March 20, 1960
OXYGEN-18
[COSTRIBUTION E O .
1650 FROM
1-Methoxyvinyl Esters.l
1411
STUDY OF ANHYDRIDE FORMATION
THE STERLING CHEMISTRY
LABORATORY, YALE
UNIVERSITY]
IL2 An Oxygen-18 Study of Anhydride Formation
B Y HARRYH. bvASSERMAN AND
s. uiHARTON3
PETER
RECEIVED JULY 10, 1969 The mechanism of anhydride formation in the reaction of carboxylic acids with alkoxyacetylenes has been studied using 01* labeled benzoic acid and 1-methoxyvinyl benzoate. Anhydride formation is shown to occur via an intermediate orthoester which decomposes intramoleculary. Limitations in t h e use of this reaction for the formation of unsymmetrical anhydrides are discussed.
The reaction of alkoxyacetylenes with carboxylic acids under mild conditions has been found4 t o lead smoothly t o the corresponding anhydrides in good yield. We have recently shown, using methoxyacetylene, that this procedure may be controlled so ;LS t o permit isolation of the intermediate l-methoxyvinyl esters.1,2 The present report is concerned with the reaction of 1-methoxyvinyl benzoate, (I, R = CsHs) with Ols-labeled benzoic acid. This study is of interest in connection with the mechanism of the alkoxyvinyl ester-anhydride conversion, and, as will be shown below, discloses limitations in the use of the reaction of I with carboxylic acids for the preparation of unsymmetrical anhydrides. Two paths, A and B, may be considered for the conversion of the intermediate I to the anhydride 111. Path A represents a direct intermolecular RiCOOH
+ HC=COCHa
--+
OCHg HZC=C
(ocn,
I H3C-C -
o=c-0 I R2
T,OCH~
O
CH,('OOCH, rzco,--o- COR: 111 +
;'O
i ,
-C=O
.4
_.t
t
R, Ia C
5,.,0 cH
3
I1
acylation similar to that postulated for the formation of anhydrides from the reaction of acids with ~arbodiimides.~ In path B, previously suggested, 4b the orthoester I1 decomposes by way of a cyclic intramolecular transition state. (1) For a preliminary communication on this subject, see H. H. Wasserman a n d P. S. W h a r t o n , Tetuahedron, 3, 321 (1958). T h i s paper is abstracted f r o m t h e Doctoral Dissertation of P. S. W h a r t o n , submitted t o t h e Graduate School of Yale University in partial fulfillment of t h e requirements for t h e degree of Doctor of Philosophy, June, 1959. (2) Paper I in this series, H. H. Wasserman a n d P. S. Wharton, THIS JOURNAL, in press. (3) Procter a n d Gamble Fellow, 1057-1938. (4) (a) J. F. Arens and P. hlodderman, Proc. Koninkl. N e d . A k a d . Welenscha$., 63, 1163 (1950); C. A . , 45, 6152 (1951); (b) G. Eglinton, E. R. H. Jones, B. L. Shaw a n d 112. C. Whiting, J . C h r m . SOL.,1860 (1954). ( 5 ) H. G. K h o r a n a , Chrin. Reps., 63, 145 (1953). N o t e also t h a t F. Cramer a n d K.-G. Gartner, Be?., 91. 704 (1959), suggest a n analtigous direct acylation of an ethoxyvinyl phosphate ester t o form the mired phosphoric-carboxylic acid anhydride, v i s . (see formulas )
-
One should be able to distinguish between these two reaction paths by allowing I to react with a carboxylic acid having isotopically labeled oxygen. Path A would yield methyl acetate containing none of the excess OIs, while path B would result in a distribution of the excess OL8between the anhydride and the methyl acetate. Experimentally, when equimolar amounts of 1methoxyvinyl benzoate and benzoic acid containing 1.06 atom per cent. Excess 0 I 8 per oxygen were mixed at 80°, benzoic anhydride (98%) and methyl acetate (91'%) were isolated. The methyl acetate was converted to N-benzylacetamide, thereby eliminating the one oxygen atom which cannot participate in the reaction and, simultaneously, obtaining a solid derivative. The total atom per cent. excess 0l8 in the benzoic acid (2.12) was recovered in the anhydride and amide (2.1l), thus showing that nothing unusual had occurred in the conversion of methyl acetate t o N-benzylacetamide. The individual analyses for 0l8in the anhydride and amide were virtually identical6 (0.53 and 0.52 atom per cent. excess per oxygen, respectively) and were also equal to one-half of that originally present in the benzoic acid. The above results are those expected for anhydride formation exclusively by path B. (Had path A alone been involved, the anhydride would have contained all of the excess 01*,or 0.71 atom per cent. per oxygen.) I t is, however, conceivable t h a t complete exchange of the benzoyloxy groups of l-methoxyvinyl benzoate and labeled benzoic acid may have occurred during the reaction, e.g., via reversible decomposition of 11, R1 = Rz = CsH6. In this event, all mechanistic paths leading to I11 would be indistinguishable by the isotope experiment. Conclusive evidence that com$dete exchange did not take place was provided from the reaction, also a t 80°, of an excess of 1-methoxyvinyl benzoate (4 moles) with a sample of the same 0l8labeled benzoic acid (1 mole). The methyl acetate reOR (C,H,O),P-O -C-C,
R'
0
l i p + 1-
:e AcO
,i
/ --j.
? +
(C2HSO)gPOAc
R"
: R
CHCOOR
( G ) Using an appropriate procedure, however, t h e analyses obtained f r o m t h e experiments r u n a t 80' were shown t o differ by a small b u t definite a m o u n t , 0.010. Neglecting a n y isotope effect, this difference could be due t o (a) exchange of 2 % of t h e reacting acid with the forming anhydride, or (b) occurrence of 2Y0 of anhydride formation b y p a t h A.
covered was converted to K -benzylacetamide which was found to contain 0.43 atom per cent. excess 0 I 8 . Although the exchange which occurred in this reaction was appreciable, almost onethird of that possible (involving cu. 20yGof the labeled acid), it was not complete,' thus ruling out the possibility that the OLEresults may have arisen from a combination of complete exchange and path A. P a t h B, then, represents the favored Further information about the mechanism of anhydride formation can be derived from the experiment in which an excess of methoxyvinyl benzoate was used in the reaction with labeled benzoic acid. The exchange which was observed cannot be due t o acid-anhydride interchange. I t is. therefore, likely that it occurs by the elimination of either of the equivalent benzoate residues from the orthoester TI, R = CBHj,a possibilitv which is significant in connection with the possible utilization of 1-methoxyvinyl esters as reactive intermediates in the preparation of unsymmetrical anhydrides. I t would appear that unsymmetrical anhydrides derived from two similar acids of the same strength cannot be prepared quantitatively from the reaction of 1-methoxyvinyl esters with carboxylic acids. Exchange of the acid residues would be expected in such cases, with the forination of substantial amounts of symmetrical mhydrides. However, in seeking to prepare unsymmetrical anhydrides where the acids involved are of different strengths, one would expect that the elimination of the stronger acid from the orthoester I1 would occm preferentially. Thus, it may well be possible to prepare the unsymmetrical anhydrides in almost quantitative yield (with little or no contamination), by adding the strongcr acid to the l-niethoxyvinyl ester prepared from the weaker acid. Sonic cxperirnental confirmation of this hypothesis was obtained from the spectral obset vations that negligible amounts of symmetrical anhydrides contaminated the unsymmetrical anhydrides formed in the reactions of 1-mcthoxyinyl acetate with trichloroacetic and formic acids. In the latter reaction, 0.5';; of acetic anhydride would have been detected in the infrared spectruiii of the rcaction mixture.'O experimental"^ Benzoic Acid-O'*.-Two saniplcs of the w i d wcrc user! , I 3 Oxygen-18 analysisi4 of samplc iz: 1.261,
m.p. 122-123'.
( 7 ) Por completc exchange otic would expect a valne oi 0.21; fur no exchange, a value of 0 . X at,,m per cent excess 0 ' 8 . (S) T h e 0 1 8 experinicnts were repeated a t 22' !villi almost the same result.; as those obtained f r < , mthe runs a t SOn. indicating t h a t tcmperat!irc has little eBect on the coiirse of tlie reaction. (9) T h e e r t c n t of exchange due to acid-anhydride inlerchnnxe rannot have been greater than in the experir e n t usiiix erpiimiilar amounts of reaclants I v h e r c i t w a s shown t o be 470 (rcf. ci), This figure is much smaller than the (10) Although i t is possible t h a t acetic trichloroacetic anhydride might have resulted from an initial mixture of anhydrides i c f J . h l . Tedder. Chem. R ~ z I s65, , , 787 ( I S X ) ) , formic acetic anhydride must have arisen directly, since iormic anhydride is not korvn tu exist. . h e latter were deter(11) All b.p.'s and m.p.'s are ~ ~ n c o r r e c t e d T mined in soft glacs capillary tubes in a Hershherg a l i p x a t u s . (12) Infrared spectra were recorded o n a Perkin-Elmer model 21 spectrophotometer. (13) T h e acid was kindly supplied b y Prof. W. vcm II Doering ( 1 4 ) By the method of W. von E. Doering and E. Dorfman. T H I Y J L ~ I I R X A L ,76, 5Jg5 (19.53).
1.260, 1.268 aiid 1.23'3 atoin per cent. 0 1 *per oxygen; mean value, l.2fcj. Sample B: 1.293 and 1.303 atom per cent. 01* per oxygen: mean value, 1.30. 1-Methoxyvinyl benzoate was prepared as previously tlescribed;2 b.p. 95-96" (0.5 m m . ) , Z ~ 1.5181. ~ D The benzoic anhydride content of the distillate was determined :is than (l.lyG by electroinetric titration of 897 mg. ( 5 mmt iti 20 nil. of a 1 : I mixture of pyridine and water. amount of base cvnsurned was 0.05 ml. of 0.129 'V sodium hydroxide, equivalent to 0 . 7 mg. of benzoic anhydride. .i blank showed a negligible correction. T h e method of determining anhydride iu this system was checked by adding 12 trig. (0.106 nieq./ of autlientic anhydride t o the aqueous pyridine solution. Iii the subsequent titration, 0.87 nil. of 0.129 S base (0.112 nieq.) was cotisunied. Reaction of Equimolar Amounts of Benzoic Acid-O1*and 1-Methoxyvinyl Benzoate .-Benzoic acid-OI8 (sample A , 1.187 g., !2.18 mmoles) and 2.173 g, (12.20 mmoles) of 1 iiiethoxyvinyl benzoate irere mixed in a sniiill flask which ivas connected to a liquid nitrogen trap. The flask WIS placer1 in an oil-bath a t 80" and the solution stirred (mag. iieticdly) for 20 minutes. After cooling the flask in iceii-xter, the system w:ts evacuated to 1 inni. and the flask irariiied t o tS.5-40° for 13 minutes. T h e residue (pale yellow j i w s seeded with authentic benzoic anhydride arid left for i j hours a t 1 i r i r r i . to give 2.170 g . (OSC;l,) o f benzoic anhydride, m.p. 42-45,", ni'tiiily 44-45', Crystallization a t 5" from a mixture of 1.3 nil. of benzene and 3.0 ml. of pentaiic raised the m.p. t o 4t5.2--!t5.7n. T h e methyl acetate which had collected in the liqiiitl nitrogen trap. was transferred t o it small flask by racuum-line technique; yield 825 mg. (91%), p . p . 55', n 2 h 1.3610. I t wits further characterized ( a ) by its infrrtred spectrum, wliicli showed (neat, 0.25-111111. cell 1 resence of less than O . l ~of c benzoic acid and l-mcthn y l benzoate, both of which absorb strongly a t 14.02 p ; b ) by gas chroiii:itc,gr;ip}iy,which a130 showed the coinpletc absence of o:her v~ilatile cr~rnpotie~its. For OiR iinal>,sis, t h e methyl acctate was converted t o S-benzylacetamide by heating it in ;I sealed tube with slightly less than the requisite arnoiu!t o f freshly distilled benzylamine, b.p. 181-182°. fZ')'D 1.541;3, for ?I t o 6 hours ;it 140". Renioval r)f volatiles frciiii tlie colorless product g;tve ??-benzylacetamide, 1n.p. 62--68". Crystallization at 5" from ether containing 2 - 3 5 ethanol raised the m . p . to 61.c5-63.30. Benzriic 0.7:30, (i.723, 0.724 atom per ceiit. 0 ' 8 per oxygeii; me;in value, 0.73. S-Betizyl~~cctamitle:'" 0.712, 0.716, 0,718; inenti v;tluc, 0.72. Four more runi. three a t 80" a r i d mic :it 22' ( 2 4 l i r , ) , were c:trried out witli almost idciiticul rest111i. Reaction of Benzoic Acid-Ois with Excess I-Methoxyvinyl Benzoate.-The general procedure tlescribvd for the reactioii of equimolar :mounts o f the two rcageiits W;!S followed. A mixture of 1.ABS g . (13.63 mrnoles) of brnzoic acid-Ol*, sample .'Iant1 . 9.7% g. (64.70 mirlolcs) o f 1nictlioxyvinyl bcnzoiite was heatcd and stirred a t 80' for 20 minutes. The inethyl acetate which had formed was COIIccteti in the liquid nitrogen tr:cp a t 1 mni. and 35' and thmi trailsferred to :I small flask :it 20 m m . : t i i d 50'; yield 520 m g . (.51(>;), tI2% 1.:j(j(W. Tlie infrared spectrum showed that the distillate cotit:iinetI less than (1.lC506of benzoic acid and 1 .rricthoxyviiiyl benzoate. S-Berizyi:icet:~mide:0.632, ().fj,'
