The efficiency of intramolecular catalysis of amide hydrolysis by the carboxy-group of a series of substituted N-methylmaleamic acids is remarkably sensitive to the pattern of substitution on the carbon-carbon double bond. A single alkyl group increases the rate of hydrolysis by a factor which increases with its size. A second alkyl substituent has a disproportionately larger effect, which is sharply reduced when the two groups are joined together in a ring. The rates of hydrolysis of a series of dialkyl-N-methylmaleamic acids range over more than ten powers of ten, and the ' effective concentration ' of the carboxy-group of the most reactive compound studied is greater than 1 O ~O M . This amide, dimethyl-N-n-propylmaleamic acid, is converted into the more stable dimethylmaleic anhydride with a half-life of less than I s at 39 "C below pH 3. The mechanism of catalysis, and the factors responsible for this extremely high reactivity, are discussed.THE extraordinarily high efficiency of enzymic catalysis depends on a combination of a relatively small number of factors, most of which have been recognised but none of which is well underst0od.l Despite the growing attention being paid to the chemistry of enzyme action it is not impossible that some factor or factors of fundamental importance remain to be identified. This pOSSi-

The highly efficient intramolecular catalysis by the carboxy-group of the hydrolysis of simple dialkylmaleamic acids is itself subject to external general acid catalysis. The kinetic characteristics of the general acid catalysed reaction are those expected for a diffusion-controlled proton transfer. At high concentrations of general acid, external catalysis disappears. This is shown to result from a change in rate-determining step, and is thus evidence for an intermediate on the reaction pathway. The intermediate can only reasonably be a tetrahedral addition intermediate. Kinetic evidence is now available for all the major steps on the reaction pathway, and the requirements for an enzyme catalyst carrying out the reaction can be specified in detail. The full mechanism specifically implicates the O-protonated amide as the reactive species in dilute acid.Smith, University Chemical Laboratory, Cambridge CB2 1 EW THE heart of any enzymic reaction is a highly efficient multiple interaction between substrate and catalytic groups brought close together in the enzyme-substrate complex. We use the reactions between the same groups held close together on the same molecule as models for the enzymic reactions. In most known systems intramolecular catalysis is much less efficient than enzymic catalysis, but it is becoming clear that the rates of at

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A preliminary study 1206. 5821.derivatives of three dialkylmaleic acids (3; R = Me, Pr', or But) and seven alcohols (R'OH) . HXPERIMEKTALThe materials were obtained coiniiiercially or as previously dcscribed.1 Di-isopropylmaleic anhydride was prepared by the method of Eberson and Welinder and di-t-butylmaleic anhydride was a gift from Professor H. G. Viehe.A lkyZ Hydrogen DinZkyZvnnZentes.-These were prepared by dissolving a small weighed amount of sodium in the alcohol concerned, then adding to the resulting solution of alkoxide an equivalent amount of the inaleic anhydride. The anhydride dissolved on swirling, and this solution was generally used directly for kinetic work. This procedure proved satisfactory for all the esters studied, except those derived from prop-2-yn-1-01. For these derivatives the excess of alcohol was evaporated off, and the white solid obtained dried carefully before dissolving in dry dimethyl sulphoxide. The solid showed the i.r. bands expected for a sodium alkyl dialkylmaleatc (ester CEO at 1705, C0,a t 1570 and 1410 cm-l for sodium prop-2-ynyl di-isopropylrnaleate ; 1695, 1580, and 1400 cm-l for sodium methyl dimethylmaleate), but correct elemental analyses could not be obtained for these reactive esters. We have prepared 15-20 sodium alkylmaleates by the technique described : in every case tried we could isolate a solid with the expected i.r. bands,

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