R 4 N N R 1 H O R 2 R 3 EtO 2 C NR 1 NR 2 O O R 4 R 3 1 2 3 4 5 1 2 3 4 5 0-MUE 1-MUE 2-MUE 3-MUE 1-PUE 3-PUE H Me Me Me Me Me H H Me Me H Me H H H Me H Me R 2 R 3 R 4 MUE, R 1 = Me PUE, R 1 = Ph MH, R 1 = Me PH, R 1 = Ph R N O R 1 H R N – O R 1 R N O Me H α R N O Me + OH – + H 2 O k OH k d + OH – k α H β k β 220 J. CHEM. RESEARCH (S), 1997 J. Chem. Research (S), 1997, 220–221† NH-Acidities of Some Sterically Hindered Ureas† Ivan G. Pojarlieff,* a Iva B. Blagoeva, a Anthony J. Kirby, b Bozhana P. Mikhova a and Ergun Atay‡ a a Institute of Organic Chemistry, Centre of Phytochemistry, Bulgarian Academy of Sciences, ul. Acad. G. Bonchev block 9, 1113 Sofia, Bulgaria b University of Chemical Laboratory, Lensfield Road, Cambridge CB2 1EW, UK Introduction of an N-methyl group in to ethyl N-methylhydantoate causes a fourfold decrease in the rate of base-catalysed exchange of the N-H proton; a second methyl group restores the rate to close to that of the N-unsubstituted hydantoate; the latter effect is observed for N-phenylhydantoates. Proton exchange in amides and ureas is of continuing interest to biochemistry. 1 The introduction of methyl groups into compounds 0–3, shown below, leads to unusual reactivities towards base-catalysed cyclization in the most heavily substi- tuted esters 3: these include both a change of mechanism and the loss of the acceleration due to the gem-dimethyl effect. 2 This prompted a study of the NH-acidity of these compounds as a measure of the nucleophilicity of the ureido groups in this series of ureidoesters. Rates of base-catalysed hydrogen exchange were measured by means of dynamic NMR. The collapse of the methyl doublet due to the NH–CH 3 coupling in the -methyl hydan- toates and the broadening of the NH peak of the -phenyl esters with changing pH were monitored in buffers. These exchange phenomena are due to the processes shown in Scheme 1. Pseudo-first-order rates of hydrogen exchange, k exch , were obtained as described in the Experimental section. In the pH region where exchange phenomena could be observed, spectra had to be recorded rapidly as cyclization to hydantoin is a competing reaction. To calculate the second-order rates, k OH = k exch /a OH , a OH was taken as antilog (pH 14), where pH is the glass-electrode value measured in the buffer containing the correct amount of acetonitrile. The acidity constant was obtained as K NH = k OH k d K w with k d , the diffusion-controlled rate for the protonation of the ureide anion, being taken as 10 10 dm 3 s 1 mol 1 and K w , the ionic product of water, as 10 14 . Because of poor solu- bility, spectra had to be run in 5:1 (v/v) water–acetonitrile. In this solvent mixture pK w is little different from that of pure water [14.33 in 20% (w/w) MeCN at 25 °C] 3 and, in view of the remaining uncertainties, refinements were considered unwarranted. 3-PUE is still less soluble and 50% aqueous MeCN was used. In this medium pK w differs considerably 3 from 14 and the respective pK values were calculated as above only for the sake of comparison. As far as the ring-closure reaction is concerned, the results in Table 1 show that differences in reactivity between com- pounds 1 and 3, in both the MUE and PUE series, cannot be attributed to the different basicity of the ureide anions. 2-MUE, with one methyl group at the 2 position, is con- siderably less acidic than 1-MUE, with no methyl group. This is not likely to be simply an inductive effect; in a Z-conforma- tion on the ester side of the urea molecule, an extra methyl group can be expected to hinder the solvation of the nega- tively charged oxygen in the anion. The reversal of this trend in compounds 3 is most likely due to a steric effect: strain relieved by twisting the dialkylamino group out-of-plane diminishing amide conjugation. This should make the NH proton more acidic because of increased conjugation within the secondary amide group. Strong acidifying effects upon N-methyl substitution of secondary acylureas have been observed. 4 The less heavily substituted ethyl hydantoates have been prepared by Kav´ alek and S  t´ erba. 5 Esters 2 and 3, however, cyclized rapidly in the presence of moisture and had to be prepared under strictly anhydrous conditions, as described in the Experimental section. Experimental Melting points are uncorrected. 1 H NMR spectra were recorded on a Bruker WM-250 instrument. pH Values were measured with a Radiometer pH M 84 Research pH-meter using a GK 2401 C electrode. Materials. Inorganic reagents and buffer components were of analytical-reagent grade and used without further purification. Buffer solutions were prepared with CO 2 -free water, to 0.03 M total *To receive any correspondence (e-mail: ipojarli@gate.orgchm. acad.bg). †This is a Short Paper as defined in the Instructions for Authors, Section 5.0 [see J. Chem. Research (S), 1997, Issue 1]; there is there- fore no corresponding material in J. Chem. Research (M). ‡Formerly Denis T. Tashev of ref. 2. Scheme 1 Table 1 Rates of base-catalysed hydrogen exchange in ethyl hydantoates and pK NH estimates in 5:1 (v/v) water–acetonitrile at 19 °C Compound pH k exch /s 1 k OH /dm 3 s 1 mol 1 pK In 5:1 (v/v) water–acetonitrile 0-MUE a 1-MUE 2-MUE 3-MUE 1-PUE 9.84 9.43 9.84 10.21 10.45 9.43 6.90 7.19 12 4.0 11.5 5.5 11 2.5 6.3 12.2 1.710 5 1.610 5 3.610 4 9.310 4 7.910 7 18.8 18.8 19.45 19.0 16.1 In 1:1 (v/v) water–acetonitrile 1-PUE 3-PUE 7.44 7.44 4.5 5.8 1.610 7 2.110 7 16.8 16.7 a For 3-NH we obtained k OH = 1.310 6 dm 3 s 1 mol 1 , pK = 17.9. Published on 01 January 1997. Downloaded on 23/10/2014 16:44:17. View Article Online / Journal Homepage / Table of Contents for this issue