In continuing efforts to learn more about keto-enol equilibrium of carboxylic acids, several ways to stabilize the enol were found. Most of the known acid enols are analogs of fulvenediol (1), stabilized by pseudoaromatic conjugation, some others are sterically protected enols (2) with bulky aromatic substituents preventing protonation on [[beta]]-carbon atom, and an enol (3) with the strongly electron-withdrawing cyano-group reducing the rate of electrophylic attack on the double bond of the enol.
In an attempt to a find new class of relatively stable enols, we decided to investigate hydration of [[alpha]]-oxoketenes. The ene-1,1-diol formed in this reaction contains a carbonyl group at [[beta]]-carbon, which may enhance the stability of enol by reducing the electron density of the enol double bond. Thus [[beta]]-carboxy and [[beta]]-carbomethoxy substituents reduce the rate of vinyl ether hydrolysis by three to four orders of magnitude. Formation of an intramolecular hydrogen bond between hydroxy group of enol and carbonyl substituent may also stabilize the enediol.
Photolysis of diazo Meldrum's acid (4), which we chose as a precursor of an [[alpha]]-oxoketene, in the presence of water gives a good yield of Wolff rearrangement product, [[alpha]]-oxoacid. Our interest in this particular diazo compound came also from the fact that the isomeric diazirine (5) (6,6-dimethyl-4,8-dioxo-5,7-dioxa-1,2-diazaspiro[2.5]oct-1-ene) is readily available7 and we were able to compare the photochemistry of both isomers directly.
The flash photolysis systems used in this study provide intensive light pulses of very short duration, allowing us to observe short-lived intermediates with time-resolved UV-spectroscopy. The flash photolysis technique also prevents secondary photochemistry and protects reaction products from photodecomposition.
Results and discussion.
Flash photolysis of diazo Meldrum's acid (4) in aqueous solutions provides a high yield of Wolff Rearrangement product, 2,2-dimethyl-5-oxo-1,3-dioxolane-4-carboxylic acid (6), with diazirine (5) and parent dicarbonyl compound (7) as minor products. We also observed the formation of some unstable material which rapidly hydrolyzed in aqueous solutions to give tartramic acid (8). [[alpha]]-Oxoacid (6), which can also be hydrolyzed to give (8), is relatively stable under the conditions used, and, most probably, this unstable compound (9) is the product of water addition to the dicarbonylcarbene (10).
Flash photolysis of diazirine (5) led to formation of the same products. However reverse isomerization of diazirine (5) into diazo (4) didn't occur photochemically, while thermally it readily happens.
The main process in the photolysis of isomeric diazo (4) and diazirine (5) is a Wolff Rearrangement leading to the carboxylic acid (6). This fact, plus formation of the same mixture of minor products shows that loss of nitrogen from both species leads to formation of the same intermediate, most probably dicarbonylcarbene (10), which then rearranges or reacts with water. Carbenes are well-known to react very rapidly, and the low yield of "carbenic" products (7) and (9) indicates that this carbene has a very short life-time. Excited molecules of diazo Meldrum's acid may also lose energy by isomerization into the diazirine.
Photolysis of diazo compound (4) in oxygen-18-labeled water gives an [[alpha]]-oxoacid (6) with one labeled oxygen in the carboxyl group as the main product, plus a small amount of carboxylic acid containing two oxygen-18 atoms in its carboxyl group (about 3%). Formation of the latter indicates that addition of water to the [[alpha]]-oxoketene (11) is reversible, although the enol dehydration is much slower than the ketonization leading to [[alpha]]-oxoacid.
Time-resolved UV-spectroscopy allowed us to detect two successively formed transient species in the course of Wolff Rearrangement of both compounds (4) and (5). The rate of decay of first transient didn't change in the pH range 1 to 9, and it also showed no substantial buffer catalysis. These features are characteristic of ketene hydration. The rate of decay of the second transient, apparently the carboxylic acid enol (12), depends strongly on the pH of the solution as well as on buffer concentration.
Hydration of ketene (11) Ketonization of enol (12)
The rate of enol ketonization was measured in perchloric acid and sodium hydroxide solutions, as well as in buffers. Ketonization of enol (12) showed strong buffer catalysis. To separate buffer- and hydronium-ion catalysis, we measured the rate of reaction in a series of buffer solutions with variable buffer concentration, but constant buffer ratio, and extrapolated those rates to zero buffer concentration. Comparison of the slopes of buffer dilution plots obtained from buffers with different buffer ratios showed that buffer catalysis was of the general acid type.
The pH rate profile, constructed from these data (Fig.1) has a typical V-shape, indicating that ketonization of carboxylic acid enol (12) may occur via two mechanisms. The left wing of the profile represents hydronium ion catalysis, which becomes saturated below pH 1, while the right wing shows hydroxide ion catalysis, which reaches saturation above pH 9. This saturation of catalysis is usually called "substrate titration", and it indicates that acid-base equilibria of the substrate are involved in determining reaction rates. This provides a method of calculating both pQa's[*] of an enol.
Fig.1. Rate profile for the ketonization of 12 in aqueous solutions at 25oC.
Hydration of the ketene (11) probably produces two isomeric enols (12a and 12b) of [[alpha]]-oxoacid (6). Proton transfer between the two oxygens bound by a hydrogen bond in enol (12) will be extremely fast and it is consequently very difficult to distinguish between these two structures. Ionization of these enols gives an equilibrium mixture of two enolates (13a and 13b), which may be further deprotonated to give dianion (14), as shown on Scheme 1.
A reasonable mechanism which accommodates the data measured in perchloric acid solutions (pH 0-4) is hydronium-ion protonation on carbon of the enolate ion (13), Scheme 1. When the H+ concentration is much lower than Qa, the equilibrium between enol (12) and enolate ion (13) is shifted towards enolate ion and the rate is proportional to H+ concentration. On the other hand, when H+ concentration is much greater than Qa, the enolate ion (13) concentration is inversely proportional to hydronium ion concentration and the rate becomes independent of the pH of the solution. Rates of ketonization of the enol (12) were measured in the solutions of deutero-perchloric acid in the range of concentrations from 0.0001 to 0.6 M. The solvent isotope effect of k'H+ / k'D+ = 2.24 obtained by comparison of these data with rates measured in H2O, clearly shows that proton transfer occurred in the rate determining step of ketonization. The general acid catalysis mentioned above provides additional support for this mechanism.
The saturation of hydroxide ion catalysis above pH= 9 suggests that reaction in the pH range from 6.5 to 14 takes place via protonation of the dianion of the enol (14) with water (Scheme 1). The concentration of dianion (14) is proportional to hydroxide ion concentration when [H+] is above Q'a , and so is the rate. When the concentration of hydronium ion is below Q'a all of the enol exists in dianion form and the reaction rate is pH independent. The solvent isotope effect, measured in the basic plateau region (k"o(H2O) / k"o(D2O) = 9.08) is consistent with rate determining proton transfer. It has an unusually high value, because the primary isotope effect is amplified by a secondary solvent isotope effect acting in the same direction.
These two mechanisms may be described by the two-term rate law shown in eq. (1). This expression, represented by the dashed line in Fig.(1), fits all of the data well except for a few points at the very bottom of the rate profile. The fit may be improved by adding a constant term, as shown in eq. (2), which could represent an uncatlyzed reaction of enolate ion (13) with water.
The latter equation is represented by solid line in Fig. (1). Parameters obtained from this fit are shown in Table 1. Enol (12) is rather acidic, with the pKa of 1.65; the solvent isotope effect on ionization constant (QHa / QDa = 1.75) is lower than for most carboxylic acids, but it is quite reasonable for such a strong acid. The second ionization constant is also close to the values reported for other carboxylic acid enols.3,5 Similarity in behavior of enol (12) with other enols of carboxylic acids allows us to suggest that the ene-1,1-diol form (12a and 13a) prevails in equilibria and determines the reactivity of this enol.
* Obtained by applying activity coefficients, recomended by Bates.
Diazo Meldrum's acid may photochemically isomerize into diazirine, but the reverse isomerization occurs only thermally.
Photolysis of both diazo compound and diazirine gives a high yield of Wolff rearrangement product, [[alpha]]-oxoketene, which reacts reversibly with water to give a relatively stable enol. The latter ketonizes to the ultimate product - [[alpha]]-oxocarboxylic acid. Ketonization occurs via [[beta]]-carbon protonation of enolate ion by hydronium ion or water, and by [[beta]]-carbon protonation of enolate dianion by water.
Diazo Meldrum's acid (4) was prepared by a modified diazo-transfer reaction from the Meldrum's acid (Aldrich) and was purified by recrystallization from ethanol. M.p. 94.5-96oC.
6,6-Dimethyl-4,8-dioxo-5,7-dioxa-1,2-diazaspiro[2.5]oct-1-ene (diazirino Meldrum's acid 5) was prepared by irradiating for 1.5 h a THF : Water (10:1) solution of 200 mg of 4 using a high-pressure mercury lamp with cut-off pyrex filter. The THF was then removed slowly under vacuum at 00C and colorless crystals of (5) precipitated from water. These crystals were washed with water and dried in a desiccator. This gave 58 mg of 5, m.p. 84.5-860C.
Product Studies were carried out by HPLC analysis (Varian Vista 5500 instrument with NovoPak C18 column).
All kinetic measurements were made at 25.0 +/- 0.05 0C, and the ionic strength of the solutions was kept at 0.1 M by addition of sodium perchlorate, with the exception of perchloric acid solutions with concentration above 0.1 M where the ionic strength was equal to the perchloric acid concentration.
We are grateful to the Natural Science and Engineering Research Council of Canada and the United States National Institutes of Health for financial support of this work.
1. See, for example: Rappoport Z., Ed. The Chemistry of Enols, Wiley, N.Y. 1990; Kresge,A.J. Acc.Chem.Res., 1990, 23, 43.
2. Guthrie,J.P. Can.J.Chem., 1993, 71, 2123.
3. Urwyler,B.; Wirz,J. Angew.Chem.Int.Ed.Engl. 1990, 29, 790; Almstead, J.K.; Urwyler,B.; Wirz J. J.Am.Chem.Soc., 1994, 116, 954; Andraos,J.; Chiang,Y.; Huang,G.C.; Kresge, A.J.; Scaiano,J.C. J.Am.Chem.Soc., 1993, 115, 10605; Andraos, J.; Kresge, A.J.; Popik,V.V. J.Am.Chem.Soc., 1994, 116, 961-967; Andraos,J. Ph.D. Thesis, Universiy of Toronto, 1992
4. a) Allen, B.M.; Hegarty,A.F.; O'Neil,P.; Nguyen,M.T. J.Chem.Soc. Perkin Trans. 2, 1992, 927; b) Frey, J.; Rappoport.,Z. J.Am.Chem.Soc., 1995, 117, 1161
5. Andraos,J.; Chiang,Y.; Kresge, A.J.; Pojarlieff,I.G.; Schepp,N.P.; Wirz,J. J.Am.Chem.Soc., 1994, 116, 73.
6. Kresge, A.J.; Ubysz,D. J.Phys.Org.Chem., 1994, 32, 316.
7. Nikolaev,V.A.; Khimich,N.N.; Korobitsyna,I.K. Heterocyclic Chem. of USSR, 1985, 321.
8. We used two flash photolysis machines, one had Xe flash-tubes, which give an intensive "white" light pulse with about 20 us duration, second had a KrF eximer laser, providing 20 ns pulses at 248 nm. They are described in: Chiang,Y.; Hojatti,M.; Keefe,J.R.; Kresge,A.J.; Schepp,N.P.; Wirz,J J.Am.Chem.Soc., 1987, 109, 4000; Andraos,J.; Chiang,Y.; Huang,G.C.; Kresge, A.J.; Scaiano,J.C. J.Am.Chem.Soc., 1993, 115, 10605.
9. Prof.Z.Rappoport suggested that ketene reaction with water might be reversible on the basis of his experiments on diarylketene hydration in oxygen-18 labeled water.4b
10. Loudon,C.M. J.Chem.Ed., 1991, 68, 973.
11. Bates,R.G. Determination of pH Theory and Practice; Wiley: New York, 1973, p. 49.
12. Popic,V.V.; Korneev,S.M.; Nikolaev,V.A.; Korobitsyna,I.K. Synthesis, 1991, 195-198.