THE STUDY of REACTIONS INVOLVED in the SYNTHESIS of MESCALINE Catherine Q.^Calraucl A. Thesis Subm Itted to the Fa C U Lty of Th

The study of reactions involved in the synthesis of mescaline

Item Type text; Thesis-Reproduction (electronic)

Authors Gairaud, Catherine Beatrice, 1926-

Publisher The University of Arizona.

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Link to Item http://hdl.handle.net/10150/347679 THE STUDY OF REACTIONS INVOLVED IN THE

SYNTHESIS OF MESCALINE

Catherine Q.^Calraucl

A. Thesis

submitted to the faculty of the

Department of Chemistry in partial fulfillment of the requirements for the degree of

MASTER OF SCIENCE

in the Graduate College, University of Arizona

1951

Approved

•" . ■ - - - : ^ A0m 6%%EDG!#NT \ :::' ' ;y/ ,;::: :' :

'Ihe author. wishes to express her .sinG.ere: appreciation to Doctor

Gerald Lappin for: tiis generous and valuable, as sist anc e. "and encourage ment throughout the entire course of this work,- " :

i i m m • -y ' TABLE- OF GONTBMTS \ ; '

■■ : ; ' . iv. '■'" : ' ■ ■■ . • PAGE INTRODUCTION . V » , . . » A. . v » . 1

1 BuIPiijRT^CEiNTAjU •;«•..« » » •. •» • • / »■ • •- .*• « >,,• « «.12-

Preparation of <%) -nit r os terrene - «> . . .» . , . . . . = 12 Preparation of co -m ethyl-oo-nitrostyrene. „ '•>/„ „ 3,2

i" Preparation of 3, 4, 5-trjjaethaxy - < o -nitrostyrene- , . . . . 13

. Attempted preparation of 3 S ■ k , 5-trimetho2cybenzaldehyde , . 23 ;. Preparation of 3, bs 3-trimethozybenzoyl chloride . > .. 23 : Preparation of 3, 45; S-trimethossybenBanilide. . A, ;v 24 Preparation of 3g 4^ S-trijflethosiybenziinid-chloride» „ . , '. 24

. Preparation of 3, k s ~ 5-trimetho2grbenzaldehyde. . . . . 25j, 30 Preparation of 4-iiydrb5?y--35 5-dimethosybenzoic acid » i . > « 25 Preparation of 4-hydroxy~3«, 5-dimethosybenzoic acid '

m ethyl e s te r « . • •*. * • • ° »•.*. .* « * •• « » *• ,® » ® « ® @ 26 Preparation of 4-ailylether-3,, 5--diniet:hoxy benzoic acid: ' ‘ m ethyl e s te r . : . . » > . . , . v. A i . . .. , . „ - = „ 26 •Preparation of the sodium salt of l-allyl-pyrogallol-3j,- A ' •' 5-dimethyl ether, . 26 Preparation of l-allyl-pyrogallpl-3<, 4^ 5-trimethyl ether , 26 Preparation' of pyro.gallol-1 ^ 3-dimethylether-2-allylether . A 27 -.'Preparation of I-allylpyrQgalioi-3j, 5-dimethylether . . . . 27 Preparation of l-allylpyrpgallol-3; 4o 5-trimethyiet.ber A: . 27 Preparation of the glycol of l-allylpyrogallol^^ .4y :’ A ; • 5-trimethylether A A • > A « » . , 28 ■ Treatment /of the glycol, with lead hetracetate ... >A: A A A 28 ■ Rearrangement of the double bond of elemicin . ■/ ■ . A .. ; to form isoelemicin® . . - ...... A: ® '» .'29 . ;;02onolysis- 'of is o e le n ic in "» A « ,« . . A , A A A, . A A ® A .■ 29 Attempted reductions of- the nitrostyrene. compounds. . „ 30

' DXDCUbDuON o* 9 o e a 1 6 a - o O o a a o. o c o o » ., o oeo.noee-o 32

sm ttiH i, a , . A . . o , . A A a »:'aa,A;, V . 41

BIBLIOGRAPHY A . A . „ A > A A ® ® ® . ,,42 : ^ ■ ■ . . :

■ - ' - v' - ; : ..■;- •■.■■■ . . - ' ' page 1. C0E)I®SAT1C® OF AIDEHlDEljTtfH iETROIierHANE; „ . , ...... 14

I I . HIGHER GOmm#ATIOH PRODWT3 > . . . . «, . .1 5

I I I . .COmEKSATIOH OF ALDEHYDE IIITH MI'TROEl'HAWE.• . . . . > ...... ;l6

'•'. IV. CCWAEISOH OF EOE.CTIOH TIME...... L ...... 17.

V . COHDENSATIOII OF ALD3HIDE 11®. NITROSfETHAME ¥1TH. : : , ; .’AMliONIUM ACE'EiTE AED: GLACiAL ACEf 1C:. AOID, / v ...... 19

VI . COHDSNS1IION OF AIDEHIDE AED NITROETHMS VelTH- acetaye m i gmoial acetic; acid., ...... , 2 0 "

V II. CONDEHSATIOK OF ALDEHYDE AMD i^MITRCFROPANE vJITH ' ' - - A ■, AMMOMlDIi ACEIATS AED GLiiCIAL ACETIC ACID . A'-.' . :.. . ..; . .. 21

'V III. • COMPARISOII OF YIELDS OF SUBSTITDA’ED-aJ.~IITROSTYREHIS./. . . '. . 35

; . IX. . 0OMFAEISON. OF YIELDS OF SUBSTITUTED-a) -H1TROSTYKMES; . . . . 36

5 . COilPARISGl. OF YIELDS OF SUBSTITUTED-®' -'EITROSTYRMES . .... 36 .v;-' --v-V ' . BrmODUGTION ; - ■

, ; Mescaline, one of thef GCnstitnents of the cacti Anhaloniim lewinii,

. has been used by liie Ind,ians of the/ 8onthw%i and,(Me%ico; for many years' ■’

in the' form of ’’Mescal buttohs” for their religions rites „ . This: use is

due to the physiological actions which - it produces, first described-by ; .I'; / ; r , " " ' i - v;; lewin. in 1894« It is Chiefly characterized ,by visual;hallucinations

• which take’the form of fantastic "shapes of various shades and dolors „:

-According-to Tayleur Stockings, there are marked sim ilarities between

certain mental disorders, and the effects .produced by m escaline.: A per

son under the influence of mescaline not only has. hallucinations, but

also experiences a change in bodily feelings, a disorder in space and

time judgment, and a feeling of•depersonalization and detached observa

tion of -oneself,.- In this way a condition similar to schizophrenia may ■

■ be artificially produced, leading to a more carefully controlled•Study . '

of this mental disorder. •. : . y - ■3 -..; i i . - "■ : / In a paper by Hey it was pointed out that if a methyl, group -is sub

stituted into-the position alpha to the amino group, the resulting iso-

. propylamine possesses.central nerrous stimulant activity similar to mes-'

. calihe. In general,, this property is not shared with the mono-- and

:: dimethozyphenylethylamines which show only a pressor effect of varying ,

degrees t . The physiological properties of these amines’and the effect

- of substitution at different positions is discussed in. more detail by : 4 -:v:'Vy: ■; ■ ■. - y ■ - y y,t;,- : Hartung . ■ Thus,-due to the resemblance between the effects produced by

: -mescaline and certain mental disorders, interest has grown In the study

of the- effects these analogues of mescaline can. produce in the' treatment

of clinical mental disorders.' . - .... : ■ 2

. ' Synthetically, mescaline had .been prepared, as early as. 1919 by 5 : ' : ".y; .v V v,;: t " j \': ■ ■■■: - Spath;' '.(Equation I,'p ,3 ), but not a great deal of work was done until b • ' ...V. ' '"'6 \ ' ^""1 \ ; v'1930 when S l o t t a ' and H e lle r ' (E quations I I j I I I , IV, V, p . 4-6).-, in v e s-

: ' tigated several other possible methods:for the.preparation of meacaline 7.

• and mescaline-lilce compounds» • In 1934 Hahn and^Vassmuth (Equation Vlb,

: P>7)> ' by methods previously used by .Maubhner (Equation Via, . p»7), pre

pared; mescaline .from elemicin, . More recently Behington and M orin-(Eq-

nation VII, p,.8) .published an /improved atethod for' the synthesis of mes-.

caline, employirig essentially- Spath1s method with the exception that the ,

7 nitrostyrene is reduced with lithium aluminum -hydride. ; . 7 -- V

' . ihe original purpose of this work was to prepare■mescaline, .and mes

caline-like compounds;and their derivatives frbm-a series of substituted . 7

benzaldehydes .condensed -with nitromethane, nitroethahe,- and 1-nitropro-

pane= These, compounds were to be reduced to- phenylethylamines and.con- . ' .

■ verted to- various, derivatives for .examination for'physiologi.cal-.activity -

by -a cooperating group under Dr, -Li G,- Cla-rk, Fils; institute for the 7

Study of Human Development, Yellow Springs, Ohio*,. However, owing.to - >

certain pecularities of the condensation .of substituted benzaldehydes

with the nitroalkanes , it/ was decided tb lim it the present investigation

mainly to -a study Of -the,factors involved in the condensation of the al~ . ■ : '7;'. ■ 7" 7 7 .V ; i:-/.;. - 77::-7 '-/.77 7 . - 7./\ -/' : V; J 777.-7 -- dehyd.es with the nitroalkanes-,/. .It was hoped -that impr°ved coiidlteions/. .. ' ..

for- this, react ion. might be developed, thus, leading to. a better method- - 7

of" synthesis for mescaline;analogs, - - / .. . V ' - ' . " '

' - 'The first, instance that .such condensations. Gould take -place was1 ' ■ ' . -7 7- ,7 ■ ; tv -710; 7;.. .. : 7.-.7 y7; '.7 :. 7 7; . Vv/;7 : . 7 discovered by Priebs in 1883 who showed that7 to -iiitrostyrene could be 7 7

. formed in a $6^ yield. by hOatlhg benzaldehyde and..nitromethaue in the7' -./

. presence of - zinc chloride, in- a. sealed tube at ."ISO0 (Equation- Vlll,- p ,8.).; ; 3

CH 3 y=\ - _ Crld CHjQ ^ t f COCu P& ^ CH30 / \cho

CH3 ° 2 C HjO

c h 3 n o 2

A X . NAOH

CH3 ° = = X C H 3 9 = \ DUST CH 3 0 ^ yOigCH^QH h =CH N0 3 AC CH3° V j T CH3O CH 3 O

c h 3 o

C H ,0 CH2 CH^ NH2 C H-.O + CLrC-CHjCL AL CL

^ c h 2 c h , n h 2 ^

KCAJ

CH2 CH2 NH2 / h2 hfeCN 1 2

^j)chfeCH2BR < U a a — 6

CH3 o CH-,0 9 0 0 H Chb ° ( x z ) CH 0 + ^ > CH 3O -CHCOOK v y coon c h 3 o C H-> O

CH3 O c h 3Q CHoO \ /7 CH2 CH2 COCL^ c h 3 ° < \ y e n ^CH^COOH

c h 3o CH3O

NH:

n 1/ CH3O CHJ/ = = \ CH3 0 ^ y C H 2 CH2 CO N ^, m C B R > CH3 ° \ x CH. CH3O CH3 ° ’ 7

5 Z T a)

c h 3o

HO, CngscHca.Bi^ _ CH c H g O ^

c h , o

CHpCHO

C H 3 ^ = C H 3 0

CH3° Z /) ch 2 CH;,NH2 < Hg CH3° \ / r * ^ ■ CH3o C H 30 8

ISJE

CHd O CHaO3 CH.O CH=CHNO, Ir! AL 1"^.------> CH30 Z XcH2CH2NHa

CH3O CH3O

3 z n i

Q c h o + ch ^ 2 0 H^ V ' - ■ . ■ ' ■ . . .: .-,- ::'. , V . ' ; 9 - \/

: . 11 ; , - . i''/: , ""; '■ ■■'-;v : ■ ■: :"/,■: ■ > •, ...... Posner found that the ortho-. a,nd meta-nitrdbenaaldehydes also condense v

in the presence of zinc, chloridei but that the para-nitro and other sub- -

stituted benzaj.dehyd.es dp not condense,- fhe fact: that-the reaction is .

,. .'limited by .the substitutions on the 'benzene ring and: the difficulty o f . r

purification of the products has probably been the.reascn .that this nie- ' ■

bhod is hot used to ahy .great: extent. " . ' . ' . : ; ' . . • . '

In 1S9C Henry found that aliphatic aldehydes condensed xfith ni- •

tromebhane in the presence of alcoholic potassium, hydroxide or potassium - " .; y "i ■ ■ ■' 13 ' ■ / - ; , , ■ . . : . - carbonate? and the follpwing year Thiele showed.that aromatic aide- ' ,

hydes also would, condense in the. presence of sicoholic potassium hydroz- : -

ide but .not with .potassium carbonate. ' I'his method seemed' to give ap-

prosdmately. the. same yield's with the ortho - 5 meta~-jl and p a ra -n itro b e n - \ ■ " ;■ ; . -: : - 14 . . . . ■■ :. ” zaddehydes. Later studies of this •method by Kemfrey . showed that the

presence of a para- hydroicyl group made condensation impossible'but as ' ' - \ 't.;.'i5. t. ;: - ; 1 . 1 . ■ ■ . t. ■ ' -. ' l a t e r - shown by .Rosetiiatind .such compounds may .be. made to condense i f .,

the. hydroxyl group is .first acetylated^. methylatedj, or benzoylated. If

• the hydroxyl group is either in the ortho or meta, position,, there seems ' . - - : / i" ; . ' • ■ .. 16 ■ - to be no effect, whatsoever "on the reaction, . ±n 19:30 Hahn and. Stiehl

found that aldehydes without:.hydroxyl groups condensed in'the presence " '

- of alcoholic, potassium hydr 02d.de to form beth-shydroxyl''compounds in- . '

stead of nitrostyrenes if .the reaction ,mixture'was acidified, with ace-. '

tic acid instead of a mineral acid,' . p ' .. ''' " '

. About 1904. Knoevehagel and Walter found that primary amines were

'excellent condensing agents, useful not only for nitromethane but also - ; y-' . ' : ^ y? 18 : ■ . t-'dy' for nitroethane.: this method has been used, by Alles in the prepare-' ■ .■ ^^.. : . ■ -y • . '■ ■ : : " - . I- 19 " ■ ' V - tion of beta-phenyliso'propylamines and also. by Hoover and Bass 3 each ' :... . . ' ; ' - :; y..- • : - ; \ , . y' :/ y .. ' ' - y 16 . ' " h .

' with slightly different variations. According to'Hahn and Stiehl s . when the ratio' of two moles of aldehyde- to one mole of nifromethane was

" used/In the 'presence, of. methylaml'ne^ they, qondensed- to give a flavone

type cdmp'omd if. an ortho hydrosgrl group is present. On reduction of . f compound B /y ¥ -Was obtained (E quation . 1%); p., 11'). ■ ... ' / - A ' 1 ' - "' V ;-: V"' ' ; , ' ' : ' ■ 20 / : : - - : In 1929 Rao and his. colleagues; • discovered that ‘on refluxing an

aldehyde;, with .ammonium acetate" and glacial acetic acid condensation

took place readily with nitromethane." Since then this method has been;. ■y;.It : . • V . .; ‘ . : 2 1 .,.': . ; . v v 22 - used successfully by.Raiford and Fox V and by Ramirez and Burger .

: ''■ In the study of the above methods 'it was seen that the yields Were

. h o t 'e o h sista n t' f o r s p e c ific compounds^, and in. some cases no y ie ld . wa,s

obtained by one method while excellent yields could be obtained by other

methods.. : • Thus i t ’ was seen that these methods .needed further investiga-

, o n . . -: ' : 1':-::'' " 1 ' 11

OH C H g N ^ CHOI-^NOg

Oh CHO o

HNO-

3 : 12

SPBEBIEMTAL

■ PART I » ' GONDEISATIOH OF AROMATIC .ilSBHYDES MITE NITROAMCAMB3; .. ' — ——— — —— —: —■ — - . A. Condensation'In the Pr&senGe. of'Alcohcilic HMroad-d^s /

1„; Oeneral Method for 'AlooholIc Potasslum/Hydroscide •

• Attempts to condenser various substituted benKaldehydes with, nitro-*

methane in the presence of alcoholic pdtassium hydr 02d.de were;carried .

out; without much success» The reactions were;, carried out on 1 g„ seai-

p le s 3 using the follomng molecular ratios „ 'One mole of aldehyde and

1. 5 moles ' of nitromethane were dissolved : in enough: methanol to prevent

crystallization between 0° and ”5°, To this was ad.ded with constant

stirring one mole Of 5'0S potassium, hydroxide in methanol» The tempera

ture' was kept below -0 , Hhen the aldehyde contained a hydroxyl group,,

,2'moles of alcoholic potassium hydroxide' had 10;be:used to neutralize

the compound before condensation- could take place = The reaction mix- j

" ture was ■diluted to equal volume and: neutralized with dilute hydrochlor

ic acid-. . Nearly all the aldehydes produced oils, which,; even: after ex- ;

; traction with ether were very difficult to' make crystallize. ' A few

crystals of'.P-methoxy—co '-nitrostyrene'and 2, 3-dimethoDcy-zyaiitro- .

styreiie were, formed:but the other compounds remained as oils. ^ ' •-

/ i - 2. ; Preparation of nj -nitrostyrene ; ; ■, , - .

The co -nitrostyrene was prepared by the method given in-Organic -; 23 ; . ■- : ■: ; v . ; " t t : - : -tt: , " Synthesis , using 0.23 moles of benzaldehyde and the corresponding :

amounts of the other reactants. The yield was 93^ of the theoretical.

of 'i' ^ ; - -' - ' ' ' ,v

3. Preparation of w -methyl-co-nitrostyrene

- This compound was prepared, by the above method, using the same amounts of eeactants.The yield^was very poor 5 being only Mp.

105O<,' . R ep o rted ‘Mp«, 65^6°: • - ; ' ;

k » Preparation of 3, 4, g-trimethoxy-q)-nitrostyrene

. ''. > 'solution of 2.4. g. -of - 3,; 4y. 5 -trim e th o 2iybenzaldhyde and 0«75 g. . nifromethane:in 5 co: methanol was cooled to freezing, fo this; was

slowly added Q, 5 2 : g. sodium hydroxide in 1,2 5 g. ice and -water, taking"-

care to keep the temperature below 10 , The reaction mixture was then;, neutralized with .'2 ,5 cc,- concentrated hydrochloric. acid in 4 cc, water,.

Yellow'crystals were‘formed. The, yield was 1 $ % ? Mp, 115-19°„ Report

ed Epv il? r 20° , vvy'; _. ;' p ../ ; w; ^ , : ' ; ' ; Id , ',:y

" B, Odndehsation jn the Presence of Primary" Mines ; "- 5

' V ; - : lv::V^Use\of;Methylamine;"i : ; - ". " " / 5 :-.; -' -- - ^ -

: : y vr. 1 - a , Condensation with Nit romethane * . /

. ■ - - The reactants-', used:- in . the molecular ratio: of 1 mole. of: aldehyde and

1 ,5 moles of nitromethane were"placed in enough methanol to dissolve the;

aldehyde. To'this was added a solution of methylamine in methanol which was prepared.by stirring.vigorously 5 g. methylamine hydrochloride, 10

g. sodium carbonate, and 100 "cc-. methanol and filtering the resulting ,

solution. The reaction "mixture - was.allowed to stand until crystals ; ■

formed which topk ,anywhere -from several hours to several days, ; The

; crystals formed were almost"immediately filtered, otherwise, a higher - V m eltin g compound tended to be f ormed by some of the- -aldehydes(Table

II), The prdducts were recrystailized from methanol, (Table 1), The ,

higher melting compounds were found to be insoluble in a ll common organ

ic solvents:, ; . . ' /. ;.r 14

TABLE I . . CONDENSATION OF AIDBHSDE .MITB NI1?R0M1THANE:: ■

Ro Rt , r- IS < • CH ; s CfflMOr

• 4 5 'Rl - V : A*:- % ' ' r 4 Mp» s_ Y ield s C ry st. Form.

: HQ . s :

s AcO s 158-9 vi ■ 60 2 pale. yell. need.

: BzO 142-9 : ; ’ 50 ■ s pale yell„ need. v .. ° CK^'Q , —- - t » "■i CILO ; :86-7 >, : 40 ;: ' yell* need. " . > %• EtO 1; ; CH30 s .CH39 83-5 : 50 pale yell, need.

s.. .CH3Q i CH30 140 . : 80 • . deep* yell, flakes

GHoO HO 167-8 : 95 . deep y ell, need.. \ 3 CHoO ; AcO- l 5 # -6 : " deep yell; need. 2 - 50 EbO ' V HO ; 165-70 s " 75 i deep yell, flakes . Or EbO AcO.. s 1 1 4 -1 6 ;: ; 50 yell. need. :

HO ? CH30

AcO •; $ GH^O 65 i 70 : clear cryst„.plate■ M - ' ^ GHo0 s CH 0 o CH 0 : ^ , 3 f 3-

AcO s CHgCOO BzO= C6H5 GOO, EbO z GH3CH90 15

, TABLE I I . HIGHER GOElJlMSATIOH PRODUCTS

Color

■216-17.5; » pale pink : , 6.20

HO 225-45 b ric k red

209-20 p a le y e ll

CHo0 s CHo0

.tan

•^Molecular weight in camphor s 663 -

. b. - Condensation with Nitrpethane . '

Ihe procedure for nitrpethane condensation.was substantially the same as . that for nitromethane ' condensation,, except, that the - reaction • time'-was much longer^- at least three days. In.-general, the-yields were low and were formed otily after cooling- in an ice bath- and in some cases after the addition of Water. In many cases only oils were obtained.

(Table III). . / " . 9 /'- : . 16

• TABLE H I 1. COI'TOEKfSATIOM OF AIDEHIDE ¥ITH MITROETFIAMg ' _ % :

y - ^ 0H::C(CH^)#p2 V. , : ' . h ^ iEL5- . " ' ' , • R-^ s . Eg s s 2 R^ : -Mp T ; /I. l i e l d s Gryst „ F o ra '

' ;•>— s BzO s s s 130”35 s 2 pale yell* solid

.' —« J ' t CHoO t — ' ; / — 2 • 48 :: : 60 : long yell. need. V ■ ' i " ” : s : - ,' ■ . ■ „ GHoO $; CH^O,"» —< t —“ 2 —: «. 76v7 « . 50 ■. » •oan-yell. need« ^ o * ft e, - o o ft o C, ft . O o * , c o HO : CHJO : — : 104 « —*'!J' s sm all " y e ll. need. ■ ’" , » . - 3 . * : . ; ft ’ . .ft ■ ■ - ft , , » - . ft ■ -

— 0Ho0 ; HO — 2; 106,5 ° ■ t . yell, flakes • ft ** ft, ft fto ft ft ft ft ft ft ft ft

2 : : ' ■ 2 ; 2 2 : % . ■ • . ^So- yields given, as too sma,ll» ■ ; .

1 . c . 'C ondensation .w ith 1-M itropropane. \ " '

- The same pro’cednre as .aboire" was used, but only oils were . obtained^,

even on addition of water and on .freezing of the reaction mizbures.

: 2. Use of Butylaird.ne ' ' ; ■ / -

Butylamine was. used as a condensing agent only for the condensation

w ith n itro m eth an e. -The method followed was the same as that for methyl-

sminey but the reaction rates appeared to be increased as seen in Table

IV. Para-Hiethozybenzaldehyde again foraed the high melting compound, as

, with: methylamine. ' ' . •• ' TABES .IV * COMPARISON OF REACTION TIME

.B0 R-v •

CHisCHNO.9 ■ % 5 s. B2 2 ' R3 ' % . Methyisiaine . Butylazoine

: BzO ' 6-7 hours ■ 6 hours

Ci-I• 9 0 : ' ' 4-5 hours 2 -5 hours CHo0' : CPI 0 : — . 2 8 hours t -3 : ™ i CHoO s CHoO . 6 -8 hours. 2-5 hours . 3 . 3 CHo0 : HO ■ 6 -8 hours, 2 hours' : ^ : 5 EfcO : HO '• 6 -8 hours 2 .hours .

HO t CHoO ; ■ 48 hours • : :■ AcO : CH^O : 'several weeks

0. Condensa-bloo.'in 'the Presence of Ammonium Acetate end Glacial

; . . A cetic. Acid, h ■ ■ " '

The.following procedure was used for all the. aldehydes as well as for the different nitroalkanes.. The quantities, of each of the reactants remained the same in all Cases. Five grams of the aldehyde were refluxed f o r 2 ;h6u fs w ith 5 cc«. of the nitroalk&ne, 2 g. ammonium acetate^ and 2 0 . cc. glacial'acetic acid . '. The reaction .mixture was then poured into ap proximately .300 cc. of ice and water, . The: solids if foraed^ was filtered and recrystallized from dilute acetic acid- If. ah oil was formed that could not "be frozen out,' it was then separated ‘and dissolved in dilute acetic acid by heating on a water bath. On cooling some of the oils were made to crystallize. All the compounds, except those containing ■ ' : . . ■; " / ■ - . ; ; . <■ ■ ■ 18

a hydroxyl group formed yellow flakes, or needles. Those containing hy-

droxyl groups formed reddish or brownish crystals. On recrystallization

'and decolonization with charcoal, this coloration seemed to be intensified

rather than diminished. - r ' TABLE V . COMDEMSATIOM OF ALDEHYDE AM) HITROt-ISTHAWE M T H AMMONIUM

' ACETATE .AMD' G L A C m 'A C E T IC ACID / ' . . •

CHisCHNC) ‘2 4 ’ 5

£ 1 - 1 ■Er R, H' Cry-st. form ■& color SB Gale-, : Fbund

; V 5S-9 : 50 Yell, diystals; '/

HO > 16H-9 6 0 . brown-purple need..

Ciyo : t 48-9 fine yell'.l;need,„;. 7.81 . 7,6 5 - i V CH^O 86-7 65 hea-vy yell*: peed. ■ ;

EtO : . 37-8 '. 20 ■ ■ yell. need. ■ 7.27,; 7.31

CHoO : CH 0 • 84-5 60 small pale yell, flakes. 6.69 ; 6 .49 - 3 — : CH,0 5 141-2 70 ■ glist. yell, flakes ' . Cff3° : ch o0 HO 1 6 7 -8 ' :: 50 ' gold, yell, need . , 5 .:. : . % ' ,r ' : ' t EtO HO i. 1 7 0 -1 dark red need. . 6.69 4 6.32;

HO : CH3 O s ;. ,122-4 75 brown need-.

AHnreported compounds.

& TABLE V I . '■ COiroMSATiQW QF A IP lH Ib E AND NITROETHANS'TTETH AMMONIUM

ACETATE AND GLACIAL ACETIC ACID

CH sYC(CH3)N02

R. R3 :: E^. s < 1 . * ■ 2 Mp. p Y ield Cryst , & : color S N : Calc. : Found

: 64-5 50 sll*. need ,

HO 124-5 35 I t , brown need. 7.88 '7.56 CH^O o il '

CH3O: 44-5 30 small yell; need.

EtO o il ch3o : OHIO : 78-9 ■ 75: , ; ■ tan yell. need, : 6.29 : 6.11 »& ' *r o o : ' : / ; CHo0 $ OH 0 t 67-8 35 ' '■small yelli flakes ' v s 3 :

: CHLO H O . ; - 100-1 20 flat gold, need. : 6.69 % ' 6.59

3;: : : - ■ : ... 4 .EtO HO. : - 108-9. 50 gold, yell. need. : 6.29 : 6.09

HO ‘ CH 0 ■ 104-5 45 ... brown'need. : ^ *Unreported compounds, TABLE V I I . / COKDBISATIOM OF AIBEHIDE AMD 1-MIfROPRQPAME TrJITH

' AIMONIUM ACETATE AMD GLACIAL ACETIC ACID

Rp R-| '0HstC(CH3 CH2)M02

i R, .R Rr: Mp, %/TieM ' s . Cryst . fora Sc'soldr : "s % N '4 5 • . L i ■ . . - ' . : - Calc; Found

CH-0 o i l 3 CH30 : Oil;

EtO- o il,,

64“’5 60 pale yell, need, : 5.90 ; 5.62 CH30 ; % 0 :4 —' - - . : : 3 i: ■ j/v; S' ■: : CH 0 : CH_0- s''; 78-9 20 flat yell, need, s- 5.90 : 5.68 o *r Cr -3 Or s i ' ' s : CHgO s^'HO'-Vsv" 79-80 8 small yell, flakes s 6.29 : 6.17

EtO HO' o i l ,

HO CH30 ‘ o i l

^tinreported compounds.

■f» PART I I . ATTEMPTS TO PBEPARB 3 . 4 , ' g-TRBflSTHOUBMZALDEHYDE . . ■ . .■ 24 : - : ; _ ■' : ; ; • A.' Som-Muller Method ' . . '

• ■ I. - Preparation of 3 , 4a S-IriiBethoaarbenaoic Aoid ■ .

Gallic Acid was methylated by using dimethyl sulfate in the .presence:; ; : ... ■ ' ■ : .. ; : ; , ■ :: ' f ; . : • 25 . : v. of sodium, hydroxide by the method given in Organic Synthesis .. To 150 g,

gallic acid dissolved in a solution of "260 g. "spdiim hydr 02d.de- in .'150.0 cc.

water was added 402 cc. of dimethyl sulfate. The reaction mixture was

Stirred during.the addition and the temperature-was kept between 30- 40 ° .

• The reaction mixture was refluxed lg :hours^ then another 60. g. of sodium.

hydroxide was added and refluxing" continued 2 hours longer. 'The solution

..was made acid with hydrochloric acid and a light tan precipitate, formed.

Several runs gave an average "yield of -112'g. (60$) „ Mp. 165-6 , ;

- 2. Preparation of 3.s 4«) 5 -T n im e th o 3cybenzoyl Chloride ■

Using the method of Sonn and Muller,, . 5 g» of the methylated acid and

5.25 g. of phosphorous pentachlorid'e were heated together over a water'

bath for 1 hour.. The phosphorous oxyohloride was removed by distillation.

The acid chloride sublimed- on attempting to d istil it at reduced pressure.

. On three identical runs >;the total yield averaged less than one gram per

ru n . Mp.' 76-7Q. . "; . •• •

■" ; - . The. Same reaction was repeated substituting thionyl; chloride for , .

phosphorous pentachloride. Five grams of the methylated acid were heated"

w ith 8 co. of thionyl chloride over a water bath for one hour. "The ex

cess thionyl chloride was removed by distillation. ; On heating under re

duced pressure^ the acid chloride- again.sublimed s leaving a dark residue

which s t i l l contained some of th e .a c id c h lo rid e . The y ie ld was. 1 . 53 g.

7 :.;:;-.6 : ^ 1 : - -

;■ A second .'run was made using double the "amounts; but after removal chloride, the. reslduejwas dissol'v'ed. in benzene and.

the .acid chloride precipitated by the. addition of petroleum ether. -The

- . .■ Mp» 79-;5-8Q°V : f - . ; "

• - ' 3 * . : : Preparation of ^ Zj., S-Trimethoscybenzanllide • : ' 26 ----.''I- ' i ■ ■■ ■. : ■ ■; v ,>OTi:.Gd:dte-fs. method :3 0 -g,-of-the acid chloride, in 100 cc. dry chloro

form was treated with 25 g. aniline in Spec, chlororfofm. Heat was

evolved and'a white precipitate formed which dissolved'when the solution v was ••washed;with dilute .hydrochloric- acid' several times' followed by water.-

’The dhiororf orm was evaporated; and the,-residue, re crystallized from hot

methanol« White heedles Were obtained» • The yield was 33 g ."(83.5%) Sp.

•• % the Sonn-Muller method 6 g . .o f "an i l i n e : in 25 c c » o f d ry e th e r

were added to. 7«5 g« of acid chloride dissolved in 50 cc. of dry ether.

The reaction mixture was cooled and filtered . - The precipitate- was shaken

several- times with dilute hydrochloric acid: and then with water. It was

recrystallized from methanol. The average yield was about 95% of the..

theoretical.: Mp. :;

■I. Preparation of 3, 4. 5-Trimethoxy:behzimid-chlorlde

-Foufteen- gratae of the anilide and .10 g. of. the phosphorous pent a-

• chloride were heated; together on a ,» te r:;bath"until reaction took, place ..

at approximately 80 '. The reaction Taixture was distilled under reduced

pressure.,;'first to remove' the phosphor bus' o^ghhlo ride, and then the „

chlor-imine which was recrystallizedfrom ligroin:; and ether yielding. '

. colorless needles. The yield was 4°5 g. (30%). Mp. 106 . ' . .

'. Using Cook1s method 8 g. of anilide in' 30; cc. of tetraChloroethane.

were added to 6 g. of phosphorous pentachioride. and the reaction mixture.'

heated,on-an oil bath at; 140-45. for about one-half hour.. The phosphorous 24 o sy clo rid e and some of,the solvent was removed under reduced pressure»

The residue was used directly in the following stannous chloride reduc- t i o n 6 . ' - . ‘ . •

5-. Preparation of 3-," 4„ 5-Trimethosybenzaldehyde .

The anhydrous stannous chloride used in this reduction was prepared : . ■ 2'7 : - ' by Stephen's method } using acetic anhydride to dehydrate the stannous chloride. _ . '■

'The chlor-imine residue in tetrachlorethane from the above method was cooled and poured into a suspension of 2 2 .4 g. stannous chloride in ,

"50 cc. dry ether which was previously saturated with dry hydrochloric q - ': ' " - • acid at 0 . The reaction rnixfcure was kept overnight "in the ice box.- A yellow-orange solid formed which was filtered, and washed with ether.

This material was boiled 1 hour with.20 cc. acetic acid, 17*5 cc; con centrated hydrochloric acid, and 32-5 cc. water and then diluted with water and extracted m th.ether. ,"The. ether .extract was washed and dried before the ether was evaporated.; A reddish liquid which gave a small amount of aldehyde was pbtained, . Mp-. 74 . , Not., enough was obtained to make the method worthwhile. _

The-Sonn-Huller method consisted in placing 4,5 g. chlor-imine and '

8 . 5 ,g. stannous chloride in 45 cc. dry ether saturated with dry hydro chloric acid. Ho reaction seemed to-take place, as on acid hydrolysis

O . / - a compound m eltin g a t 137-8 . was obtained.

' ‘: ■ , ' • 7 ; . . ■ . . - • B. Hahn and Wassmuth Method - .

1. Preparation of 4-Hydrotqy-3, 5-dim.ethojqybenaoic Acid (Sy- ringic Acid) ■ : ' 4- •'

Syringic acid was. prepared by heating 50 g. of 3> 4 ,,S^trimethoxy- bensoic. acid with 200 cc. of concentrated sulfuric acid at 40 for approximately 17 hours ,1 The reaction^ m ixture was. -poured over ic.e and; allow ed

to stand1.' The.'product was. reci^rstalllzed from. water^ yielding tan needles.

■ The ayerage .y ie ld was i8»5 gp ::-( 6QS). •]>^. 7Q5°». -' -p ; r .; ■ " - --

■ ' 2 ,' ' Preiiaratlori. of . 4 ~Hydro 2!3^ 3 , 5 ^dimethossd)enzdlc ' acid methyl

’Dry hydro chloric acid 1 was passed into ■ a -solution, of ;17tg» ...of sjorih-

:gic' acid- in 90 cc. methanol over boiling water ■ -for 7 hours. lihite crys-

•tals were- obtained on codling.^ The yield-, xfas 11.3 ,g»' ( 5 B % ) Mp.' 10,5°.

:■ ' . 37 Preparation- of 4--Ally!ether-3, 5-dimethoaybenzoie acid

'. ■ . methyl ester; - , 1 ■ ' . ; f '. ' . , ; t 1 . . ' '

x y&even grams .of the ester Mas heated with 9 .3 g. of potassium car- '

bonat.e,-- 6 cc, allylbromide^. and .40 cc'. of acetone for; 36 h o u rs. The r e -

a.ctIoh:mixture was; poured into 400- cc. of water and filtered-.. .The yields

were 4 b o u t 6 g. (45^). 75.- - -. ' -. P h -

1 -4 . Preparatldri. of' the. Sodium Salt of ■ i-A lIyipyrogallol-35- '

. '"t";.. dimethylether ' 3,-■,; 1 . . - :' ; 1 y: /

- - Ten grams of- the allyl ether was heated Ig hdurS: with 190 cc. of >

2N sodium hydroxide. At the .rate of 10 ,g« .per g hour^' 30 g. more of -

sodium hydroxide was "added atid the reaction mixture was heated 10 hours

longer. -. On cooling the sodium salt was obtained as. light .-tan flakes.

The y ie ld was 7.9 g.^ (93.7%)»■ : ; ... . y / - t

-' 5» Preparation • of l-Allyl-pyrQgallol-3, :4> 5-triiftethylether ; -

;-. The above sodium salt was heated on an oil bath. at .140 for 7 hours

w ith 15 g« calcium.- carbonate,, 8 ; cc..difaethyl sulfate, arid. 25 ;cc.' of to lu

ene. -After cooling the reaction;-mixture was acidified with .12h-hydro-

’chloric,acid and then .extracted--With ether. . A solution of 5 g. of sodium

. hydroxide , i n '30 cc. of water was added to the ether . solution arid, the , ether evaporatedo l1he resulting nilxture x-fas steam distillpd. Nothing

hut toluene was obtained. .. . - ; ' i : : - . '8 - ^Vv' :/ ' 7 - C. Goiabina.tion of Mauthner and Hahn-Massrauth,Methods

': ' 11 Preparation of Pyrogal-lol^l ■> 3-dimethylether-2-allylether

. " Fifty-eight grams of pyrogallol-13-hitaethylether, was heat ed for 10

hours with 6?-5 g» potassium carbonate«, 52.3 g. allyl bromide5 and 145 cc*

acetone. The reaction mixture was diluted with 200 cc. water and extracted

with ether. After washing with sodium hydroxide,, the ether layer was

dried . and evaporated. The ■residue was distilled under reduced pressure,. \

giving a . compound that was colorless but ■ on. standing turned yellow. The;-

average yield, was. 2? gi (72%). Bp?17G-90> Reported Bp^.. - 140-41- - .- ' ■ - - ' . . v : . : . ' . 14 . ■ . ; v • •. - , • 2. Preparation of l-T-Allylpyrogallol-3. 5-dimethylether. ■ r The above 27 g. of allyl ether.was heated at 220-240° for.1 hour on

• a metal bath, then distilled between 175-90 at 50 mm. - pressure. It ■

distilled colorless but on standing went through the following.color"

transitions, green to red to orange.' Oh redistillation at reduced pres- :

su re 8 g. (30/2) o f a p a le yellow compound was - o b ta in e d . Bp, 130-40. fBcport.edi - Bpp i: 168-9 °-i ' 5 ■ . . • '

• Another run was made using . the undistilled .product s of r eaction 1.) *

'The compound Was heated-: f or 2 hours on; a metal bath at 160-90°. The

product was vacuum distilled, yielding.two fractions, Bp^ 119-25° and

Bp^ 125-30°. Both were very pale yellow: and gave nearly the same re- :

fractive-indices, 1.5453. and 1.5452. •: The to tal yield was 50.2 g. (68.8^).

' 3* Preparation of l-Allylpyrogallol-3. 4l 5-trimethylether ' ,

.V (ELemicin)

■ A solution of. 15 g. of sodium hydroxide in 200 cc. of Water was

added to 50 g. of the above allyl compound, - forming a yellow precipitate ■ - . ^^\^^^:-:'::: v^ : ;■". ■' v m

. p i the sodiuin salt . To this was added 3.5. g- dimethyl s'alfate in 300. cc„

of tolnenei . 'Hie reaction mixture was stirred and reflmced for 7 hours |

then it was cooled ^ .extracted "vd.th etherj,. -and dried = The ether and tolu

ene .were removed^; leaving .an orange liquid which.on vacuum d istillatio n .-

was colorless But turned yellow on standing. The average yield was a.bout .

; 43 g .. (W), B p 6 120-30. , n = -1.5369. ; Reported % Bp10 144-47.' rr=l, 52914,

: 4, ;Preparation of the'Glycol of l-Allylpyrogallol-3. 4y 5-

'''■ -trim e th y l eth e r '• ■■ • ■ . / i \ ' - . : ' ' : : 28 The method used was sim ilar to that used by Srdtman:and Robinson. .

in the .preparation of safrole glycoli . Five grams of the ally! compound,

elemicin, were placed in 100 ec. of-ice.and water. Stirring vigorously,

3.5' g7 potassium permanganate in 400 cc. of ice-water were added 'quickly,

‘Baevreactioh mixture became hrown :imni.ediately and, on passing; sulfur -di-- ,

• oxide into: the.mixture, it becatae colorless except for a lights yellow- . .4.

orange suspehsion; of an oil, ■ .it was e^ctracted with ether and washed - ...

with --2R sodium .hydroxide which removed the yellow color. The ether; so-.

. lution was dried" - over magnesium sulfate and then the ether was removed,'

'The residue was distilled under vacuum, yielding a nearly colorless li-.

. quid. The yield was 2.29 g. (39.4%). 'Bp2<5 105-10 . n - 1,5266. . . '

' - 5 . ' Treatment of the Glycol with lead Tetracetate t

The glycol was placed in.boiling bensene and 4.5 g. lead tetrace

tate: wsc add.ed in small afiiouhts. No reaction seemed to take place even 4 -

after heating for 1 hour. The compound was reisolated» On testing it , ...

;xriuh periodic acid,, it gave a test for a glycol. No tests for acids or

aldehydes could be obtained. The yield .was 1*85" g» Bp0 > 105-10°. ■ ' ■ ■ ' , : ■ ' 4-': " n r 1 .5 2 7 1 , ■" - - ■ ' •• . ' . ' 4 . 6. Rearrangement .of the Double Pond of Bleraicin to Form Iso-

elemiciti _ ;. ' ; ' ' ' V ■

An .alcoholic oolutlon of '45 g. of elejaicin was reflinced 24 hours

with 15 g. of , potassium - hsrdroficle .: . The . product was vaciium distil.led,

giving: several fractions^ The two middle' fractions had refractive in-

dices of 1.5467 and 1,5569. ' 153-56p h = 1.54735, ; The above '

yields .were 9,g. dpd 30 g. respectively, ' . .

7. Qa'onolysis .of Isoeleaiicln .. - . ;

rJ>ro gram -samples of the fraction 144-50. were dissolved in ethyl

acetate arid ozone passed through the solution for 4 to o hours. Most of

. the solvent was- removed and thd residue was treated, with zinc and acetic- i -acid. After refluxing 1 hourp water was carefully added and refluxing

was continued for 1 hour longer. The reaction mixture was cooled and

filtered 'and the resulting solution was evaporated under vacuum to re

move the water and remaining solvent. Only' a faint test for ah aldehyde

could be obtainedj -not enough was present to make isolation worthwhile»

• The same procedure, was followed on the fraction :Bp^ q 150-80°;with

the same results ,•. From this ;;it was thought that possibly the. rearrange-1

Hient did ■ hot. take /placetor. th at ;th.e hydro^zyi groups had riot been methyl

ated, Therefore,. 1,8 g, of .fraction i i were reflmced with' 7,12 g of .

potassium, permanganate in 50:cC,. of acetone for.1 hour. - The solvent was'

removed and'the nesidue was treated with dilute sulfuric acid and sodium

bisulfite to remove, the manganese dioxide. The resulting solution con

tained, white crystals which bn reerystalizatiqn from water yielded,0 .5 6

g. of a compound with aITp 164-5^.which is identical with that' of 3, 4,

5-trimetho3£ybenzoic acid." This showed that.the compound'was completely

methylated. • : ■ - ' . ' n ;‘i 1'./ - - ' . . . / - ; - : .: Y''. ■ . 5 : , . ■ ■ ; ■' ^ ■■ . ,D.= The Spath Method ' •

. 1, Preparation of 35 4, g-Trimethoxybenzaldehyde " : " - . ' ■- ■ . ■ ’ .; ; . . 29 - . - ^ - , % following the general procedure given in Vogel , - .the Roseanrand

reduction vms: .carried out on 22.$ g. of 3 s 5-trimethoiiybenzoyl chlor-. idSj,. using 6 g» paliadititn-hariw sulfate catalyst and 0*45 cc. of sulfur- quinoline 'p"oisbu« .Two of the reductions proved unsuccessful3 but a.

third gave a yield of 16 g ,•'(84$)’. Mp. 69-70°. 2 S 4-Dlditrophenylhy- drazineM p. 242-3°. : . ' ■ '

I I I . : ATTEMPTED' REDUCTIONS OF THE MITROSTIREMS COMPOUNDS .

A. /Catalytic : . . ' : ' ' 6 : .

. The. reductions were carried out in ethanol on 1. g. samples using: :

0.23 g. palladium-charc oal catalyst per gram of compound.■ The theoreti cal: amount' of. 60/K perchloric acid was added as an accelerator. ‘The com pounds took up the ■theoretical amount of hydrogen in 15-20m inutes. 'The catalyst was filtered and the solvent evaporated. A reddish oil and a ;' small .ambuht'of white: crystals were obtained. On passing dry hydrochlor ic apid into a dry ether solution of the reddish oil, no hydrochloride was formed.. The white crystalline substance which should be the perch- . lorate of the phenylethylamine was decomposed by neutralizing with sodium. carbonate. On extraction with ether and passing dry hydrochloric acid through-the solution, no hydrochloride formed. Further testing of the solutions by attempting to make the tetrahydroquinone proved.unsuccess ful .:: Therefore, it was assumed that the phenylethylamine, was not formed. .

.; Another set of the .reductions was •attempted by varying the amount of perchloric acid from; one' fourth td twice.the theoretical, amount, but each reduction' took up slightly less than the theoretical amount of hy-: /■ drogea. On doubling the amount of catalyst^ the . same results were- ob

tained.- .None of the reductions, would give a pier ate of the amine j there'

fore^ it was assumed that thereduction ..did not take place.

' B. Electrolytic i : . . ■ . 1 : ; „ ... ■ . .; ' 30 i ' 1 1 1 ; - .. The method of Koildo as described- by Jansen . was used for the most

part-witn slight variations. The cathode and anode were-lead, strips.

The anode .compartment contained (20^" sulfuric acid and a, cooling tube

for lower temperatures. The cathode contained. 5S-:hydrochloric acid in

alcohol and the -compound to be reduced. The reactions were;run from 10

to oO at 6-^8 amps 12—18 volts. The resulting solutions were filtered, .

made basic,- and extracted with ether. Nothing could be obtained which

would give a test for an amine. .- / ' ;. DISCUSSION

. '[lie most• important, part of th is work was the stucly'of the ’ condensa

tion of substituted benzaid:'eB.yd.es with nitrbalkanes in We -presence of .

various condensing agents. . As no thorough investigation has been made

on th e use'of the different condensing agents in relation to each other,

this problem was studied as it 'might prove useful in the further study

of preparation of mescalirie-like compounds.

The method used by most of the early workers in the condensation of

aldehydes, with nitromethahe involved the use of an alcoholic hydr 02ci.de

as the condensing agent. , This, method gave good yields in some instances

.but more often it seemed, especially in this work, to lead to the forma

tion of oils. ' , '

This method proved most useful in the condensation of the unsUbsti-

• tubed', benzaldehyde and gave- fa ir yields -when used with, the -3 ^ 4>: 5 - t r i -

methbscybenzaldehyde as long as' the temperature was kept below 10.°'. .‘At - '

.higher temperatures there was a tendency for highly colored solutions to

be formed and on acidification o f.such solutions a powdery, insoluble . - ■ ■ - • - ; O - -. . . precipitate which charred above 200 was formed. This method- was not

studied.;t 6 any further extent to determine what conditions would be ne

cessary for the reaction to take place satisfactorily as some of, the

other less studied methods seemed to be more useful.

• ..Many, of the later workers have found that the use of amines. is of

ten more successful, giving in most cases higher yields. : Methylamine

has been used the most, but higher amines such as butyl and amylamine

-and even secondary amines, have been used to some, extent. ' /•

Using methylamine good yields were obtained in the condensation of

,those aldehydes.and nitromethane which yielded nitrostyrenes.m elting at- least above 100°. . Those melting below this temperature ga.ye lo# yields" or none at all. This is probably partially due .to-tiie fairly high- solu bility of the nitrostyrenes in methanol. Matiy of the compounds were ex tremely difficult to recrystailige from methanol, but low melting point was hot. always; necessary- for high solubility in methanol as ^-hydroxy- jg-methozy-u) -nitro-styrene, which .-melt ed at 16'?° was so soluble in me- - thanol that it could not be .recrystalliged, " ; . ' ; ■. ;; ,

The. outstanding disadvantage of the reaction was the tendency to , form high'm elting compounds. - These, compounds -did not fora-- unless the i reaction mixture: containing t.he Crystalline product was allowed to stand some tim e ' a f t e r th e - f i r s t C ry s ta ls formedUsing para-methoxyberizalde-- •. hyde as an.example5 it was seen that its higher.condensation product had

• a nitrogen percentage of approximately the same, as that for para-methoxy-

60-nitrostyren.ei but j if s molecular ^weight was between .two and three times that of the para-methoxy-w-nitrostyrene. From th is. it could be postulated that the: compound may -be a dimer or trimer of the nitrosty- . rene. .This compound was also formed if para-methoxy-

;placed-in an- alcoholic.methylamine solution and allowed -to stand over

■night. - Time-did. not'perm it a-more- thorough investigation info the na ture, of this material.; : . ’ - y . '■ .

There are only two references in the literature made to these higher ' ' " -■ ' ■ ' ■ y ' : . . 16 . - condensation products. Hahn and Stiehl found that a flayone type com pound could be formed by orthohydroxy substitued benzaldehydes, (Equa- - t i o n 3X,' p .ll). The condensation products obtained were not the same . as those-obtained by Hahn and Stiehl as their type of condensation would give, a compound with a. molecular weight of about 333 and a nitrogen per centage of 4.2 while the compound obtained' had a molecular weight of 663- ; and. a nitrogen percentage of 6 < 6. The" ortlio hydrosgr gnoup necessary , for

the final, condensation to the flavone was also lacking; therefore^ the.

■possibility of this type of condensation is.virtually ruled out. - _

The only other reference to higher condensation products" was that• •

■ ' . , : ■ , ""'-.'it: 'p;-" i y "■ i-,., of Walter made by Jansen „ Here. para-methoxybehzaMehyde formed large •" •

amounts of a, yellow polymer which charred about . 230. and was. insoluble

in nearly all organic solvents. This .compound.appears to be similar to ;

the polymers obtained in the; present investigation. It seems, probable ;;

that these polymers are the result of the familiar polymerization of.

many substituted: styrenes. . . f . .. : . ' ; . :

"When methylamine was used as the condensing agent for the. reaction .

of nitroethane and 1-nitrdpropane with aldehydes 5 only with para-methoxy-:

and 2, g-dimethozybenzaldehyde were: satisfactory yields obtained. "The

other aldehydes gave only traces of solids or oils which were not fur-

th e r .c h a ra c te riz e d . : . ■ . ■; . ■ . ' • y-. -. ., f :

further study of the use of amines as"condensing agents: was:done by

' replacing methylamine with- butylamine. " This amine did not .raise the

yields,, in fact 5 they were slightly lower, but it did increase the re-

. a c tio n rate." Host of the condensation in the presence of methylamine re

quired six to eight hours while these same reactions using butylamine ■

took only' about two hours. Actually before any decision can be reached f

as to whether the higher amines accelerate the" condensation,, many more If

primary5 as well as secondary amines5 must be studied in conjugation

with a larger variety of substituted -benzaldehydes. ‘ f;:'-

The best general method applicable-with success to^almost all thb

•combinations studied was the use of ammonium acetate.and glacial acetic

acid as the .condensating agent ;;V In liany instances it gave fair yields . where the otfier methods did not succeed at a ll. The ;chief advantage was; ■

the difflenity which, ws^ sometimes encountered in purification of the .

tarry, crystalline masses obtained. •

The aldehydes on condensation with nitromethane all gave yields of

50/S or better 5 except the ortho-ethosybehzaldehyde5 which gave.only 20% '

ahd this was in all probability due to the low melting point of 37°ji mak

ing isolation difficult. In general. the yields were much better than

with methylamihe as the condensing agent 5 except in the case of l^hydrozy-

■ 3ymethosy arid ■ 4 -hydro 2gr- 3-^ethoxybenzaJ.dehyde" which gave yields 25“50$ .. . ",

' higher with .methylamirie. Nearly, all the aldehydes condensed with nitro- :

ethand-and- several also did with 1-nitropropane. • ( Tables . Vlll) IX, X).. v. ; •

TABhS ¥111. . 0 0 # ARISON OP YIELDS OF SUBSTITUTED- (A-MITROSTYRENES . ' 3 5

TABLE . IX . V.

HI .'R:

QH s;C(CH3)N02

% % :: : % YIBD • Hi s R Rf R2 r 3 h C¥ ° 2

HO 35

ch 3°

CH_0 60 3 : 30 mo

CHo0 : CKJO 50 -75

CmO : GH 0 ■ 35 ^ i . 5 CHgO HO 20

m o HO .Trace 50

HO s eH0o Trace 45

TABLE X,

E 0 Hn

s;c( ch2 ch3 )no 2 r 4 r 5 X ; T H e M ” Hi :R2 . R3 7 % He oh 3mo 2 m ^A c-HAc 'GHoO : GHd0 60 3 . ; 3 GILO s GH 0 20 : 3 » 3 ■CHO HO & These'latter, two sets of compounds were . very; difficult to cr^stal-r.-"

lize out of solution' due to their lower melting- point „ The oils f ormed '

had to be first separated from the water layer> then dissolved in dilute.

acetic acid and decolorized with charcoal, After this the filtered so

lution was diluted further^ while warm, to a point just before oil forma

tion and allowed to cool slowly. If this dad not induce .crystallization,

then the dilute solution was placed in ice or an ice-salt .mixture«,

Pure nitrostyrenes form yellow needles, or flakes. .'This was true of

the compounds formed by use of methylamine, but those formed by the am monium acetate-glacial acetic acid method tended to form." reddish, or

brownish-yellow compounds when the aldehyde contained a"free hydroxyl

group. After repeated recrystallizations from dilute acetic acid and

decolonization with charcoal, the coloration persisted.- ’However, the- .

compounds gave sharp melting, points which' agreed' with' that of the com- . pounds prepared by the methylamine method, and recrystallized from me- ,

thanol, the color being due to very small .trapes, of impurities. ■

Ey using the ammonium- acetate-glacial acetic acid method, the twelve

new compounds-"listed -as following, were^prepared^ - .

1, ■ O-methoo^-w-nltrpstyrene . - • - :

2. ■ O-Ethozy-w-nitrostyrene . . v." . , : 'f t f;'” : . f

2, 3-Dinietho^-m-nitrostyrene' ' " '-yf"

• 4. A-'Hydroxy-S-ethoxy-eo-nitrostyrene. . .ft- . "' \

- P-Hydroxy-cJ~methyT-"W‘-n itro sty ren e '■ -

. ■ - 6.; '-.2, 3-Dimetho^-m -m ethyl-m -nitrbstyf ene

7. . A^WdroDcy-S-Methossy-to;-methyl-to-nitrostyrene ;

• 8 . • A^Hydroxy-S-ethoxy-co.-methyl-iO.-nitrostyrene ■; . . > r . 9» 2-Hydro2cy-3--iiietho5q7--

IQ.-.. 25 3-BMetho^~60-ethyl-

11 o 3; 4^Dimetho^-a)-ethyl-z^)'--;nitrostyrene . . ' ;

12. 4-HydroDiy-3-niQtho3Qr-cd -e th y l-fi) - n itro s ty re n e ' :

; Kjeldahl nitrogen determ inations' were run: on these edmpounds for addi

tional, proof of-their identity 0 . .The det erminat ions; were slightly low in -

nearly all cases due to 'the difficulty in reducing the nitro group. - t

In generalj, the nitrostyrenes are very, soluble in' methanol and acetic

. ac'd4'orl-,Ihose containing a fre e ’hydro 2$yl group are very difficult to re-

cry stallize from methanol o They can be readily recrystalliaed <, however..,

•from acetic acid, but this often results in the formation of traces of .

highly colored impurities = • . ■ . -•■ • - ' ' ... ; "

The melting points of the nitrostyrenes'; decrease as the length of the

side ohain containing the double, bond Increases . This increase be- . V-;

comes smaller as the molecular weight of the compound increases. This

probably accounts for the;:fact that so few of .the aldehydes condense - .:

successfully with 1-nitrdprppane, . .. . . vi . -

■ .Physiologicallys these compoundss especially the .phenolic ones, may

show some t o r i c e ffe c ts:; " B y experience it was found that, these compounds■

cause phenolic type burns and cause burning sensation of the shin while -:

working.with them. Thus perhaps a physiological study of thesetcompounds,

might prove valuable in-that they may help to.. eicplain the properties of ';

similar-compoundso , ' . .'v. ■ 1 .. ' v'. . " :..;l

Prom this vstudy of' 'condensation methods y. it has been shown that the

use of the ammonium acetat e-glacial a.ceti'c acid method is . probably the .:

best method to .use in the preparation of condensation products of. nitro-;. ■ v;: ’ . . ■. ■ s *

* * alkanes with aromatic aldehydes.as "it. proved' to', give more ednsis'bant

, yields over ;& greater range of %compoimd.s \than did \ an]'" of the other me-• :

thodsv : In ;some individual .Oases ajaihes ma^r lie better cond'ensing agentsy

•but' for each aldehyde thetspebific conditions world have to be deter

mined; therefore^ the ammonitmi a,c'etate-gla.cial acetic acid method would

be best , as it always works at least moderately well. / , . . -■

A' short time-was devoted totattempts to prepare mescaline or at ' '

least to the preparation, of the 3, 4 ,^ 5-tritoetho2Qrbenzaldehyde leading -.

to mescaline; but when the need for further study of the aldehyde-nitro-

alkane condensation was perceived^ this project was abandoned in favor'....

of determining better methods•for the preparation of . the. nitrostyrenes.

As a result only ,an.incomplete .study of the methods for the preparation

of the 3; % g^'t^iHiethozgrbengaldehyde was made. . : ' . . . -

Of the various methods' tried that of Spath is probably the. best . ' . / ; :;i:; 6t - - ./it '. , h ; - .• 7 - -; ; s ■ ihe methods, of S lott a and •-Heller. , Hahn' and. Was smut h , and Mauthber '

w ill all give some of the aldehyde if large 'amounts of starting material-:-

• are used. . In the case of the Hahn and Wassmuth and the kauthner methods,

the aldehyde could probably bey obtained, if an efficient 'fraetiohating •'

column is available for. the intermediate distillations „ t • - - -

■ In the Spath method ■ the acid chloride had a tendency to char bn ' v

.distillat ion; If the '. acid. chloride was .prepared by using thibhyl chlof-

ide instead of phbsphorous pentachldride, the distillation of the acid.-

' chloride "is hot necessary and' it -may be ■recrystallized directly-from beti--.

zene and petroleum ether .: ■ Ihe direct reduction of the.acid chloride by \

the; Bosentaund method is not •always Satisfactory, as sometimes it produces

. excellent yields: and -at other, times- no :yield at all with the same com- 39

: 'Ei-e reduction of the nitriostyr.enes: to phenf-lethjriaBiiiies was .iiot

studied to any extent other than to find that they are extremely, diffi

cult to reduce.. . Both catalytic and electrolytic methods were attempted without success. From.the literature it was known that both of these; methods have been used5 although not always with success.. 40

1, From t-he; study1 of severali- ■Condensation raethods it was concluded that

" the ■ ojaraoniuia' acetate-glo.cial, acetic acid, method was the best general

: . method for condensing aromatic aldehydes and nitroalkanes.

2o Twelve hew' nitrostyrehe compounds were prepared by the ammonium: ace-:

tate-giacial acetic.acid method. 1 ‘ '

3. Further study of amines as condensing agents is- necessary before it

can .be decided whether higher amines accelerate, the reaction/ :.

4 V From incomplete studies^ the Spath- method for'preparation, of 3 > k s _'

■ ; 5"trimetho35ybenzaldehyde: appeared..to;: be the best. 42

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