalysts gave 17.90 It; ealealatet, 18.01% 1. The

Biting poiat of the puoe oeatped wee 170.7-171.?.










25

3. 1-Phenyl-4-(2-carbemaid-eathyll)piperasieo

Chemical equation:




A I OosN






-- C CH2C22

2 ,2


Molecular Forml . . .

Molecular Weight. . . .

Melting Point . . . .

Yield of Pure Product ..

Analysis -- Witrogen, %:

Calculate

Found.

Recrystallizing Solvent . .

Solubilities:

Water..

Ithanel.

Ither..

Acetone.

Benzene.


. . . . . .C319N0

. . . . . . 233.30

. . . . 170.7-171.6*

. . . . . . .55.75


S. 18.01

S. 17.98

. Water


. . . . . Insoluble

S. . .. .Slightly soluble

..... Insoluble

. . . Insoluble

. . . . . Insoluble














4. PrepW*tioa of l-PIWrl-k-(2.a.wbetwharethyl)piperaine dihyiro-

dilori d



A mixtui e of 0.1 mle. (16.2 g.) of 1-peaMylpiperazin

an. 0.2 mole (20 g.) of ethyl aerylate is 25 ml. of aerhdroan

beneea was heated undMe retflux for 18.5 heurs. When c~ol the re-

action mixture was extreeted tlhee times with 31 hltrealloric

aeid (200 Im.). The aoid solution wafs baified with potaesiua

ear-lRate eliution *I then extrated three timee with ether.

An aoAmn of amtkemelic hydrogen chloride was added to the dry,

filtered ether solutite frm wiMeh the dihydrochloride of the

ester precipitated. The e*upounA was filtered with suetion, nir-

dried, and rerpiytlr li& d three Mde frm anhydrous methanol,

yielding pwrt white crystals. The yield of th er ude product

was 71.6 per eant of theoTetleml, and the yield after three re-

crystallisationu was A4.5 per sent of theoretical. The plified

preinet was dried j vlsal over eanoentrated sulfuric acid before

it was amrlyme. naalyeis gave 8.36 1N ealewnlated, 8.36% N.

The meltiag point of the :pure compaowd 'se 216.2-216.70.












4. l-Phmyl-4-(2-Orftl Who Othyl)pipera.i.. 4ihydroehlorlde

CLaemical Xquatim:

(D CH2-C52\ iv



(-.- 2C1aC 1
-H +2 2- ,-C-o- X5
0


Cff 2O-CN2


Nleclar Formla. . . . .

Moleealar Weht . . . .

Melti Point. . . . . .

Yieli of Crde Prodet . . .

Yield of Ptre IPeat. . ...

Analyis -- NitrQgea, %:

CalenlateA.

FewA . .

Rerystalliine Solvat .. .

Solubilities:

Water. .

Bthbaol .

other . .

Aeeteam .

Benese .


. . . o15 ~~o~C 'h

. . . . . 335.28

. . . 216.2-216.7*

. . . . . 71.60

S. . . . . 48.5%



. . . . . a.36

. . . . . 8.36

. . Anhydrous matheaol



. . . . Soluble

. . Soluble

. . . . Insoluble

. ...... Iaoluble

. . . . Iseeluble










28

5. reparation of l.lP yl--(2-erti e b t tbetiettrl)pipewsise

mwnytehel ride



A mixture of 0.1 ole (16.2 g.) of l-phlnylpipera.iae

and 0.2 mole (25.6 g.) of a-r1tl aeM l*lte in 25 ml. of anhydre

benzene was heated under reflux for 18 hours. ThLe cool reastioa

mixture was extracted three times with 3jhydrochlorie acid (200 ma.).

On acidifientin a solid hydrochloride formed in the extrseet io

flask and was Molvel in water with great d~ifkrful The acid

solution was basified with potassiua carbonate solution, extrabaed

tAwie with ether; and the ethereal solution was dried over anhyrema

potassiu carbonate. An excess of mettanolic hydrogua ehloride

was added to the dry, filtered ether solution from which the

3Bnohyd6rociloride of the ester precipitated. The compound was

filtered with suction, .ir-dried, and reerystallimed three times

freo alhydrous methaaol. Treatamnt with activated carbon during

one recrystallizatiom was necessary to yield pure white crystals.

Tho yield of the crte product was 96 per cnt of theeretioal, and

the yield after fea reerystallizatioaas was 25 per cent of theo-

retieal. The purified predeet was ArifA l av O oever aenB atzrato.

sulfuric acid before it wae analyzed. Analysis gave 8.39% N;

ealaleated, 8.57 I. The molting point of the lnpre eapound we

211.7-212.20 (deemspositieo).













5. l-Phflyl-4-(2-carbe-n-butory.-thyl)piperaziine monehytdrochloride

Chemical Zquat iea:
0
i- C-2\, 11
C/-H2 ) K + 0C 0- -0
CE2-CH


-n .HC


Molecular Formul . . .

Molecular Weight. . . .

Melting Point ....

Yield of CTdr~ Preet . .

Tield of Pure Product .

Analysis -- Nitrogen, %.

lcalenlata

Found. .

Reerystallining Solvent . .

Solubilitie s

Water.

ithaaol.

Ither..

Acetone.

Benzene.


*. . . . 0177A 202081

S . . . 3 26 .87

. .. .211.7-212.2 (dec.)

. . . . . . 98%

S . . . . . 25



d . . . . . 8.57

. . . . . .39

. . Anydrous methanol



. . . . Soluble

. . . . . Soluble

..... Insoluble

. . . . Insoluble

. . . . I. lnsoluble










30

6. Pnpafiatei of the Phemlthiairw at l--PharlS.4 -(3-inmp'pwl)-

pipeasime


Twv-ethr e thueeitaatiw ol (5 g.) of l-pb=el-4-(2-

oeysmehgl)pipebiaela was disselTjv in 180 l. of abaslute ethael

in a 50-al., rcmud-bottomed flak fitted with a reflux eondmner.

This solution was related with 7 a. of sodium eat into small pi:e*e.

WhVn the medAs har dilsapeared alehol and water we~ Pwarme by

distillatiea. Ptrthwr eaporatits of the resi&tal solution pre-

dnent an oily lay~ which was a solid when eol. The primry fala

was oxtmcted with beilingq ei The ether solutioa as filtned

hot and was allowed to evaporate wa the seam bath. An impua ,

lo&meltlne soli cae elMained whieh Ws soibleI in wter, at. r,

almehol, aad beneame.

Five-teal gra of this iipren mine was mimed with 0.6

ml. of phioyl isetbieaeyam A. Heat was given off speatiuaeaFly.

After the initial reation a be-ied the reaction mass wm melted

over a small flame. This was them ecoled in am iee-bakth util a

solid derivative ford. The .opevud was filteiw with swetioa,

wmhas well with heptama am 50 per wnt ethaml, and thin reerys-

talli B teiet f e 95 per Mat ethmel, yielding a pawe prodeet

which melt' at 132.6-133.6. The pure prodtet Vai d rie .A TaM

ever comnentrated sulferie aeid before it was atalysed. Analysis

gMe 15.61% 1; ealeulatbed, 15.81% 1.













6. Phenylthiourca of l-Plenyl-'-(3--minopropyl)piperazine

Chemical Zquatioa:


--- C-CH2-C-2N H2





CH2-CH2 C2

& C y 2- -)I2
"\ 2H.-C22 ;,3 2 2 2.J


Molecular Formla . . .

Molecular Weight . . .

Melting Point . . ...

Analysis -- Nitrogen, %!

Calculate

Fomd. .

Recrystallizing Solvent . .

Solubilities:

Water.

Ethaaol.

3ther..

Acetone.

Benzeae.


. . . . .C20 6 S

. . . . . 354.50

S. . . 132.6-133.6



S . . . . 15.81

. . . . . 15.61

. . . . 9% thaol



. . . Insoluble

. . ... .Insoluble

. . . ... .Insoluble

. . . . . Soluble

. . . . .Soluble














7. Preparation of 1-(2-Nethylphonyl) -4-(2-cyauwthyl)pipesdimne


Faou-teathse mele (70.4 ,.) of 1-(btIW1prlmw sl)n1P -

rLme was heated to 53' in a 1-liter, 3-neeke flask equipped

with a thermeeter, mechanical stirrer, and dropping funnel.

Aeryloait-le (0.42 mole, 22.3 g.) was slowly added during an

half-heur while the temperature was maintaiMm betiewa 55-580

by oessioeaal external cooling. After the addition of acrylo-

nitrile was oepletedl stirring was contisiel for three hlaes

at a temqpe~ra e of 50-55e. When cool the reaction mixture was

a solid. The erade product was transferred to a Bucebnr fuNael

and vwalste well with water. The composed was air-dried. The yield

of the crude produet was quntitative. A ema11 portion of the

crude product wae reerystallized three times frea 95 per cent

eheml, yiellang pure white crystals. The purified prode t

was dried ia vaswt over concentrated. slfuric aeid before it

was analysed. Analysis ave 18.29% ; calculated, 18.342 N.

The melting point of the pure compound wea 78.4-79.4.













7. l-(2-Methylphenyl)-4-(2-cyaanoethyl)piperamiue

Chemical iquatioa:


C C-C'2)*x + Ca-=CH- CE ---
C-CH22
C03

rC(Dt~i~'~ -C = N_


Molecular Forls . . .

Molecular Weight . . . .

Melting Point . . . . .

Yield of Crude Product ...

Analysi -- Iitrogen,%:


. . . . 1419

S. . . . . 229.31

S. . . . 78.4-79.40

S. . . QQantitative


Calculated. . . . .... .. 18.32

7eF nd. . . . . . . 18.29

Becrystallizinc Seolvent. . . . . . 95% Ithaaol

Solubilities:

daterr. . . . . . Insoluble

Bthanol ....... .Slightly soluble


Sther. . . . . ... Soluble

Acetone. . . . ... .Soluble

Benrene. . . . . ..Soluble













8. Preparuti a 1 l2-Nethylphfryl) --(2-eadbrethyl,1 )piperamime

memh-twreekleride



0-t-at me ele (22.9 g.) of 1-(2-mtshylphe yl)-4-(2-

aialmthgyl)pipers&aia. was hated under reflux with 0.15 Dole

(8.4 g.) of poeseeta e hydroxide in 250 am. of 60 per eont ethamel

for 4 hours. The eondenuer wasset for distillatioe, and volatile

materials wwre removed by heating on the stea bath. The reeidu l

solution was eeel, aend extracted once with ether, and then was

heated on the etem bath to remove dissolved ether. The cool

a&qAw.e olutias was acidified with dilute hydrochloric aeid

to preeipitate the eamin acid minonehyroo looride. The cruie co-

pound was filtered with auction and air-dried. Two recrystallisa-

tionm from water yielded pure white crystal. The yield of the

crse product uew 86.1 per cent of theoretical, and the yield after

two reerystallisatioem was 63.4 per seat of theoretial. The puri-

fied prodeut was dried ihtaf* over concentrated sulfuric acid

before it was analyzed. jlytie ave 9.91% 1; o-lculated, 9.84%

N. Analysis for chlorine gave 12.4a% 01; calculated, 12.40% Cl.

The melting point of the pure eeasan was 221.7-222.70 (dee~ po-

1it Uc).












35

8. 1-(2-sbthylpheMyl)-4-{ 2-eataoyethyl)pipuiarsede .amedwdFnklor!A


Chadeal 29atleat


irj-Ci- Cm N


Molesalar ermala. . . .

Neleoalar 'eFIat. .. ....

MltLt ?P l*nt. . . . . .


. .... C12420N202"BG

. . . . . 2# .79

. . 221.7-2aa.7. (dew.)


Yield of Crade Pre-oct .


. * *


. . . .86.14


TYeld of P r M PrAett. . . . . . ..

SnMalysi -- Nitofgen, %: .

Cal1 lat& . . . .

eni C... .. ... . *

Analysls -- Chloiu., %:


Callated. . ..



RecrySaalls1!i Sol~vet .. . .

Sol' biliti&s

a4er. . . .

Ah mo1l . . .

therer . . . .



Neseewe . . ..


* .


.63.J4


S. . *9.

..... 9.91


* S 59

S

. S S S


12.45

12.48

Vabe


. .Sl tir slbi,

. . . InseltbAle

. . .. .aelMble

. . . InrAoltle

. . . laMlseble













9. Pfrparatis of 1.(2-Mesthyklpsmyl)-4-(2Mrsem'b eathul) p>gasiJA


roubt-fetr th sthe male (10 g.) of l-(2-metIlwlmel)-

4-(2-eysasetlbl)piper&elae wM disewlvn in 40 .l. of ooaneentrtd

Cs te as i. %his dIFe hebto& opeateaetinly. After st-vl-

ing for five tant.s at 9-100$ the reaction mixture was cooled

and porls ilte 200 Il. of ieo-old water. The amqpiu solution

wvs aMe beeli to litmas with a solution of sodium hydroede.

The saatorr was filter6i with option. The eeeompo d was i e-

diately recy4alllftw1 two timee fus 10 per seat othel, yielA-

iLa pare white oomtal s. The yield after two reerystallisatioir

aso 66.6 per sent. The purifis& proed.ut was driod i IgM over

emoeatrated. slfuric B.id beoere it wa analysed. Aaulysis gare

17.0% N; eniialaato, 16.99 I. The malting point of the par

o-eunln was 129.1-129.9e.










37

9. l-(2-Msthyl1nhenyl)-4-(2-oarbonpaide-ethyl)piperazine

OkGeical Iquatisa:


loo
,______'*
J; IhkOHI


Molecular Formula .......

Molecular Weight . . . .

Melting Point . . . . .

Yield of Crude Product . . .

Yield of Pure Product . . .

Analysis Nitrogn, %:

Calculated.

ewd . .

Recrystallizing Solvent . .

Solubilities:

Water . .

thnol .

Ither..


Aere. .

Beaseme. .


. . . . . 14 1N3

. . . . . . 247.33

. . . . . .129.1-129.9

S. . . . Quantitative

. . . . . . 66.6%



. . . . . . . 16.99

. . . . . .. 17.05

. . . . . 10l lthanel



. . . Insoluble

. . . . . . . Soluble
..Soluble

. . . . . Insoluble

. . . . Inseluble

. . . . . . Insoluble











38
10. Preparation of 1-(2-Methylpheyl)-)-(2-ar"beaapaihyljl anM

rmrinhydreooMoride



A mixt-ai of 0.1 lole (17.6 g.) of l-(2-nethylph.nyl)-

piperasine and 0.2 mole (20 g.) of ethyl acrylate in 25 ml. of

nahydrous benseae was heated under reflux for 18 hours. The

cool reaction mixture was extreeted three times with 3 hydro-

chloric acid (200 ml.). The acid solution was basified with po-

tassium carboente solution and then extracted twice with ether.

The ether solution was dried with aehydrous potassiut carbonate.

An excess of methanolie hydrogen chloride was added to the iry,

filtered ether solution freo which tho hydrochloride of the ester

precipitated. The compound was filtered with suction and aime-

diately reerystallised from a methanel-ether solution, yielding

pure white crystals. The yield after two recrystallizations was

72 per cent of theoretical. The purified preauet was dried in

oieM over coecentrated sulfuric acid before it was analysed.

Analysis gave 8.97% NI calculated, 8.96%. analysis for chlorine

gave 11.52% Cl; calculated, 11.33% Cl. The melting point of the

pure oeewpead was 200.7-202.20.













10. 1-(2-Methylphenyl) -I4-(2-carbethoxyethyl)piperasine emorhydro-

chleride

Chemical lquatioa:


0
II
+ cK2-cH-0-vC2I


HE1


II
2 2B5
':-200-"


Molecular Forala .............. 162202

Molecular Weight. . . . . . . . . 312.83

:Melting Point .......... . .. 200.7-202.20

Ticld of Pure Product . . . . . . .... .72,

Analysis -- Nitrogen, %:

Calculate. . . .. . . .8.96

Found . . . . . .8.97

Analysis -- Chlorine, %:

Calculated .. ...... 11.33

oun . . . . . 1152

Recrystalliziag Solvent. .... . . Methaaol-ather

Solubilitie:

after . . . Slightly soluble

Ethanol. . . . Slightly soluble

Either. . . . .Inaoluble

Acetone. .. . . . .. .Insolble

Base. . . . . .. Insoluble


scl













11. Preparation of 1-(2-Methylphenyl)-'-(2-carbogLbutogethyl)]Pip*r-

zine dihydrochloride



A mixture of 0.1 mole (17.6 g.) of 1-(2-m9thylphenyl)-

piperazine and 0.2 mole (25.6 g.) of j-butyl aorylate in 25 El.

of adhydroes bena en was heated under reflux for 19 hours. The

cool reaction mixture was acidified with 290 Il. of 3 j hydro-

ohlerie aid. The hydroehloride of the ester precipitated upon

acidification. The compe nd was filtered with suction and air-

dried. Basifieation of the acid filtrate, extraction with ether,

and subsequent addition of nethanolic hydrogen chloride yielded

no appreciable amounts of the hydro hloride of the ester. The

crude oeaposnd was reerystallized three times from mnhydrous

methanol, yielding AMro white crystals. The yield of the crde

product was quantitative, and the yield after three reerystalli-

matioas was 53 per cent of theoretical. The pa ifieA produet

was dried Ja maS over concentrated eCteMrle acid before it was

analysel. Analysis gave 7.63% N; oelealate, 7.43 N. The melt-

ing point of the pure compeme was 212.7-213.70 (d*eespesitioa).










41

11. l-(2-Kethylphenyl)-4-(2-carbo-a-batoexthyl)piperazine dihydro-

ohloride

Chemical Nouation:


ca -ch)2-\ + CH on- -ec -t -S*
C 20
*/.H + cH2-.Hg-O-C9-

_03 0


CI2Z- 2
Molecular Formula. . . . . .... 1828N20 22HC1

Molecular Weight. . . . . . . . .. 377.37

Mblt-t Point. . . . . . . 212.7-213.7* (doec

Yield of Crude Preare4 . . . . .... Quantitative

Tield of Pure Prodnet. . . . . . . ..... 53%

Analysis Nitrogen, %:

Calculated. . . . . . 7.43

Found ..... ......... 7.63

Recrystallizing Solvent. . . . .Ahydrous methaael

SolubilitiMs:

Water . . . .... Insoluble

Ithanol ...... .Slightly soluble

Either . . . .... In3oluble

Acetone . . . .. Insoluble

eze . . . . . Insoluble












U. Preparation of 1-(3-Wethvl~gipl)-4-(2-eyanethrl)pipe rasae


FTow-tatUs mele (70.4 g.) of l-(3-~thylpheny1)pipera-

sine was heated to 55* in a l-liter, 3-neekeL flask equipped

with thsemoter, me iaaieal stirrer, and drepp1ag fuel.

Arylonitrile (0.42 mele, 22.3 g.) was slowly added during as

half-hour while the teperature was maintained between 55-58e

by occaeionmal exteval cooling. After addition of aerylo-

nitrile was eeqpleted stirring vas continued for three hours

at 50-55. he ersie reeation mixture was treneferred to a

Claisen flask end distilled tvins at redued pressure. The

desired preodut was obtained at 197-1990 at 1.3 W. and was a

celerless, visems oil. The yield of pmre product vas 77.5 per

eoat of theeretleal. Analysis gave 18.04 I; calculated, 18.32%i.










43

12. l-(3-Methylphenyl)-4-(2-cyanoetkyl)plperadine

Clemieal Equation:


S> -CH"-CH)- +C E -N


;RHC^-CE N


Molecular Formula . . . .

Molecular Weight . . . . .

Boiling Point . . . . . .

Yield After Two Distillatios . .

Analysis -- Nitrogen, %:

Calculated .

Found . .

a25D . . . . . . .

2525 . . . . . . .

Solubilitioe:


Water . .

Rthanol .

3ther . .

Acetone .

Benzene .


. .. C14H1913

. . .. 229.31

197-199V/1.3 -.

. .. .. 77.5%


. 18.32

. 18.04

. 1.5580

. 1.052



Insoluble

SSoluble

. Soluble

. Soluble

. Soluble













13. Preparatian of l-(3-.*helylphal)-4-(2-acieat thl)pipera ua



On-tthmk mele (22.9 g.) af 1-(3-eth ylph.nyl)-4-h(2- emea-

etbyl)piperazine was heated under reflux vith 0.15 mole (8.4 g.)

of pofteiim hydrexide in 250 al. of 60 per oat ethna3l for 4

hours. The eeaAm er was set for distllatieo, amd volatile

materials wee -~ra by heating on the steam bath. The real-

dual solution was eelel t&mnd extrao*d osce with other, and the

isoeas svfeta was heated as the steam bath to remov diseolved

other. The ceol alueos solutle woe a omtally Mastralioea vwik

dilute hyadrelorie acid. farther cnoling of the solution an

scraping the eide of the beaklr seaseL the erMo a aI- .id to

be preipitateda silky, wkite nestle. The e Womip w&a filter-

a. with suctiem asd air-tiiel Two re rytallisattions from watr

produced a pure prtewt. Sw yield of the eruie prednet wa 69.5

peo ent of tiset timeL, and the yield after two recrystallin-

ti e was 40.4 par e*at of theieoti*l. The purified pevnet was

dried j TMlp over eeneeatrated sulfarie acid before it wse aalyset.

Analysis gave 11.02% I; eelelatet, 11.20% N. The smelti poiat

of the pewo aaged Ng 138.8-139.e (mtter s at 120O).










45

13. 1-(3-Hethylphe.yl)-!4-(2-earboryethyl)piperazine

Chemical Equatiom:


CfW __ )2N --CZ2L-C"r X


0

r-OE


NoleeElar Forla . . . .

Molecular Weight . . . .

Melting Point . . . . .

(Softeas at

Yield of Cnide Product . . .

Yield of Pare Preda. . . .

Analysis -- Nitrogen, %:

Calelated.

Found . .

Recrystallizing Solvet. . .

Solubilities:


Water .

Ethaaol

Father .

Aeetoe .

Benzee .


* C 1120202

S. 248.32

138.8-139.8*

. . 120i

. 69.5%





. .. .11.28

. . .11.02

. .Watr


.Insoluble

.Insoluble

.Insoluble

.Insoluble

.Insoluble













14. Preparation of l-(3-Methylpheiyl)-4-(2-carbonamide-ethyl)piperantae



Porty-four thousandthe mole (10 g.) of 1-(3-mtkylphemyl)-

4l-(2-euabeetyl)piperasin. was dissolve& in 40 ml. of concentnated

sulfuric acid. This mixture heated poentaneously. After standing

for five mirates at 90-1000 the reaction mixture w* poumied into

200 al. of ice-cold water. The aqueewa solution was mad basic

to litm-s with a solution of sodium hydrox3de. The compound was

filtered with suction. The crude product was air-4ried and reins-

tallised two times frm water, yielding pure white crystals. The

yield of the erade pro6aat war 69.5 per cent, and the yield after

two recrystallizationI was 37 per cent. The purified product was

dried i iMn J over concentrated sulfuric acid before it was ana-

l~eA. Analysis gave 16.99% M; osalclated, 16.99 1n. The meltiag

point of the puare eMepod was l4.9-145.9e.









47

14. 1-(3-Methylphanyl)-4-(2-carbonamide-ethyl)piperazine

Chemical Equatiaen

f ~,"~ L~"t\MTI -_.H -=K --2Sb-


ObO3n
os1


H0
a20
& -dOlIK


Molecular Formula . .

Molecular Weight . .

Melting Point .....

Yield of Crude Product.

Yield of Pure Product .

Analyst -- Nitrogen, %:


. 01421O,0

. . .247.33

.144.9-145.9e

. . 69.5%

. . 37%


Recrystallizing Solvent.

Solubilities:


Calculated.
Found..

* . .


S. . 16.99
S. 16.95

* . Water


S. Insoluble
. . . Soluble
. . ..Insoluble
. Slightly Siuble
. . .Insoluble


Wator .
Ethanl .
rther .
Acetone
Beaseae .












15. Preparlties of 1-(34MethylpheMrl)- 4-(2-carbetholyethyl)pipera-

sine dihydreailoride



A mixture of 0.1 amle (17.6 g.) of 1-(-amethylpheat)-

piperazine and 0.2 mole (20.0 g.) of etlyl aerylate in 25 ml. of

anhydreus beamene was heated under re-flux for 18 hours. The cool

reaction mixture ws extPaeted three times with 31 hydrochloric

acid (200 ml.). The acid solution was basified with potassium

earbonate solution and then extracted three times with ether.

The ether solution was dried with ianhydrou potarsium carbonate.

An excess of methanolic hydrogen chloride was added to the dry,

filtered ether solution from which the hydrochloride of the ester

precipitated. The compound was filtered with suction, air-dried,

snd recrystallized two times from anhydrous methanol, yielding

pure white crystals. The yield of the crude product was 73.1 per

cent of theoretical, and the yield after two recrystallinations

war 57.6 per cent. The purified product wse feit in vaei over

concentrated uulrarie aeid before it was analysed. Analysis gave

8.22? N; ci-culated, 8.024, The melting point of the pure com-

pound was 1I6.6-197.20.













15. l-(3-MKthylphenyl) -!e-(2-airbethoxyethyl)piperazine dihydrochloride

Chemical quatin n:
0
0H-,\ -C NC1
S-J 05C-0 -H + CH2=GHa-0-OC%5

oR3 0
CH2 2 --O HC1
-Aw W 1 -CHL-900 5*2*


Molecular ormla . . .

Molecular Weight . . .

Melting Point . . . .

Yield of Crude Product. .

Yield of Pure Product ..

Analysis -- nitrogen, %:

Calculate

Iound.

Reesyatallizing Solvent . .

Solubilities:

Water .

th-anol.

Zther..

Acetone.

Benzene.


C16W24 02 22C1

. . 39 .30

. 196.6-197.20

. . 73.1%

. . 57.61


Anhydrous


S. 8.02

. 8.22

flthaael


. . . . . .Soluble

. . . . . .Soluble

....... .Insoluble

. . . . . .Insoluble

. . . . . Insoluble













16. Preparation ef 1-(3-Methylphtayl)-I-(2-eaL-re-b-buta!eheyl)-

piperazine meohydro chloride



A mixture of 0.1 Dole (17.6 g.) of l-(3-methylphenyl)-

piperazine and 0.2 mole (25.6 g.) of t-lkBtyl ecrylate in 25 ml.

of anhydrous benzene was heated under reflux for 18 hours. The

cool reaction mixture was extracted three times with 31 hydro-

chloric acid (200 Nl.). The acid solution was batifie with

potaesima carbonate solution and then extracted three time with

ether. The ether solution was dried over anhydroeu potassium

carbonate. An exrees of methanolic hydrogen chloride was adAS

to the dry, filtered ether solution from which the monohydrochloride

of the euter precipitated. The compound was filtered with suction,

air-dried, and recrystallised two times froa anhydrous methanol,

yieldinC pure white crystals. The yield of the crude product

was 91.8 per cent of theoretical, and the yield after two recrystal-

lisations was 38.2 per eent of theoretical. The purified prodaet

was dried in vaete over concentrated sulfurie acid before it was

analyzed. Analysis gave 8.01% 1; calculated, 8.22% 1. The melt-

ing point of the pure compound was 191.5-192.50.











51

16. 1-(3-Ncthylphenyl)-'-(2-carbo-a-butoxyethyl)piperazine mono-

hydrochloride


Chemical Equation:


Molecular Forla . .

Molecular W'eight. . .

Melting Point . . .

Yield of Crude Product.

Yield of Pure Product .

Analysis -- Nitrogen,%:


Calculate

Found..

Recrystallizing Solvent . .

Solubilities:

Water .

Ethanol.

Ether..

Acetone.

Ben zene.


0

+ CB2=CHF-0-OCE9 -c


. . . . C1 Z281 202.*C1

S. . . . . . 30.90

. . . . . 191.5-192.5'

. . . . . . . 91.8%

. . . . . . . 38.24


. . . Ahydaroas


S. 8.22

S.8.01

-athaMel


. . . . . .Soluble

. . . . .Soluble

. . . . . .Insoluble

. . . . . .Insoluble

. . . ... .Inasoluble












17. Preparation of l-(4-Nethylphenyl)-4-(2-cyanoethyl)piperasime



Oan-half mole (88 g.) of l-(,;-aetkrlpheayl)piperaeim

wee heated. to 553 in a 1-liter, 3-necked flask equipped with

therarmter, *se&ehioal stirPer, and dropping funnel. Aeryloai-

trile (0.52 mole, 27.6 g.) was slowly added during an halflkoar

wile the temperature was maintained at 550 by ocoasional extern-

al cooling. After the addition of acrylonitrile was completed

stirring was oontinmed for two hours at 50-550. The cool reec.ieo

mixturn war a solid. The crude prodaet was transferred to a Buehnr

fumnel and washed well with water. The crude compound was air-

dried and reerystallized once from 95 per cent ethanol, yielding

pure white crystals. The yield of the crude product was quanti-

tatire, and the yield after ono recrystallization was 86 per

oet of theoretteal. A small eaornt of this product war reerys-

tallized three times from 95 per cent ethanol to obtain an analyti-

cal sample. The purified product was dried in vXya over concentrated

sulfuric aaid before it was analysed. Analysis gave 18.14% 1; calcu-

lated, 18.32 1. The melting point of the pure oo pound was 70.4-

71.4













17. 1-(C-Methylphenyl)-4-(2-cyaaoethyl)piperaziae

Chemical .quatioa:





C2-- /)-0CH2)

/ -CHL-C2


Molecular Forla . . .

Molecular Weight ....

Melting Point . . . .

Tield of Crude Preduct ..

Tield of Pure Produtt ..

Analysis -- Nitrogen, %:

Calculate

Found .

Recrystallizing Solvent . .

Solubilities:

Water.

Ethanol.

Ether..

Acetone.

fanzene.


. . . . 14 93

S . . . 2 9. 31

S. . . 70.4-71.4

S. . Quantitative

S . . . . 86


4. . . . . .18.32

. . . . . .18.14

. . . .95 thraol



S. . . .Insoluble

. . . . . Soluble
.......... Soluble

. . . . Soluble

. . . . .Soluble
. . . . .Soluble













18. Prep~ &tios of l-(4-Methylphenyl)-4J-(2-oarboayethyl)piperazine

monohydroekloride



One-temth mole (23.9 g.) of l-(-methylphesyl)e4-(2-

cyaamethyl)piperaui~n was heated under reflux with 0.15 mole

(8.4 c.) ef petnn6tf hydroxide in 250 al. of 60 per seat *t~Va-

ol for 4 hours. The aoxde a r was set for distillation, and

volatile materials were removed by heating on the stem bath.

The residual solution was cooled and extTraete once with other,

and the agfmers solution was heated on the stem bath to remove

dissolved ether. The cool aeaousL solution was acidified with

dilute hydrochloric aeid to precipitate the amine acid hydrochlor-

ide salt. The empouead was filtered with suction and air-dried.

Two recrystalliations front water yielded pure white crystals,

The yield of the prediet after two reerystallizations was 42.2

per eaet of theoretical. The purified product was dried ja

vamL over eoaeeattated sulfuric acid before it was analysed.

Analysis gave 9.70 I; calculated, 9.84d Alnlysis for ellorite

gave 12.49% 01; calculated, 12.46 Cl. The molting point of the

pure compound was 221.2-222.2.











55

18. 1-(4-Methylphenyl)-L-(2-carboxyetbyl)piperazine monohydrochloride

Cheaieal 3qiatiem:


C -., 2 2i C)-CH-CH -C=-


0
.3- --aCK II
5 CH.2--,K2 2 2
0 -cr452 r!~-a


Molecular orml. .......

Molecular Weight . . . .

Melting Poit . . . .

Yield of Pure Product . . .

Analysis -- Nitrogen, %:


Calculated . .

Found. . . . .


C 14,1.202.- OC

. . 284.79

. 221.2-222.2*

.....42.2%


... 9.84

... 9.70


Analysis Chlerine, %:


Calculated. . . .12.45

Fouad. . . ... .. . .12.49

RecryFtallizing Solvent. . . . ....... . Water

Solubilities:

Water . . .. ..Slightly soluble

Ithanol. . . . ... Insoluble

Ether. . . . . ... Insoluble

Acetone. . . . ... Insoluble

Benzene. . . . .. Insoluble


* . .















19. Pre aratie of 1-(4o f Alay ehml)-4-(2-earbinidae-ttit)lipeasliM



Forty-fter tmmaaLtbmale(10 g.) of 1-(4- thlipbe1r)-

4-(2-eyamew brly)pipe~aie as diselve in 40 al. of eenoatated

sulfuric aCid. This mixture heated spen a wemely. After staMning

five mina te at 90* the reactie mixture was m ele ad poured

into 300 al. of ice-cold water. The aqeean solution wea maeL

basic to litms with a solution of soMdi hydrexide. The oWeied

we filtered with suction, air-4.wt, and reerystallized te

tins from water, yieldi g pre white erystals. The yield of

the eraue prodat wa 79.8 per amat of therettieal, aad the yi~el

aTer two Peerystallivations was 46.4 per oeMt of theeStial.

The purified predaet was dise i a aTM over concentrated s lfurls

a&id before it was aalyse. Analysis gave 16.87% 3; salealate,

16.99% I. The melting poat of the peo e~empu a was W.J-L9.5*.








57

19. l-(4-Methylphenyl)-4-(2-carboa mi-e-ethyl)pipees2ine
Chemical Equation:

(C -C2 -20
N-C -/H2-C I
O -- 2 20
.1-3- -092. E 2 2 XROl[
2 205031
oso3x


C
I

CH,n(Dc


Molecular Forula . . . . .

Molecular Weight . . . . .

Nelthna Point . . . . . .
Tield of Crude Product . . . .

Yield of Pure Product . . . .
Analysis -- Nitrogon, %:


S. 0121N30
. ..247.33

.191.5-192.5
. . 79.8

. .. 46.1%


Calculated . . .... .. 16.99
Found . . . . .. ..16.87
R erytallising Solvent . . . . .. . .Water
Selubilities:


Water . .
thaMil.. .
Ether. ....
Acetece.
Actone. . .


. .. I.seluble
Slightly soluble
. . .Isoluble
.Inseelble
. . .Insoluble













20. Prepaattioa of l-(4-Methylph.oenl)-4-(2-oerbeth~t flqrl1)pipera-

mime dihyd e-ohlorid



A mixture of 0.1 omle (17.6 g.) of 1-(4-methlphaeyl)-

piperasinu mad 0.2 wole (30.0 f.) of ethyl a.rylate in 25 al.

of anthYdreuasi bnse was heat under reflu for 18 hears.

The mel reactism mixture was extraeted three times with 31

hydroehlorie aid (200 al.). The acid solution was boiflle

with netamslm earboaate eslution and then extracted three

times with other. The ether solatio was dried with aahydrene

petasisiu caromate. An *exo n of methaolis hydrogen chloride

wa added to the dry, filtered other solution from which the

dihydrochleri&e of the seter preeipitate.. The oeopead was

filtered with uetieo, air-drie, aad reerystallized three time

from anhydrew methamel, yielding pere white eryutals. The yield

*f the erade preeuat wa 48.8 per ceat of theoretical, and the

yield after three reerystalli atime was 25.8 per eait of thee-

retieal. The purified prednet was dried ai ....a over oaesan-

trated sulfuric aeid before it was analysed. Aaalysis gve

8.05% 1; calculated, 8.02% 3. The melting point of the puin

ea-mand wa 203.2-204.2*.










59

20. 1-(4-Methylphonyl)-4-(2-earbethcayethyl)piperazine dihydrochleride


Chemical Iquatiot:
0

CH3--- ,- .C2 -H + CH2- C,-OC -2K5
-K + --Cc-. x
2
0
/CC / ")I02\ 1 *2
CI/- ()C N -C"2-C'02-2-OC 1"


Molecular Formula . . .

Molecular Weight . . .

Melting Point . . . .

Tiold of Crude Product . .

Yield of Pure Product . .

Analysis -- Nitroags, %:

Calculate

Found.

Recrystallizing Solont . .

Solubilitiaz:


. ..... C1 2 2 2*201

S. . . . . 349.31

S. . . . 20J.2-204.2*

. . . . . 8.8

. . . . . . .25.8


Ashydreus


Water. .

Ethanol.

Ether. .

Acetone.

Benrene.


. 8.02

8.05

methanol


. . Soluble

. . .Soluble

. . Inoluble

. .Insoluble

. .Insoluble


* . .


. . . .













21. Preparation of 1-(4-MethVlplienyl)-4-(2-carbe-i-but oyethyl)-

piperazins dihydreehleside



A mixture of 0.1 mole (17.6 g.) of 1-(4-methylphenyl)-

piperazine aa. 0.2 mle (25.6 g.) of j-butyl acrylate in 25 al.

of anhydrous benzene was heated umier reflux for 19 hours.

The ceel reteM a mixture was extrasbed three times with 31

hydroohlarie aeid (200 sl.). The aeid solution was basified

with ether, and the ethereal solution was dried over anhydrous

petaeeim earboaate. An excess of methamelic hydrogen ehloride

was added to the dry, filtered ether solution froe which the

dihydroehloride of the ester precipitated. The eempouan was

filteaedl fth lotion, air-dried, and reerystallized three

times from aahydrenu ethaaol, yielding pure white crystals.

The yield of the ene product u e 71.6 per oeat of theoretioal,

anM the yield after three reerystallisatiens was 26.5 per oeer

of theoretical. The -r-ified product was dried I r Ae over

coMmeemtmate svlfurt.c acid beter it was aalysed. Aamlysis

arve 7.v3% ; lealated, 7.45% W. The melting peiat of the

pure eomeian. wMe 201.7-202.7*.











61

21. 1-(4-Methylphenyl)-4-(2-carbe-i-~b o bOelrTl)piperazine dihydro-

chloride

Chemical JIqatioa: 0

C- C2 2 + CH2 =G-G-00C 9B -
? -0O _4Hq


Molecular For a . . . .

Molecular eight . . . .

Melting Point ...

Yield of Crude Product .

Yield of Pure Product. . . .

Analysis -- Nitrogen, %:

Calculated.

Pound . .

Recrystallizing Solvent .. .

Solubilities:

Water. .

Ethanol..

Ether. .

Acetons.

Benzene.


. . .. 28202

. . . . . 377.37

S. . . .201.7-202.7"

. . . . . 71.6%

. . . . 26.5%



. . . . . 7.43

. . . . . 7.24

....Ahydrous methanol



S . Slightly soluble

. . . . Soluble

. . . .. Incoluble

. . . . .Insoluble

. . . .. Insoluble










62

22. Preptratlet et 1-(3-bl)orahkeayl)-4-(2-eyuw Mhyl)i:pmiaine



Sixty-r ven h4InLre&the mole (132.0 *.) of l-(3-ahlero-

pheayl)piipraszi was heated to 55* in a 1-liter, 3-m ekeS flask

equipped with thoMrameer, mIeelniaLl stirrer, aad droepiag ferel.

Aerylomitrile (0.69 mole, 36.5 g.) was slowly added during twen-

4rty miute while the tempertare was mainrtaino between 50-55*.

by oceasieoal external cooling. After the addition of aeryle-

nitrile wav completed stirring was costil ed for far hoars at

50-55*.

The reaction nirt.we was tnmsfeurred to a 200 al. roiad-

bottomed flaek attachkS to an efficient fraetiemation column; and

after de-egasing at 5 m. pressure, distineatie was cona.ated

at 1.3 =-. The desir l p&odnt wee obtained at 210.6-212.6'

at 1.3 -. as a slightly yallow-selored, vieems oil. The yield

ef pare proaeft war 46.7 per esnt of theoretical. Analysis

gave 16.890% ; ealeMlabet, 16.83% I.











63

22, l-(3-Chloropheanyl)-4-(2-cyaaeethyl)piperaeine

Chemical quamtiem:


)-"- ) CH-C -



( ? 2- )Nl-CH2,-CH,--C=


Molecular Forwl . .

Molecular Weight . ..

Boiling Point . . .

Yield after Dittillatie .

Analysis Nitrogen, %:


Calculated.

nad .

. . . .


25 . . . .

252 . . . .

Solubilities:


Water. .

Ethanol.

Ether..

Acetoae.

Ben enw.


. . .. 13 16 1

. . . . 249.74

. .210.6-212.6"/1.3 -.

. . . . 4. .7%



. . . . 16.83

S . . .16.80

. . . 1.5762

. . . .. 1.163


.Insoluble

S.Soluble

S.Soluble

S.Soluble

S.Soluble













23. Preparation of l-(3-Chlorophenyl)-4-(2-oarb.exyethyl)piperazine



One-tenth mele (24.97 g.) of l-(3-chlorophenyl)-4-(2-

cyanoetkyl)piperazine wan heated under reflux with 0.15 sole

(8.4 g.) of potassium hydroxide in eS ml. of 60 per cent ethamel

for 5.25 khomr. The 9eedenser was set for distillation, and

volatile materials were removed by heating on the steam bath.

The residual solution was cooled and extracted oase with ether,

and the aqueous solution was heated on the steam bath to remove

dissolved ether. The cool aqueous solution was carefully neutral-

ized with dilute hydrochloric acid. On cooling the amino acid

precipitated. The compound was filtered with suction and air-

dried. The crude material was decolorized with activated carbon

and recrystallized from very dilute ethanol (10 per cent) to

yield pure white crystals. The yield of the crude product was

quantitative, and the yield after three recrystallizations was

62 per cent of theoretical. The purified product was dried

in vacuo over concentrated sulfuric acid before it was analyzed.

Analysis gave 10.52% X; calculated, 10.43% N. The melting

point of the pure cowpwed was 164.4-165.3'.










65

23. l-(3-Chlorophenyl) -'!-(2-carboxyethyl)piperazine

Chemical Iquation:

Q- -(CAi.ONZ) VSH

1 ) h2 C 2
0

CH2-CB2|

1 "^2


Molecular Formula . . .

Molecular Weight . . .

Xelting Point. ..

Yield of Crude Product .

Yield of Pure Product . .

Analysis -- Nitrogen. %:

Calculat

Found. .

Recrystallizing Solvent .

Solubilities:

Water.

Ethanol.

Father .

Acetone.


.0 H13 N2021
X 13 17N0 2 2
. . 268.75

.164.4-165.3*

.Quantitative

S. . 62.0%


. . 10.43

. . 10.52

10% Ethanol


. . . . Insoluble

. . . . Insoluble

. . . . Insoluble

. . . . Insoluble


. . .. .Insoluble


Benzonc. .













24. Preparation of 1-(3-Chlorophenyl)---(2-carbonamide-ethyl)piperazise



oear one-hundusethu mole (10 g.) of l-(3-chlorophenyl)-

4-(2-agmee*thyl)piperfime was dissolved in 40 nl. of concontrat-

ed sulfuric acid. This mixture heated spontaneously. After a 6rt-

ing for five minutes at 90-100* the reaction mixture was cooled

and poured into 200 al. of ice-cold water. The aqueous solution

was made basic to litmus with a solution of sodium hydroxide.

The compound was filtered with suction and washed well with water.

Filtration was extremely slew. The compen d %a air-dried and

recrystallized two times free 15 per cent ethanol, yielding pure

white plate. The yield after two recrystallizatione was 59.9

per cent of tl:eoretioal. The purified product was dried i; vaLe

over concentrated sulfuric acid before it was analysed. Analysis

gave 15.67% I; eoalulated, 15.70% 1. The melting point of the

pure compound was 147.5-148.2*.










67

2!. l-(3-Chlorophcnyl)-' s-(2-carbonn-ido-ethyl)piperasine

Chemical Equatioa:


S0
1819


Molecular Formla . . . . . .... .01183001

Molecular Weight ................. 267.76

Melting Point . . . . . . .147.5-1.2

Yield of Pam Product ................ 59.9%

Analysis Nitrogen, %:

Calculatd . . . . . 15.70

Found. . . . . . . 15.67

Recrystallizing Solvent . . . . . . 15% thaol

Solubilities:


.......... Insoluble

. . . ... . Insoluble

. . . . . Insoluble

. . . . . Insoluble

. . . . . Insoluble


Water .

Itbaaol.

Ether. .

Acetone.

Benzene.















SWIMARY


Twaety-fer new additiua amevad anid derivative f 1-

phoylpiperazine, l-(2-methylphenyl)piperazine, l-(3-methylkpmayl)-

piperazine, 1-(4-methylpheal)piperauine, or 1-(3-ealorophonyl)-

piperazine with acrylonitrile, ethyl aerylate, or l-butyl aerylate

have been prepared and studied. Data on these oompounds are summar-

isd in Table I.

Four a,P-uaaturated nitriles and estere which did not reaet

with l-phenylpiperazine u der conditions which wesr sneeaeful with

acrylonitrile and unsubstituted acrylate eaters are:

1. Crotoemoitrile

2. r-Ne thylacrylemit rile

3. Methyl methaerylate

4. Ethyl metheArylate

Methyl methacrylate and ethyl metha~rylate did not reset

with l-(2-methylpheayl)piperasine under conditions which were sueesn-

ful with uRuabstituetd acrylate estere.


























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SIBLDJOGRAPW

1. J. Thele, Am., 2~., 87 (1899).

2. T. K. Lowry, !J. CaL. Sac., =, 822 (1923).

3. H. Bru-ae, ea if Ci tiesm Jehk Wiley & Sans, Inc., evw Tork,
1949, Tol. V., p. 79.

4. U. Hoffe-a mnd B. Jaeebi, U. S. Patent 1,992,615; .-A.. ,. 2548 (19S).

5. F. C. Whitmers, H. S. MDo er, R. R. Adam, R. B. Taylor, 2. C. Chaina,
C. Weisel, and V. T,,n, J. A. C_9 Sc., A6, 725 (1944).

6. 0. F. Vielems and W. H. Montgomery, ibid., 1994 (1945).

7. A. H. Cook and K. J. Reed, J. Chea. Soc., 1945, 399.

8. D. S. Tarbell, N. Shakespear, C. J. Claus, and J. F. Bunnett, J. AR.
Chan. gg., 68 1217 (1946).
9. D. E. Pearsoa, W. H. Jones, and A. C. Cope, Jij, M, 1227 (1946).

10. A. P. Teret'er and E. A. Terent'era, j. f_. CBla. (U.S.S.R.), 12,
415 (1942)1 C. A., 327 3095 (1943).
11. J. H. Burehalter, t. K. Jemes, W. F. Helcemb, and L. A. Sweet,
I. hA. .M Soc., 5, 2014 (1943).
12. J. Corse, J. T. Bryant, and H. A. Shonle, ibid. 68, 1986 (1946).

13. J. A. King and F. H. NeMillan, ibid 68, 1468 (1946).

14. J. Corse, J. T. Bryant, and H. A. Shem., Ibid, 68, 1912 11946).

15. L. C. Behr, J. H. Kirby, B. N. MacDonald, and C. W. Tedd, iLA, 68,
127 (1946).
16. I. G. Farbeind. A.-G., Brit. Pat. 457,621; U.. A., I. 3066 (1937).

17. The Wenemerie Aerylie Isters, Roea and lEas Coamany, 2nd. ed., 1949.

18. S. M. MoWl ain and G. Stork, J.. A. CaM. Soc., j6, 1049 (1946).

19. R. C. Ftsen, W. B. Parham, and L. J. Reed, ibid,. 1239 (1946).









73

20. R. Mozingo and J. H. McCracken Or2. SyIrhtees, 20, 35 (1940).

21. D. R. Hnoton, J. 2r. O h- ., 10, 277 (1945).

22. 0. Trauatka,. Mr., Z 131 (1942).

23. C. A. Weisl, R. B. Taylor, H. S. Mosher, and F. C. Whitm-re,
Aa.. ChM. Sac., 62, 1071 (1945).
24. W. B. Thmas and 3. N. cNSlvain, i'd., 54, 3295 (1932).

25. R. Adam and N. J. Leonard, ibid, f6, 257 (1944).

26. C. 3. Pollard and L. G. MacDowell, ibid, 5 2199 (191).

27. V. Prelog and G. J. Driza, Collection COaeeiaslov. Chai. Cowmmn .,
497 (1933).

28. V. Prelog and Z. Blastk, bidA 6, 211 (1934).

29. T. H. Wicker and C. B. Pollard, unpublished work.

30. A. P. Phillips, J. Ag. Ch. Soe., 2, 3298 (1950).

31. D. E. Adelso and C. B. Pollard. ibld, 5Z, 1430 (1935).

32. H. A. Bruson, ibid, 6., 18 (1943).













ACMKOWLEDOWMTS

The author wishee to express his sincere apnreeiatioa to

Dr. C. B. Pollard, chairman of the supervisory eemittee, under whose

direction this work was performed. Dr. Pollard's patient guidaoee,

.ecouramenat, and ceeperatioa h.ve beea largely responsible for the

kftMasee t semleties of the project.

Appreciation is epreeeod to Dr. 3. G. Rietz, co-chairman,

and the other members of the supervisory committee who have inspired

and aided the author during this investigative.

The author alse desires to recognize the eonstruetive aid

and oneourrement given by the staff and the gratnate students of

the Department of Chemistry of the University of Florida.

Finally, to his wife, AmnaEtte, aknaowledgeat is made of her

support and .ncouragement and to whom the aath.or wiishe to dedicate

this disetrtation.















BIOGRAPHICAL ITEMS


Robert Roains was born in Gainesville, Florida, on June 11,

1916. le pursuem his undergraduate studies at the University of

Florida mad was awarded the degree of Bachelor of Science in June,

1936.

Mr. Robbins entered the Graduate School of the University

of Florida in June, 1936. In February, 1938, he entered the Graduate

School of Coraell University, returning to the University of Florida

in September, 1939. He continued his graduate study until he entered

the U. S. Amy ii July, 1940. He was honorably discharged, as a

Captain, free the U. S. Arn in November, 1945. In September, 1949,

Mr. Robbins resumed his graduate studies in chemistry at the Univer-

sity of Florida.

From January, 1946, to September, 1949, Mr. Rebbins was em-

ployed by the Division of Tests, Florida State Road Department, at

Gainesville, Florida, where he became Chief Chemist before returning

to the University of Florida.

Mr. Robbins is a member of Gaama Sigm a Psilen, honorary chmi-

oal fraternity, and Tau Upsilon Phi, a social fraternity. 3e helA a

graduate assistantship in chemistry froe September, 1949, to October,

1950, and a graduate fellowship from October, 1950, uatil completing

of the requirements for the taeree of Doctor of Philosophy.












Oe-meitte epert


This dissartatlo was prea.red under tho direction of the

Chairman of the eeadidate's Sunervisory Comittee and has been apmpev-

ad by all members of the Caemittee. It wnq saebitted to the Graduate

Council s.Rd was apprevnA at marital fulfilment of the roquiremants

fnr the (egroe of Doctor of Philor.epky.


~7l7e


SUP.RYV ISORT COMMI S:


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