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NUCLEOPHILIC SUBSTITUTION REAC'riONS UTILIZING

HEXAMETHYLPHOSPHORIC TRIMHDE (HMPT)

I. l\RO~t~TIC NUCLEOPHILIC SUBSTITUTION

HEZ\C'1'IONS IN HHPT

II. ALIPHATIC Nl.J:2LEOPHILIC SUBSTITUTION

REACTIONS IN WlPT

A Thesis

Present:ed to The Gruduate Faculty

California State University, Hay,vard

In Partial Fulfillment of the Requirements for the Degree !v:aster of Science in Chemistry

Py Deggary N. Priest

,JunE.'} 1972 NUCLEOPHILIC SUBSTITl.JTION REACTIONS UTILIZING

HEXi\MSTHYLPHOSPHOqiC TRIAl-fiDE (HMPT)

I. Aqm-fA'I'IC NUCLEOPHILIC SUBSTITUTION

REACTIONS IN.HHPT

II. .i\LIPHATIC NUCLEOPHILIC SUBSTITUTION

REAC'l'IONS IN HHPT

Deggary N. Priest

Approved: Date: ACfCNONLEDGEHENT

The author w~ . shes to thank Professor Richard s. Monson for his guidance and undying patience throughout the course of this w·ork. 'The assistance given by the staff of the Chemistry Stockroom at California State University, Hayward in the procurement of chemicals and equipment Has greatly appreciated, as was thE.• talents of Hrs. Jessie Laston in the typing of the final manuscript. TABLE OF CONTENTS

Page

Abstracts 2

I. Aromatic Nucleophilic Substitution

Reactions in HMPT

Introduction 5

Background \'lork in HHPT 8

Results o.nd Discussion 12

Experimental 27

II. Aliphatic NucleophilicSubstitution

Heactions in H.NPrr

Introduction 31

Results and Discussion 31

Experimental 42

Heferences 46 P.'\l

Aromatic nucleophilic substitution has been found to occur 1dth aryl halides lvhich are activated by benzoyl or cyano groups when subj2cted to refluxing hexamethylphosphoric triamide (I), resulting in substit.ution of a dimethylamine group for the halide. The follmring compounds give the corresponding dimethylamino derivatives in the indicated yields: 4,4•-clichloroben~ophenonG, 11.6 ~ ~. ;

<'1-·chl orobcmzophc'nom~, 4. 5%; 4-bromo:benzophenon0., 7. 3%;

_Q-bromobenzonitrile, 94%; Q-chlorobenzonitrile, 9.35%.

'I'he r.~echanism of the re:action, '"hich appears to procePcl through an intc:·rrr;(~diate sigwa -complex, is discussed ir:. detail, Pl-.RT II. !-----1BS Ti~ .'\ CT

Aliphatic nucleophilic sub:3titution ha.s been fo,Jnd to occur with a series of benzyl alcohols when subjected to refl uxin;r hr~xamethylphosphod . c triamide (I), resuJ. t- ing in substitution of a dirnethylarnino group for the hydroxyl group. The foll<.nJing compounds giw~ the co!:"- responding dimethylar:'li.no cler i vati ves in the indica te6 yields: benzyJ. alcohol, 587'~; br:mzhydrol, 46%; triphC?.nyl- carbinol, 41. 576 ; Q-methoxyben?.yl alcohol, 47%; rn-ni tro- 3 benzyl alcohol, 31%; .2.-chlorobenzyl alcohol, 68%. The mechanism of the reaction, which appears to proceed through either an SNl' SN2' or SNi pathway, is discussed in detail. 4

HEXAHETHYLPHOSPHORIC TRIM-HDE (HNPT) (I} Part_la Aromntic Nucleophilic Substitution Reactions in HMP'I'

INTRODUCTION Aromatic nucleophilic substitution reactions, in which a good leaving group is substituted for by a strong nucleo phile, have been known and studied for many years. 1 The results of this work indicate that successful reactions of this type fall into three basic categoriesa 2 1) reactions activated by electron withdrawing groups ortho and para to the leaving group; 2) reactions catalyzed by very strong bases, proceeding through aryne intermediates; and

3) reactions in \vhich ciazonium salts are reacted wi t~:1 a nucleophile.

Sine~ diazonium salts ~vere not used in the reactions being explored, this mechanism may be discarded as not applicable. 'I'he aryne mechanism, which requires a strong base and necessarily results in a mixture of isomers

(neit.her of ~..:hich is the case here), may also be considered not t.o apply in the pn~sent. experiments. That leaves then, the class of reactions in which aromatic nucleophilic sub stitution proceE:~ds at a leaving gronp ortho or para to an electron 1-.ri thdra,ving group as that most probable to con t.ain the reactions under investigation. The mechanism operating in this class of reactions

5 5 is knmvn as the intermediate-complex mechanism, a.nd is a two step process 3 • Th? fit"st step consists of attack by a negatively-charged nucleophile to form a resonance- stabilized intermediate (Eqn 1),

•• 'K X X J e "\ -? '1 7 '1 [ 0~.0-Cfe J

and the second step is the subsequent loss of the leaving group as an anion (Eqn 2).

e 2. ) X

The first step is generally slo'", and consequently rate-determining, while the second step is relatjvely rapid. Thus t he renction is bimolecular and dependent on the con- centrations of both reactants, differing from the usual SN2 reaction only in that attack and departure are not simultaneous. Isolation of "Meisenheimer Salts" (Eqn 3) in 1902 gave good c-' vidence for this meclw.nism. ..., I

These salts, resulting from the reaction of ethyl picrate with methoxide anion, are stabilized through resonance to such an extent that they can be isolated and idP.ni:if ied. Further evidence for the intermediate-complex mechanism arises from the fact that in the reaction (Eqn 4)

the rate was not appreciably different for the cases ~1ere X was Cl. Br, I, SOPh, or £-nitrophenoxy. This is as ex pected, s:i.nce the departure of the leaving group is not the rate determining step. 8

BACKGROUND i[ORK IN HNPT

Interest in this area began with the discovery of thP- dehydration of secondary alcohols by hexamethyt 4 phosphoric triamide (HMPT). It was found that reaction between secondary alcohols and refluxing HMPT resulted in high yields of the corresponding unrearranged olefins

(Eqn 5).

H M re.f\v»<.\n~. 'c= c" '"'"" 9\ ¢"' '~ ~C\

It was also found however, that small amounts of alkyldimethylamines were formed in the same reaction 5 (Eqn 5). Further evidence of th.is substitution was found in the case of primary alcohols, where dehydration is less favored (Eqn 6).

6. C\-\:\(CH._\.0\-\ '"'""'~'to CH'l(Cl-\a.)5 C.H:C.\"\~ S 5 '?o, 0~ f'Y"O d\ol C.t

+ C\-\l (Ct'{~) 7 N (c H3)~ '\-) Ofo 0~ prootvc.~ 9

.Z\ n investigation was then launched into react ions

between refluxing HMPT and alcohols whose structure pre- eluded dehydration. The specific compounds chosen were a 6 series of phenyl carbinols. Benzyl alcohol was refluxed

in a threefold excess of HMPT for approximately one-half hour to give benzyldimethylamine in good yield (Eqn 7).

7. ¢cH~OH HMP\ ~ ,¢cH"'-N(Cr\3)--.;

7 \ Olo C o 't\. v e Y" S \ o""

A dimethylamino group from HMPT had substituted

itself for the hydroxyl group of the alcohol. This reaction

is the subject of the second part of this paper and will be discussed thoroughly in that section. Suffice it to say that reaction with benzhydrol, triphenylcarbinol, and several substituted benzyl alcohols all produced fair yields of the corresponding benzyldimethylamines (cf Eqn 7).

This work then prompted an investigation into reactions bet,.,reen HMPT and enolizable ketones, such as cyclohexanone

(Eqn 8).

8. 10

The question was, whether or not HMPT would effect a substitution of the dimethylamino group for the hydroxyl group of the enol form; i.e., could the ketone be converted to the dimethylamino enamine. Therefore, work was done on the reaction between HHPT and a variety of cycloalkanones, 7 and the discovery made that indeed this reaction occurred: a substantial amount of 1-dimethylaminocyclohexene was obtained through reaction with cyclohexanone (Eqn 9).

0 OH 9. 6 4 ' 6.

The resulting enamine was reacted in situ with alkyl halides and hydrolyzed to yield fair amounts of alkylated cyclohexanones (Eqn 10).

10.

This latter reaction was no surprise, since enamines are known to undergo this type of alkylation and will readily hydrolize bi.lcl~;: to the ketone, 8 but it further substantiated

the presence~ of the enamine. Closer scrutiny of the products from cyclohexanonc 11

reacting vrith HHPT however, revealed the presence of

dimet.hylaminocyclohexane ( Eqn 9). Here it appears, the

dimethylamino group has substituted itself for the oxygen

in the carbonyl moity, resulting in a reduction at the host carbon atom. It is .not clear if the reaction has

occurred bet'\·:een H~!PT and the carbonyl group itself

(Eqn 11), or if there has been a disproportionation of

the enamine (Eqn 12).

0 11. 6

12.

Consequently an investigation into the reaction betvreen

non-enolizable ketones and refluxing HMPT was initiated in

an attempt to elucidate this question. Reactions w·ere run

on a series of benzophenones, with an eye to finding

ana loqons products. As the next sect ion of this prt r.'or •.d 11

show, the results of this investigation are int.erest.ing in 12 their own right, but leave unanswered the question as to the mechanism of the formation of the saturated amine ( Eqn 9).

RESULTS AND DISCUSSION In an attempt to ans'iver the question presented in the previous section of this paper, benzophenone was dissolved in HMPT and refl uxed for various and increasing lengths· of time, 'ivith no results.

HMPT

Consequently, working on the idea that possibly some type of an activating group substituted on one or both of the phenyl groups 'ivould initiate a reaction, 4,4•-di- methoxybenzophenone was subjected to refluxing HHP'I'; no identifiable products could be obtained.

'\-\~ fA('oc:~ 1 14. ~C~ HMPT ~ no ·,so\o.'o\e II p~od. \Jc."'c;. 0

Having now tried a benzophenone containing an electron donating group, the next logical compound to 13 try seemed to be one substituted with an electron withdrawing group. Therefore, reaction was attempted between . 4,4•-dichlorobenzophenone and HMPT, and a definite product was obtained which was soluble in aqueous acid (Eqn 15).

15.

Elemental analysis of the sublimed product suggested the empirical fo~mu1a c 15H14clNO, and its infrared spectrum indicated the presence of a carbonyl group. At this point, with the product as yet unidentified, reactions \vere run on 4-chlorobenzophenone (Eqn 16) and 4-bromobenzophenone (Eqn 17) in refluxing HMPT and the somewhat disconcerting discovery made that the products of both reactions were the same compound!

co 16. '©lcJ©l II 0 14

17. ~'©lc~,, 0

This compound showed basic behaviour in aqueous acid, and its infrared spectrum also showed retention of the carbonyl group. The NMR spectra of the two unidentified compounds both contained singlets consistent with the existence of N,N-dimethyl protons. The compounds were identified by comparisoh with literature infrared spectra and melting points to be 4-chloro-4•-dimethylaminobenzophenone (Eqn 18) and 4-dimethylaminobenzophenone {Eqns 19 and 20).

18. HMP"T,. ca.~c.JOrN(cH~)~ '6 .

Ci 19. ~CJ{Jr 'r\MI>i 0 II 0 15

20. !Clc~II'HMP:I• ~c:.©'N(CtiJ);~.

II \I 0 0

Thus, the refluxing HMPT had effected an aromatic nucleophilic substitution of a dimethylamino group for a halide para to a benzoyl group. This result was surprising, since the expected reaction 'tvas one involving the carbonyl moi ty, and since aromatic nucleophilic substitutions usually do not occur 9 und er con d 1t1ons. . t.h' 1s m1l. d • Experiments were then carried out to determine the amount of electron withdrawal necessary for this substitution to occur. Bromobenzene (Eqn 21) and D(.-bromo- naphthalene (Eqn 22) were both subjected to refluxing HMPT and in neither case was any of the expected product obtained.

21. 16

22.

It was now apparent that substitution would not occur without the activation of an electron withdrawing group, and the failure of m-dichlorobenzene (Eqn 23) to react indicated that the activating group would have to be quite strongly so.

23. NO r-eo.ct \OV'\

It was now decided to embark on experiments to determine just to vhat extent ring activation by electron withdrawal "ivas nec0.ssary to effect nucleophilic substitution and to determine if the reaction was synthetically useful.

For this purpose, attention "1\ras turned towards a series of halide-substituted benzonitriles • .Q-Bromobenzo nitrile was synthesized10 and subjected to refluxing HNPT to give an exr.ellent yield of .Q-dimethylaminobenzonitrile (Eqn 24). 17

CN CN 24. ¢ HMPT • Q "''t.,o covwev-s\o"' Sv- N (C H:l)~

Since the conditions for aromatic nucleophilic substitution reactions activated by electron withdrawal enhance attack at the ortho as well as the para positions, Q-chlorobenzonitrile (Eqn 25) and Q-bromobenzonitrile (Eqn 26) were reacted under similar conditions with no detectable products.

25.

CN reo.c-tiOY"\ 26. @'".. HMP'T • NO

At this point sufficient evidence of the behaviour of activated aromatic halides in refluxing HHPT has been gathered to allow· some t.houqht. to be put tm-rards the most 18 probable mechanism operating in these reactions.

For reasons stated in the introduction of this paper, the diazonium and aryne mechanisms of aromatic nucleophilic substitution may be eliminated. Therefore the intermediate-complex mechanism, or at least a modification of it, '\orould seem the most likely place to begin. This mechanism requires attack by a negatively charged nucleophile, although, reactions may also occur through the attack of a neutral nucleophile. Activated aromatic halides undergo this reaction with ammonia, primary, and • 11 secon cl ary am1nes. Refluxing HHPT results in a continuous, slmv evolution of dimethylamine:

27. HMP\

Thus the conditions for such substitution appear to be met.

If this is the case, HMPT may be merely acting as a source of dimethylamine which, at the reflux temperature (around

235°), may be nucleophilic enough to effect substitution.

To test this possibility, a sample of 12,-bromobenzonitrile was dissolved in Dowtherm A (a eutectic mixture of biphenyl and eliphenylether with a boiling point above 19

250°), brought to 235°, and gaseous dimPthylamine was bubbled through the hot. solution from a gas dispers jon tube. After a reaction t:i.me of 48 hours, no amine product could be isolated (Eqn 28).

28. ~ -+ HN(CH))a. Qow-!;br.'"""' A) 110

Even though the fact remains that dimethylamine might be much more soluble in Hl'1PT than in Dmv-therm A at that temperature, this experiment seems to indicate that HMPT is taking a more active role in the reactior. than merely as a source of dimethylamine. The next most likely mechanism seems to be one in which HMPT forms a complex ~vith the aryl halide, and reactions occur bet,,reen the t'vo molecules while complexed. 12 BMPT is known to complex quite strongly •vi th many organic molecules such as alcohols, amines, and alkyl halide s. These complexes are between the oxygen of m.. fPT and the o<:-hyd>:ogen of the aH::yl halide (for instance}, aE· shown: 20

Bond length and polarity studies have shown that the

P-O bond in HMPT must be assmned to be of 50% ionic 12 character,

and it is well known that HMPT is a good solvator of cations 12 and a poor one for anions. This latter evidence indicates that HMP'r has a diffuse positive end and a concentrated negative end; the partial positive charge on the phosphorous being spread out onto the dimethylamino groups.

Obviously there are no activated ~-hydrogens on an aryl halide molecule, but ignoring the steric hindrance as well as the diffusity of the phosphorous• positive charge, one might imagine a complex between the halide atom and the partially positive phosphorous. 21

Considering the fact that the reflux temperature is supplying enough energy to break the P-N bond (Eqn 26), it is not unrealistic to imagine an intra-complex rearrangement in which a P-N bond is broken and a P-Br bond formed. Thermal breakage of the P-N bond would result in the formation of a dimethylamino anion which would then be free to attack the aromatic halide.

1 22

The resulting intermediate, while still strongly complex~d \vi th t.he cat. ionic m ,f P'T' fragment, ~-rould then very rapidly lose the halide ns an anion. Bromide attack on the· positive phosphorous would be instantaneous, resulting in the formation of a phosphorous-bromine bond. Although the charge diffuseness and the steric hin-

drance appear to render this mechanism unlil{ely, somethi~g similar must be operating. \'1/hile refluxing HMPT slowly gives off dirnethylamine, refluxing HHPT containing an activated aryl halide n_,sul ts in rapid evolution of di11ethylamine. In other •vords, i·rhen reaction is occurring behreen HHPT and a sufficiently acti.vatcd aryl halide, decomposition of the HMPT is accelerated markedly. Hhen the aryl halide is not activated enough to initiate substitution, dimethylamine is evolved at the same speed as for pure reflux:ing HMPT. It is very possible that once formed, the bromo-substituted

HHPT compound decomposes at the reflu..x temperature, result-

ing in the copious generation of dimethylamine. Further evidence in support of the intermediate- complex mechanism is the fact that Q-bromobenzonitrile failed t:o react. 'I'his could indicate the inability of the reactants to complex due to steric hindrance by the cyano group. Reaction H'i th m-bromo- and m-chlorobenzonitri les gave

no substitution products, 3S is to be expected from this mc>chanism. ?.3

One result '\vhich at first did not appear to fit an aromatic nucleophilic substitution mechanism is the fact that aryl bromides react much faster than aryl chlo~ides when activated by a para cyano group. Reaction bet,.reen HMPT and £-chlorobenzonitrile for 4 hours resulted in a very lOlv yield of £-dimethylaminobenzonitrile,

II eN CN

tiM ~'T ) ¢ ~ \ow.~ ~' ~\cl a t-1( C:.\-\3)~

The possibility that the product might be forming quicl

30.

31.

While chloride and bromide are usually rather close to each other in leaving group ability, fluoride is always much greater or much less, depending on the rate determining step of the mechanism operating. According to

'L 15 Marcrl , if step 1) of the intermediate-complex mechanism I is the slow one, fluoride is by far a better leaving group I i than chloride or bromide, I I ~

1) 25

t 'I t .. e ' ~ 2) X

while if step 2) is the rate determining process, fluoride is the poorest leaving group. Consequently, an experiment yet to be done is the n~action of HMPT with £-fluorobenzo- nitrile and the comparison of its rate with that of £-bromo benzonitrile. Despite the partial nature of the present results, the fact that bromide reacts faster than chloride seems to indicate that if the intermediate-complex mechanism (or a close modification) is operating, the last step is rate determining. The benzyne mechanism, as stated earlier in this paper, does not appear likely to be operating since it results in substitution at two positions; a result not found here. Also, there is no reason why Q.-bromobenzonitrile would not react if the benzyne path~;vay was being follo ~v.? d. Nhile much 1vorlc remains to be done concerning the reaction mechanism, enough data has been gathered to indicate the synthetic utility of these reactions. Re- agents 1vhich effect aromatic nucleophilic substit.ut.ions on aryl systems that are not highJy activated are not 26 numerous, The usual reaction requires activation such as that given by a 1,3,5-trin:i.tro system, Under those condit..ions a halide can be quite easily displaced, lvhile compounds with successively fewer nitro groups require incn..,asingly stronger nuclecphiles to effect substitution,

Thus reactions between HMP'r and an aryl halide activated merely by a b::mzoyl or a cyano group are quite novel. Most analogous reactions discovered require more vigorous conditions or result in lower yields. The reaction (Eqn 32) between £-bromobenzonitrile and piperidine16 (a better nucleophile than dimethylamine) results in only a 10% yield afte!." 8 hours of reflux, Hhile E-bromobenzonltrile is aminated in 94% yield after 4 hours of reflux 1vi th HMPT.

32, "'c-\0)-e""+ NJ .r..;~* ~·Nc-{Q)-NC)

/0% ~\e\cl.

The HMPT reactions being discussed offer a synthetic route to aryl dimethylamines that is one-step, simple to work up, and requires only mild ring activation. At the present time they are valuable in a rather narrow scope, but 1vill possibly prove useful on a wider scale if they are effective when applied to aromatic non-benzenoid systems, Reactions with compounds such as substituted pyr.idines (Eqn 33), 27

33.

activated naphthalenes (Eqn 34),

G... 34. ©Q CN

and other aromatics, are all possible fields of research

utilizing t.he amination of activated aromatic systems with

refluxing HHPT.

EXPE~UHENTAL

HexamE~thylphosphoric triamide (HMP'!') and all other

reagents not specifically described below were commercially

available and -,;.;ere used without further purification.

Nelting points were determined on a Fisher-Johns apparatus

and are corrected. Infrared spectra were recorded on a

Perkin-Elmer Model 337 spectrophotometer. Nmr spectra

were taken on a Jeolco Hodel C-60 spectrometer with THS

as internal standard. Analyses were done by Chemical

Analytical Services, University of California, Berkeley, ',: ~,

California.

The Reac_tion of 4, 4' -Dichlorobenzoohenrme t-Ji th HHPT 4,4•-Dichlorobenzophenonc (5.0 g, 0.02 mol) and HHPT (150 ml) were mixed, and the solution was refluxed for 2.0 h. At the end of the reflux period the reaction mixture was cooled to room temperature, diluted with 500 ml of water., and extracted three times with ether. The ether phase was washed once with brine, dried (HgS04 ), and concentrated (rotary evaporator). The resulting oil was chromatographed on a neutral alumina cohunn with hexane as elutant. The third and fourth visible fractions were collected and the solvent evaporated to dryness (rotary evaporator) to yield yellmv crystals, mp 117-118°. These crystals \vere sublimed under vacuum yielding 0.6 g (11.6%) of 4-chloro-4•-dimethyl• aminobenzophenone, mp 116-118°: ir, (nnjol mull) 6.17 (C:O),

8.15 (C-N); nmr (CC1 4 ) f/"3.2 {S, 6, CH 3 ), 7.0 and 8.0 (m, 8, aromatic protons).

Calcd. for c15H14ClNO: C, 69.36; H, 5.43; Cl, 13.64; N, 5.39. Found: C, 69.50; H, 5.33; Cl, 13.56; N, 5.49. ·, ;

4-Chlorobcnzophenone (5.0 g, 0,023 mol) and HMPT (150 ml) were mixed, and the solution was refluxecl for 1.5 h. The reaction mixture was worked up and chromatographed in the same manner as in the preceding case. The hexane solution containing the fourth visible band of the elution was extracted with 10% aqueous hydrochloric acid. The acid sc 1 ut ion 'tvas washed with ether, then made basic with 10% sodium hydroxide. This solution '\vas then extracted "tvith ether, the extract washed with brine, dried (MgS0 4 ), and concentrated (rotary evaporat.or), whereupon yellow crystals formed. These 'tvere dissolved in hot ligroin, decolorized with Nori t A and allm·red to recrystallize, yielding 0. 25 g (4.8%) of 4-dimethylaminobenzophenone, mp 84-88° (lit17, mp 90°).

4-Bromobenzophenone (5.0 g, 0,019 mol) and HMPT (150 ml) ,..-ere mixed, and the solution 'tvas refluxed for 2,0 h. The reaction mixture '\vas worked up exactly as in the preceding case, yielding 0,30 g (7.3%) of 4-dimethylamino benzophenone, mp 81-85°, A mixed melting point "tvith the 'i product from the reaction of 4-chlorobenzophenone 'tvith HHPT gave no melting point depression, The ir and nmr spectra of the products of the latter t'\\'0 reactions were identical. i 30 · ~

The 3eact.ion of p-Bromoben7.onitrile \Vith W·!PT

g-Bromobenzonitrile (2.0 g, 0.011 mol) and HHPT (75 ml) were mixed, and the solution refluxed for 4.0 h. The reaction mixture was cooled, c1iluted with 300 ml of water, and extract.ed three times with ether. The ether phase 1vas washed once 'vi th "'va ter and extracted with 10% aqueous hydrochloric acid. The aqueous phase was then washed once with ether, made basic with 10% sodium hydroxide, and extracted 1vi th ether. The ether phase was then· "'vashed once vTith brine, dried (MgS0 4 ), and concentrated (rotary evaporator) to yield 1.5 g (94%) of crude product. Re- crystallization from ligroin gave 0. 6 g of £-dimet.hylamino benzonitrile, mp 67-70° (1it18 , mp 75-76°). The nmr spectrum is consistent 1vith this structure and the ir spectrum matches the published spectrum19 of the kno1vn compound.

g-Chlorobenzonitrile (5.0 g, 0.037 mol) and HMPT (150 ml) '\vere mixed, and the solution 1vas refluxed for 4.0 h. The react.ion mixture was worked up as in the case of the

2-bromobenzonitrile reaction, to yield 0.5 g (9.35~~) of crucle .2-dimethylaminobenzonitrile. The nmr and ir spectra matched those obtained from the g-bromobenzonitrile reaction. 1 I

Part II. Ali.nhatic Nucleophilic Su~stitut:ion Reactions

in HMPT

I!\'T'RODUCTION As stated in the background section of the previous half of this paper, during the dehydration of primary and secondary alcohols in refluxing HMPT, small amounts of alkyldimethylamines were formed. The result indicated that even though dehydration was the preferred reaction, HHPT would to some extent effect substitution of the dimethylamino group for the hydroxyl group. Consequently reactions were run on a series of benzyl alcohols in refluxing HMPT to determine to what extent substitution would occur on alcohols whose structure made dehydration impossible. The results of this study con- firmed our suspicion that a useful one-step conversion of alcohols to dimethylamines through reaction with HMPT existed.

RESULTS AND DISCUSSION Reaction between benzyl alcohol and refluxing HMPT

afforded benzyldimethylamine in a 71% yield (Eqn 35), This result implies that indeed substitution of a dimethylamino group for the hydroxyl group is competing with dehydration and will occur in good yield ,.,here dehydration is not

31 32 possible.

Reactions were then run on benzhydrol (Eqn 36) and triphenylcarbinol (Eqn 37) with similar results.

HMP"T,. ,.J. CHN(CH) ~~ ') ~

37. ¢ C 0 H 3

Benzyl alcohols with various electron withdra,ving and donating groups substituted on the phenyl group were reacted next. Q-Hethoxybenzyl alcohol reacted to give a 47% conversion ( 2qn 38), 33 m-nitrobenzyl alcohol afforded a 31% conversion {Eqn 39),

39.

and e-chlorobenzyl alcohol gave a yield of 68% {Eqn 40).

40.

In the preceding series of reactions, the yields of products corresponded to length of reaction time. Thus, the nature of the substituent appears to have little effect on the extent of reaction. It was noted however, that while the 12.-chloro- and E.-methoxy-substituted compounds reacted to give clear light:-brown solutions, the m-ni tro- - - substituted compound gave a very thick dark black solution. Apparently reaction is occurring at some other point as ,.,ell as at the hydroxyl group in the case of the strongly electron withdrawing nitro compound. When any of the above-mentioned benzyl alcohols are refluxed in HMPT, a substantial amount of a thick glassy substance settles on the bottom of the reaction flask. 6 This material is water soluble, and has been ana1yzed - as bis-dim:thylammonium dihydrogen pyraphosphate:

0 0 1\ II HO-P- 0- p- OH I \ Oc;, Oe

Consequently, any mechanism proposed for the conversion of benzyl alcohols to benzyldimethylamines in refluxing HNPT will have to account for the formation .of this pyrophosphate. Another observation of these reactions is the copious generation of dimethylamine throughout the reacti.on period. ~ Much worJ\: remains to be done before the mechanism of 'i. this substitution reaction will be known with any degree "i of certainty. The data at hand however, indicates that one of several aliphatic nucleophilic substitution mechanisms is operating. Follo,ving a r.1echanism suggested by Normant 12 , the initial step in this reaction may be assumed to proceed as follm.;s: \ ..,N' -;N- P=O + \-\OC.H-.~ I .... ~ ~

...... 35

-N' + - OH ' 'fi J' ' 9 _...N -P-O-H-Ocr\~<;f> < N- + 0 / E9~P.' CH~rp 'N ... N N ' I \ I'

OH 0 0 ~ ~.. pi> ' • " • " -tHN~~ /~'~H I ' -N~P.'N- N \ ... N N 1' -N N \ I ' \ I ' ' I '

0 p" / \' OCH rk -N N a.Y' \ / ' (:II)

The mystery lies therefore, in the fate of (II) once it is formed. One poss ible mechanism is a standa rd SN2 reaction, wherein attack by dimethylamine and loss of thG phosphate fragment are simultaneous: 36

H ¢ 0 ' ---...... \ \\ CH3-N:/" H-C-0-P, ' . / I N C H H N I' 1 I \ lf • ,-~. H -o d "', , rf " ( C H3 )a N- -- C - - - 0 P -N~ H' N' I ' + 0

9 l'p" .... "'" 0 \ ' N I ' ) 0 .J. ,p," +---oJI ' + HO ' N- N \ I \

This path1-1ay would necessarily result in inversion of configuration and could be proved or disproved by reacting an optically active alcohol and determining whether optical rotation ,.,as retained or inverted. This mechanism is un- likely however, since triphenylcarbinol, which would be quite sterically hindered, reacts readily. Another possible mechanism is the SNl path\vay, in vlhich 37 the reaction is a two-step process, going through a car- bonium ion intermediate: 0 Q \\ 0-P-N~ \ N ' '

~... ""' $/C.Hl ¢cHaT H NM•~ •4-• tp C Ha.- ~- CH 3 H (9 ,c H1 e ¢cH~- ~ .... CH1 + OPO(NMe~)~--7) ¢CHa,NMc~ H +

H 0 ~0 ( N Mea.)-.

The SNl mechanism 'vould result in complete racemization of any optical activity. A third possibili · y is the SNi mechanism (substitution nucleophilic internal) in which substitution through internal rearrangement occurs. The first step is the same as the very first step of the SNl mechanism: dissociation into an intimate ion pair. However the second step entails attacl-. by a part of the leaving group from the front since it is unable to get to the rear. This mechanism results in retention of configuration. 0 \\ ~ ¢ CH -o- ?-N a. \ ' N I ' l H 0~ ~ t P-N, ~-C.- NMea + ,, l H 0

0 0~ ~ \\ p- N, ~P, I~ _.f\ N-- -N N \ o \ I '

0 0 'N-P-0-P-" '\ N~ / \ ' ' N N I ' I ' ------

The pyrophosphate molecule 1vill probably be quite reactive, and can very easily lose its dimethylamino groups in the presence of even slight traces of moisture to become a pyrophosporic acid anion. This last pathway seems to account for most of the physical observations such as excess evolution of dimethylamine and formation of the pyrophosphate bond. IVhite and Elliger20 have succeeded in converting alcohols into amines via an analogous reaction for which they suggest an SNi mechanisma

•• ~ -N-~ R'

The above three mechanisms (SNl' SN2, SNi) could be distinguished between by running an HMPT reaction on an optically active alcohol such as g- or !.-Q.-nitrobenzhydrol and checking the optical activity of the amine product. An SNl reaction will give racemization, an SN2 will give inversion, and an SNi path\'lay will give retention of 39 configuration. The HHPT induced aliphatic nucleophilic substitution for the hydroxyl group of a benzyl alcohol by a dimethylamino group makes possible for the first time the one-step conversion of benzyl alcohols to benzyl dimethylamines. Its synthetic utility vd.ll very likely prove significant when applied to any other alcohols whose structure makes dehydration impossible. The yields are respectable, the work up simple, and the starting materials easily obtain- able. Previous methods of producing benzyldimethylamine include the reaction of benzyl chloride with dimethylamine

(Eqn 41), ·i.

the electrolytic reduction of dimethylbenzamide (Eqn 42),

- e ,. ¢-CHaN (C H1);..

and the reaction of benzylamine with formaldehyde (Eqn 43);

- 40

43.

none of which start w·ith the alcohol, and in each case application to various substituted benzyl compounds is either difficult or impossible. Methods of converting alcohols to amines in relatively few steps are scarce. One of the most common is the two- step route "'vhere an alcohol is converted to the halide or tosyl analog and then converted into the amine21 (Eqn 44).

This method, because of the displacement nature of the steps, is usually restricted to primary alcohols. Another existing "'vay to convert alcohols into amines is the previously mentioned three-step method of \fuite and 20 E1 l1ger. , J_n. wh. 1c h t h e alco h ol IS. converte d 1nto . 1 . ts sulfamate ester, the ester is rearranged into a betaine analog, and then hydrolized to the amine (Eqn 45).

-- 41

0 ' Q 45 • ~ OH--+ ~-o- r-NR• _.,.. RiN-503 __,. N R3 0

Although the sulfamate ester method results in yields which are com~arable to those obtained in HMPT reactions, the experimental procedure is much more complicated. Logical extensions of the present "'VOrk include reactions with compounds such as allyl alcohols (Eqn 46);

46.

pyridinyl alcohols (Eqn 47),

a.nd the naphthalyl (Eqn 48) and larger ring aryl alcohols. 42

48.

ThP. o<-hydrogens on any of the above alcohols can be · replaced by aryl groups; a factor which greatly expands the utility of this reaction.

EX PER H1EN'T'A L Hexamethylphosphoric triamide (HMPT) and all other reagent.s not specifically described belmv were commercially

available and vrere used without further purification. Melting points were determined on a Fisher-Johns apparatus and are corrected. Infrared spectra were recorded on a Perkin-Elmer Hodel 337 spectrophotometer. Nmr spectra were taken on a Jeolco model C-60 spectrometer with TMS as internal standard.

The I~eaction of Benzyl A.lcohol ~H th HMPT Benzyl alcohol (10.8 g, 0.1 mol) and HMPT (65 ml) were mixed and i:he solution refluxed for 45 min. At the end of the reflux period the reaction mixture was cooled to room temperature, taken up in ether, and washed three times with 43 brine. The ethereal solution was extracted with 3N hydrochloric acid and the aqueous acid extract was "tvashed 'tvith ether and then made distinctly basic >vith 3N sodium hydroxide solution. Thj s aqueous mixture was then extracted "tvith ether, the ethereal solution dried over potassium hydroxide pellets, and concentrated (rotary evaporator) to yield

8.0 g {58%) of crude benzyldimethylamine. Distillation gave 0 • 22 0 the pure product, bp 56-59 /0.75 mm {11t. bp 185-186 I

1.0 atm). The picrate was recrystallized from ethanol, 23 mp 94.5-95.5° (lit. mp 96°).

The Reaction Of B~nzhvdrol With HMPT

Benzhydrol (19.2 g, 0.1 mol) and HMPT (65 ml) were mixed, and the solution was refluxed for 30 min. The reaction mixture was cooled and worked up as in the preceding case to yield 9.6 g {46%) of crude benzhydryldi methylamine. The crude product was taken up in hot 60-90° petroleum ether, decolorized with Norit A, and cooled to 24 yield the pure product, mp 67-69° {lit. mp 68.5-70°).

The P~?.!.:-=tion Of Trinhenylca.r-binol \'lith HHPT

Triphenylcarbinol {26.0 g, 0.1 mol) and HHPT {65 ml)

WE~re mixE~d, and the solution refluxed for 30 min. The

reaction mixture was cooled and worked up as before to yield 11.9 g (41.5%) of crude triphenylcarbinyldimethylc:tmine. 4 4

Decolorization with charcoal and recrystallization from 25 60-90° petroleum ether gave pure product, mp 93-95° (lit. mp 95-97°).

The Reaction O-F. p-Hethoxvbe nzyl Alcohol Nith HHP'I'

£-Methoxybenzyl alcohol (13.8 g, 0.1 mol) and HMPT

(65 ml) were mixed, and the solution refluxed for 30 min.

The reaction mixture was cooled and worked up as before to

yield 7.8 g {47%) of crude E-methoxybenzyldimethylamine. 26 Distillation gave pure product, bp 59°/0.75 mm {lit.

bp 109°/13 mm). The hydrochloride was recrystallized from 26 methanol, ~P 151-153° (lit. mp 152°).

The R~action of m-Nitrobenzyl Alcohol With HMPT

m-Nitrobenzyl alcohol (15.3 g, 0.1 mol) and HNPT (65 ml)

were mixed and the solution was refluxed for 30 min. The

reaction was cooled and worked up as before to yield 7.8 g

(31%) of crude m-nitrobenzyldimethylamine. Distillation 27 gave pure product, bp 89-90°/0.75 mm (lit. bp 144°/16 mm). 27 The picrate \vas recrystallized from ethanol, mp 220° (lit.

mp 2170 •

The Heaction Of p-Chlorobenzyl Alcohol Ivith Y.U·1PT

£-Chlorobenzyl alcohol {14.2 g, 0.1 mol) and HMPT

(65 ml) were mixed and the solution refluxed for 45 min. 45

The reaction was cooled and worked up exactly as before to yield 11.5 g ( 68%) of crude E-chlorobenzyldimethylamine.

Distillation gave pure product, bp 47-50°/0.75 rnrn (lit. 28 bp 96-98.5°/14 mm). The picrate was recrystallized from ethanol, rnp 127-128 0 REFERENCES

1. J. Miller, ".Z\ror'!a tic Nucleophilic Substitution,"

Elsevier Publishing Company, Amsterdam, 1968.

2. J. March, ".1\dvanced Organic Chemistry: Reactions,

Mechanisms, and Structure," McGra.iv-Hill Book

Compo.ny, Neiv Yorl<:, N. Y., 196R,

3. 'rhis brief description of the intermediate-complex

mechanism is based on the discussion found in

reference 2, pages 488-491.

4. R. s. Monson, D. N. Priest, ~Org, Chern., 36,

3826 ( 1971).

5. R. s. Henson, Tet.r;she~ron Lett. 567 (1971). 6, R, s. Honson, D. N. Priest, Chern, Commun., 1018

{1971).

7. R. s. t<~onson, D. N. Priest, J. C. Ullrey, Tetrahedron

1ctt. 929 (1972).

8. See reference 2, page 658.

9. See int:roduction section of this paper.

10. The method described in R. _I\ dams, J. R. Johnson,

c. F. \·!ilcox, "Laboratory Experiments in Organic

Chemist.ry," 6th ed., 'rhe MacMillan Co., London, 1970,

p 323 ivas suitably modified for the synthesis of this

material.

11-6 11. See reference 2, page 502.

12. H. Norrnant, Ang§~Chern~_l.nternat. Ed,,£, 1046 (1967).

13. G. s. Hammond, L. R. Parks, J. AmerL-Ch~~Soc., 77, 340 (1955).

14. J. F. Bunnett, J. J. ·Randall, J, Arner. Ch~..!!l_,_Soc., 80,

6020 (1958).

15. See reference 2, page 498,

16. w. c. Spitzer, G, lv. Nheland, J. Arner, Chern, Soc., 62,

2995 ( 1940) •

17. H. H. Bosshard, H. Zollinger, Helv, Cgj~_Act~., 42,

1659 (1959).

18, P, A, S, Smit.h, Tung-Yin Yu, J. Org. Chern,, 17, 1281

(1952).

19. c. J. Pouchert, "The Aldrich Library of Infrared Spectra," Aldrich Chemical Company, Inc., 1970, p 828.

20. E. H. \vhite, c. A, Ellinger, J •.Z\mer, Chern, Soc., 87,

5261 (1965).

21. E. J. Sakellarios, He1_y~im. Acta., 29, 1675 (1946).

22. K, Kindler, Justus Liebigs~AnrJ, Chern, 431, 187 (1923).

23, J, von Braun, M, Kuhn, o. Goll, Chern. Ber., 59, 2330

(1926).

24. H. Sornmelet, Compt, Rend,, 175, 1149 (1922).

25. L, N. Jones, M. ~'I. Seymour, ~mer. Chern, Soc., 50,

1150 (1928).

26, E. Stedman, J. Chern. Soc,, 1902 (1927). 4 8

27. G. M. Bennett, G. H. \'Iillis, J. Chern. Soc., 256 (1929). 28. N. Q. Beard, Jr., c. R. Hauser, J. Org_,__Q.be!!!·• 26, '!. ! 371 (1961). I ~ 29. E. E. Elie1, T. N. Ferdinand, M. c. Herrmann,

J, Org, Chern., 19, 1693 (1954).