Pothen Varughese Indiana University of Pennsylvania Indiana. Pennsylvania 15701
Quaternary Ammonium Salts Some recent applications in organic synthesis
Most undergraduate organic textbooks give only a passing reference to the unique class of compounds called quaternary ammonium salts. ~ h arekoften ~ referred to merely & the find products of exhaustive alkylation of primary amines. A student may get the erroneous impression that they are of no particular use in chemistry and that, being ionic, they are all soluhle in water. Manv textbooks make unaualified statements about their the;mal stability. In the last ten vears there has been a " ereat uosuree of in. terest in the chemistry of quaternary ammonium salts. As a result, a number of interesting applications of molten quaternary ammonium salts have resulted (1-5). More recently, Starks reported that a small amount of quaternary ammonium salt added to certain two-phase organic reaction mixtures would catalyze these reactions to a remarkable extent (6).This phenomenon of phase-transfer catalysis has spurred considerable study in the United States, Europe, and Japan as evidenced by the large number of papers published in this area during the past four years. Part of the attractiveness of this area of research stems from the fact that it is within the scope and reach of most institutions where undereraduate research in chemistrv is encouraged. No expensive and suphisticated instruments are reauired. and most of the chemirals needed arr relntivelv inexpensive. Quaternary Ammonium Salts Quaternary ammonium salts are compounds of the general formula RaN+X- where R is alkyl, aryl, or aralkyl group and X i s any anion. T h e R groups could be identical or different. These organic salts are ionic compounds which are made from primary, secondary or tertiary amines and an appropriate alkyl halide, sulfate, or some other similar compound carrying an excellent leaving group. Synthesis from a primary amine involves treatment with a n excess of alkyl halide in methanol, acetanitrile, ethyl acetate, or benzene solution in the presence of a mild base. T h e last alkylation step is recognized as the Menshutkin reaction R-NH2 + 3 R-X
-
hC0a
Solvent
RaNtX-
+ H20+ Con+ 2 KX
with a number of nonpolar organic compounds a t certain temperatures (3). Applications Ouaternary Ammonium Salts as Reaction Media
Molten quaternary ammonium salts provide a totally ionic medium relatively free from ion solvation and ion association which would normallv affect the reactivitv of substrates and the rate of reaction. Another great advantage is the ease of separation of nonionic organic products from the ionic solvent medium. 2.4-Dinitrobromohenzene is inert towards silver nitrate or quaternary ammonium nitrate in refluxing acetonitrile. But, it is readily converted by molten tetrahexylammonium nitrate to products derived from 2,4-dinitrophenol which may be isolated in excellent yield (5).
Br I
NO,
OH
OH
NO, 86 %
6%
A chemical reaction between carbon tetrachloride and silver nitrate in molten tetrapentylammonium nitrate was reported by Gordon and Varughese to produce a nitrating agent which was capable of reacting with tertiary aliphatic amines to produce N-nitrosamines (10). Damico found that same tetraalkylammonium tetraalkylborides have low melting points and were relatively stable in air (11). Ford and coworkers have described the synthesis and potential uses of some low-melting tetraalkylammonium tetraalkylborides (12). These molten salts were found to be stable to light and heat in sealed tubes. They decomposed in air and were not very soluble in water and aliphatic hydrocarbons, but were miscible in all proportions with many organic solvents. Reagent for Mesylation Methanesulfonylammonium salts, CH$02NfRsX-, react under very mild conditions with amines and alcohols to give the corresponding methanesulfonamides or mesylate esters in high yield (13).
Reflux
Many of these salts are crystalline solids a t room temperature and are stable a t their melting points for short periods of time. Low-melting salts may not&ystallize easily at room temperature and a few salts are liquids a t laboratory temperature (6-9). Their melting points depend on molecular weight, symmetry of the cation, and the nature of the anion. Thermal stability is related to the nucleophilicity of the anion. Strongly nucleophilic anions promote reverse Menschutkin reaction. Elimination nroducts will also he obtained if the tertiary amine formed in the reverse Menschutkin reaction is not promptly removed from the reaction mixture. Hygroscopic properties vary in poorly defined fashion. Low-molecular weight salts up to Cs-salts are highly soluble in water, but beyond that the solubility in water decreases r a ~ i d l v However, . incor~orationof ether linkages in one or more of the a ~ k ~ l ' ~ r otends u G to increase thesolubility in water remarkably. Quaternary ammonium salts are generally highly soluble in a variety of polar organic solvents. One can design quaternary ammonium salts which are also miscible 666 / Journal of Chemical Education
Catalyfic Hydrogenation
Tetraethylammonium salts of trichlorogermanate(1-) and trichlorostannate(1-) ions have relatively low melting points and are stahle in the absence of oxygen at 150-200' for long periods of time. These melts are reasonably goad solvents for alkenes. They also dissolve chlorides of all group VlIl metals to give deeply colored solutions. These molten quaternary ammonium salts dissolve up to 7%
PtClz to give deep red solutions which catalyze the hydrogenation, isomerization, hydroformylation, and carhoalkylation of alkenes (14). Micellar Catalysis Quaternary ammonium salts containing at least one alkyl group of chain length CIZor more farm cationic micelles in aqueous solutions when the concentration is above the critical miceller concentration of salt. Ionic micelles contain 10-100 monomers. The hydrophobic hydrocarbon chains aggregate to form the core of the micelle while the hvdranhilic head .. erouos locate themselves at the micelle water inwrtice '?he small r*,untcr ions are Icawd in the outer regim irf the mirplle and may even he a iew angstromvvuwide the mirellp surface. T ~ P Siunic P miceIIe~have rxrellent caralytlr properties in many organic reactions, especially suhstitution and elimination reactions. Roblot, Meyer, and Viout studied the effect of cationic mieelles of CE,H~N+(CH~). (CH20H)2Br-, and CI~HS~N+(CH&BIon the rate and OHof E2 elimination reaction between X-CsHd-CHzCHrY to from X-CsH4-CH=CH2 where X = CH30-4, H, CI-4, Br-3 and Y = Br, I. Hammett correlations between the suhstituent effect and the rate and analysis of the deuterium isotope effect gave substantial information on the transition state of the reaction (15). The interactions between the organic suhstrate and the hydrophobic and the hydrophilic parts of the cationic micelle are responsible for the rate enhancements or inhibitions shown by these micelles on organic reactions. More precisely, the rate enhancement or inhibition of organic reactions in micellar solutions arises from the different rates of reaction of the suhstrate in the micellar ohase and in rhc hulk wlutiun and the relative mmntrationsot thesubstrdtri~. thrip two ~ ~ R S (Ia~ltmc P C . micclles are expected to accelerate the raw uf reactwn of nucleophilic aniow wirh uncharged substmtes. In many instances micellar catalysis shows substrate specificity and resembles enzyme catalysis in obeying Michaelis-Menten kinetics (16). Tahushi, Kuroda, and Kita have shown that N-methyl-N-lauroylhydroxamic acid, CltH23-CO-N(CH3)OH. when used in a hexadecyltrimethylarnmonium bromide micelle in an alkaline solution, exhibited a very large catalytic activity, an activity greater than or close to the activity of the enzyme chymotropsin itself in the hydrolysis of p-nitrophenyl acetate (17). The enhanced catalytic activity of the hydrophobic hydroxamate indicates that the hydroxamate wrapped in a cationic micelle becomes a strong nucleophile because of poor salvation, separation from its counter ion, and its situation in a highly polar environment.
.
~~
.
~~
~
~~
~
~~
Phase-Transfer Catalysis Many organic reactions are carried out in twa-phase solvent systems because one of the essentialreagentsis insoluble in the organic phase but highly soluble in the aqueous phase. Such reactions are often slaw and ineffective because the reagent in the aqueous phase, usually an anion. is hiehlv .. , solvated and is ineaoahle of enterine.. the bulk oreanic phase Escn if a h ~ ~ m ~ y e n n ~ ~ r s s csyctem ~ l v e nicr chosen, [he anion xlll I,P highly sol\~ntedand sumr mloolytic side reaction m l ~ h also t ~ n terferu 181 Such t w - p h a r r organic rrattiuns have hem shown to be greatly catalyzed by trace amounts of quaternary ammonium salts, tetraalkylphosphonium salts and some crown ether camplexed salts, and cryptates (6). A large number of reactions have been conducted in aqueous-organic two-phase systemsin the presence of catalyticamounts ofammonium and phosphonium salts (19). These include carhene generation, nucleophilic substitution, alkylation of ketones and nitriles, Wittig reaction, oxidation of alkenes with KMu04, hydrolysis of esters and alkanesulfonyl chlorides with NaOH, horohydride reduction of ketones, formation of ethers and esters, alkylation of ambident anions, and some condensation reactions. The function of the phase transfer catalyst is to transport one reactant across the interface into the other phase so that reaction can proceed. The reactant in the aqueous phase is an anion which will he transported to the organic phase as an ion pair with the quaternary ammonium or phosphonium cation. The organic phase will thus contain ion pairs and substrate. Even though the cancatration of ion pairs in the organic phase is low, the reactivity of the anion is so high that they rapidly react with the substrate and are thus removed from the organic phase. Immediately, more ion pairs will migrate into the organic phase in order to reestablish the partition equilibrium. Thus the ammonium salt mierates hack and forth between the ohases. All
~. ~
+
~ , i k Y-
I
Aqueous phase
1
* ---- -- -- ------------- ----------- ----+
[R,NY-] ion pair
+
R-X
==+
+
[R,NX-] ion pair
+
R-Y
Organic phase
Quaternary ammonium salts used in phase-transfer catalysis are relativelv unaffected hv. hvdroxvl . . and alkoxv anions in stronelv ~. , hasic media a; temperatures below "O°C 126,. hey wi.1 undergo tlimina. tiun and powbly substitution reactlon xvith strongly hasic and nu. cleuph~lirnniom at high rtmperntures. Huuewr. phasetransfer catalyred reactmu are rnrricd out at temperature.. btluu.'O°C. Examples Displacement Reactions. Nucleophilic displacement reaction by an anionat asaturated carbon is accelerated by phase transfer catalysts. The anions that have heen "activated" by phase transfer are generally hydroxide, cyanide, iodide, bromide, thiocyanate, cyanate (la), phenoxide, naphthoxide, and thiophenoxide (21-22). The leaving groups involved in the system are halides and alkane- and arene-sulfonates. The reaction of coned HCI with primary aliphatic alcohols to form alkyl chlorides and the alkaline hydrolysis of esters transfer catand alkanesulfonyl halides are also catalvzed by. phase . alysts (23). Alkylation Reactions. Tosylmethylisocyanide can be alkylated in high yields by primary alkyl halides under phase transfer conditions to ahtain manoalkyltosylmethylisacyanides. Secondary alkyl groups can also he introduced under these conditions (24). Tosylmethylisocyanides are used to convert Michael acceptors into substituted pyrroles in one single operation (25).
0
CH,Cl,iaq NaOH
+
Bu4NI, -HX
0 R Methylenation of catechols has heen carried out in 80-85% yield under phase transfer catalysis conditions (26). Previously, this reaction required anhydrous conditions and erotic catalysts.
~
organic phase. A scheme for the nucleophilic substitution reaction of Y- with R-X to form R-Y and X- under the phase transfer conditions is given below.
+
CHIBri
OH
aq NaOH Adogen 464 -2HBr
Many organic compounds containing weakly or relatively strongly acidic C-H bonds can he C-alkylated under phase transfer catalysis conditions (18,211. Asymmetric alkylation of cyclic beta-ketoesters or beta-diketones can he effected by means of a c h i d phase transfer catalyst (27).
OH '+
:H,Cl,laq NaOH
R-X
Z
- N-benzyl. N-methvle~hedrinium 0 Bromide II
=
0
II
^
OCH.,, OC,H,, CH,
Alcohols are methylated by dimethyl sulfate in two-phase systems containing 50% aq NaOH using phase transfer catalysts to obtain good yield of ethers (28). On addition of about 1mole %of tetrabutylammonium iodide, alcohols react with dimethyl sulfate to give essentially quantitative yields of methyl ethers. Even saturated primary alcohols and stericallv hindered alcohols react efficientlv to eive mod vields
Volume 54, Number 11, November 1977 / 667
onescan be easily carried out in neutralsolution by neutralizingone eouivalent of acid and one eouivalent of tetrabutvlammonium hvthe r r drugrnwlfnt~wtrh rwu cquiv;denti of aq Sa0H and ho~l~ny rulring mixture uith on dkylaring ~ o c n fclr l IS :Ill inir~12!1, 181 ..llpho-El~rnt,,ot,c,~~ Fwmcrly, zarhvn~gewratwn from rhIon,hrrm and a haw reqwrcd n n h y h u \ cunditiow ro prc%rnthsdrdvb~si r f the inwrnwdiate CCI, . 'l'hc a d d l r ~ mof CHCI ro a mixture d r y cluhexenc ond 2 S r . n ~NaOH cave I N than 5%virld of ?;2-dichlorohieyclo(4.1.0)heptan~.In the presence of 5%qukernary ammonium eatalvst. , . a 6 N vield was obtained (6).I t is found that the dichlororarbrnr yanwared by phase tr;msler reatrim iiercrprionall~rcarrw tuwanl* iuhitratet which wldorn WdCI wrh cmben~\gcnersvd under anhydrous conditions using potassium tert-butoxide and chloroform (18). Single and multiple dichlorocyclopropanations can he carried out unde; phase transfer conditions depending upon the specific reaction condition employed. C1
0
C:,/a4
CH
NaOH
a.'
,
+
CH,C12/aq NaOH TBAI. 20 hr 50"
0 75-85%
R
= H,
CH,, OCH,,
Wittig reactions can he carried out in fair yields by generating phosphorous ylides from nonstabilized phosphonium salts under phase transfer conditions. Since quaternary phosphonium salts themselves are good phase transfer catalysts, there is no need for further addition of ammonium salts (37).
R1-CHO
+
t
/R2
(C6H5),P-CH
\R:'
CH2Cl2 NaOH
aq
& C
Et,NCH>Ph c1CI Moderate yields of insertion products of diehloro- and dihramocarhenes can be obtained under phase transfer conditions. The insertion is very selective and extremely facile at benzylic and tertiary C-H bonds of hydrocarbons and alpha-C-H honds of ethers (30). Insertions into C-S, C-N, and N-H bonds are also known (31,321. CHC1,/50% aq NaOH * R-NHR1 + PhCH>NEt,CI' R'
I
R-N-CHO
where R = C?H,, CH2=CH-CHI,
a% Aliphatic and aromatic amides and thioamides are converted into nitriles in varying yields using carbenes generated under phase transfer conditions (33,34).
0 Alkyl isocyanides can be prepared in good yield if the classical carbylamine reaction is carried out under phase transfer catalysis conditions. Oxidation by KMnOi. Olefins generally react slowly withneutral aq KMnOd at room temperature. However, when a small amount of 5%trihexylmethylammonium chloride dissolved in benzene or toluene is added, the oxidation takes place exothermically and vigorously to produce carboxylic acids or cis-glycols (6,351. Ylide Reactions. Merz and Markl generated a sulfur ylide from trimethylsulfonium iodide and sodium hydroxide in the presence of tetrahutylammonium iodide in the two-phase system CHnClnIwater (36). Benzaldehyde reacts with this sulfur ylide a t 50" forming 2phenyl oxirane in greater than 90% yield in 48 hr. +/CH~ CH,-S
\
ICHa
+
CH,CIxI~qNaOH R-C\
TBAI. 4 8 hr
50°
R
~
> 90%
Oxosulfonium ylides generated under phase transfer conditions react smoothly with alpha, beta-unsaturated aromatic ketones to form cisltrans mixtures of eyelopropane derivatives.
lon-Pair Extraction. It is well known in analytical chemistry and inorganic chemistry that certain ionic compounds can be extracted into the organic phase from aqueous solutions (for general reviews, see references (38-40). Organic primary, secondary, and tertiary amines as well as quaternary ammonium salts have been used efficiently for extracting metal complex anions into organic solvents as ion pairs (38). The extraction increases with increasing molecular weight of the amine and also with solvents of high dielectric eonstant. Specificity of extraction can be achieved through control of variables such as thetetraalkyl group and organic solvent. Ce(1V)is reduced by tertiary amines, but may he extracted with tetrabutylammonium nitrate from nitric acid into nitromethane. Quaternary propyl or butvlammonium nitrate is used to extract uranium and olutonium from nltrate solutions. More recently, Brandstrom has described methods by which amme salts are extracted into organic solvents as ion pairs almost quantitatively. Tetraalkylammonium salts of inorganic acids and weak arganicacids are extracted and obtained in crystalline forms. In the ion pair extraction procedure, equimolar quantities of quaternary ammonium salt and the inorganic salt or organic anion are used. The extracted tetraalkvlammonium salt of oreanic carbon acids can he alkylared w r y riticirntl~in m:nut~susmy d k v l halide-. Thiq prorrdure i . i ~ ~ m m o n l v c o lextrarri\~calkylat~on l~d 1.11. 121. Suppwrtnl: Klr2clrr,l\lra It is a \cry rurnnlon practice Lu use trtraalkylammonium salts as supporting electrolytes in palamgraphic measurements and preparative electrochemical reactions with organic substrates dissolved in aprotic organic solvents (43). Following a critical study of several quaternary ammonium salts as supporting electrolvtes for a wide varietv of electrachemical reactions. House and couorkrrs rccommrndrd rhr use or rrrrabutylammon~umrrtrafluoruburnre 41 t T h r r w r e unshk r u 00mm pure qunternar) ammonium carboxylates, which would be the ideal supporting electrolytes. Dolphin, et al. pointed out that anodic oxidation reactions between tetrafluoroborate and electrochemically generated cations and cation radicals may interfere with the electrochemical reaction under investigation and suggested tetraalkylammonium trifluoromethanesulfonate as an alternative (45). Catalysis by organic ion exchange ('o1ol)rtr b) Ion Kxehon&s resin> ia well dwumentcd !-1ti1.Asrle has summarized a \.ariety uf organic reactions catalyzed by polymeric quaternary ammonium ion exchangers (47).
OFuture Developments T h e lack of data concerning bisquaternary ammonium salts a s catalysts provides great potential for further study. Base catalyzed condensation reactions a n d ionic molecular rearrangements are possible areas of further investigation using suitable phase transfer catalysts. Synthesis a n d purification of low-melting salts have t h e great potential of providing extremely useful molten media for organic reactions. Solvent extraction of anionic complexes of rare metals into ion-association systems m a y he developed a s a good method for purification of such metals.
Acknowledgment
The author wishes to thank Dr. John E. Gordon and Dr. Deanna J. Nelson for reading the entire manuscript and for the valuable suggestions they made. Literature Cited (I) Gordon, J . E., "Tech. Methods Org. Organometal. Chem.," (Editor: Denney, D. 8.1. Marcel Dekker, New York, 1969. pp. 1.51. (2) Dockx, J.. Synthesis, 8.441 11973). (3) Varughose, P.. '"Chemistryin Organic Fused Salta."Ph.D.Theais, Kent State University,
D'lncan, E.. and Viout, P., Tetraherdon, 31,159 (1975).
Herriot, A. W., and Picker, D., J. Amer Chem Soc., 97,2345 (1975). Landini, D..Rolla,F.,ot al.,Synthesis. I, 37 (1974). van Leusen, A.M., Bouma, R. J., and Poml, 0.. Telrodehran Lett., 40,3467 (19751. vanhusen,A. M.,etsl., TeliahodronLeLL., 5337 (1972). Bashall, A. P., and Collins, J. F., Tetrahedron LdL, 40,3489 (1975). Fiaod. J. C., Tetrahedron Lett.. 40,3495 (1975). Mem A A n s e u . C h m l n f a r n a f . Ed.. IZ.846119731. v., L ~ W ~ S S QS.~ o. . , ' ~ ~ i ~ ~ his, & 5341 ~ , (1972). L.A&,'F. Goh.,Swee-Hoek,Chan,Kai-Ch~ng,ctsl.,Ausf. J. Chem., 28 (21,881 (1975) Andrws.G.,and Evsns,O.A., TeLrohedronLalt.. 5121 (1972). Juergen.G.,Fraehlich. I.. and Muehlatsedt,M.,Z. Chem.. 14 (11),434 (1974). Ssrsi.T.,et 81.. Telroh~dronLelf..2121 (1973). Hoflo. G., 2.Naturlorseh. 28 (61,831 (1973). Weher. W. P., and Shephered, J. P., Tdrohedron Lett., 4907 (1972). Mem.A.,and Markl. G..Anble~.Chrm.,Intarnot. Ed., 12.845 (1973). MarkI.G..and Men.A..Svnlhesia. 295 (1973).
C
112) Ford, W.T.,et.al., J. Or8 Cham.. 38.3916(1973). (13) King, J. F.,andduManoir, J.R.. J. Amel Chem. Soc., 97,2566(1975). (14) Psrshal1,G. W., J.Amer Chem Sac., 94,8716(1972). (15) Roblot. G..Mcver. G.. and Viout. P.. Tetrohrdron Left., 2331 (1975). (161 Fendler, J. H., &d Fendlor, E. J., '"Catalysisin Miallar and MaemmoleeularSystems." AcsdemiePress,New York, 1915,Ch. 2. pp. 30.3*Ch.4, pp. 86.102. 1171 T ~ h m h 1.i. Kurnda. Y..and K3ta.S.. Tetmhedrnn Lett.. 8.643 119741.
(40) Marcus, Y..Chem. Re#. 63.139 11963). (41) Brandstrom, A., and Gustavic, K., Acla Chem. Scond.. 23,1215 (1969). (42) Brandstrom. A,, and Junggren. U., Acto Chem. Scand, 23. 2203, 2204, 2536. 3585 (19691. (43) Mann, C. K., "Electroandytical Chemktri." (Editor: Bard, A. J.), M a d Dekker, New York, 1969,uol. 3.pp. 57-134. (44) House,H.O., Fang, E..sndPeet,N. P., J. Org Cham., 38.2371 (1971). 145) R0usseau.K.. Fanineton. G. C..and Dolohin. D.. J. Ore. Chem.. 37.3968 119721.
(I91 Fend1er.J H..and Fendler, E. J., "Cataly~isin Miallsr and M.%mmdec~l81Systems." Academic Press. New York, 1975. pp. 390-409. (20) Freedman, H. H., and Duhois, R. A,, Tmohedion Lett., 38,3251-3254 (1975).
p. 519. 147) Calmon, C., and Kresaman, T. R. E. (Edclors). "Ion Emhaneen in Organicand Biochemistry." Inlerscienee Publishers, Inc., New York, 1957, pp. 662-666.
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