Half amides and imides of cis-cyclohexane-1,2-dicarboxylic acid and cis-4-cyclohexene-1,2-dicarboxylic acid

Abstract

A obsd which by rearranging and squaring results in Equation 11.) where d is the partition coefficient (concentration of iodomethane in liquid per concentration of iodomethane in gas phase), D is the diffusivity of iodomethane in the liquid (square centimeters per second), and the other quantities have already been defined. The partition coefficient of iodomethane between water and air has been determined in this laboratory to be 1.5 a t 50°C. for very dilute solutions of iodomethane. The diffusivity of iodomethane was assumed to be 2.5 x lo-' sq. cm. per second, which is of a correct order-of-magnitude value when compared with the diffusivity of various haloalkanes ( 5 ) .The liquid reaction rate constant which is calculated from the data in Table I1 is proportional to the square of the mole fraction of hydrazine hydrate in the solution (Equation 11 and Figure 2) for the concentration range which was studied. The calculated liquid reaction rate for a 5.1-mole per liter solution-Le., 0.11 mole fraction-is 0.34 second-' which corresponds to a second order rate constant of 0.07 liter moleThe liquid reaction rate constant is estimated to be ca. 0.3 liter mole-' second-' which is a factor of four faster than that calculated by use of Equation 11. (The liquid reaction rate constant has been determined directly in this laboratory to be 0.02 liter mole-' second-' a t 21°C. for 0.03 to 0.1M hydrazine solutions which are 0.05M in sodium hydroxide. With the assumption of an activation energy of 18 kcal. per mole, the reaction rate constant a t 50°C. is calculated to be 0.3 liter mole-' second-'.) The experimental dependence of hl calculated by Equation 11 on the square of the mole fraction of hydrazine hydrate is quite unexpected and is difficult to rationalize with respect to the second order kinetics which were found for dilute (ca. 0.1M) hydrazine solutions. The application of Equation 10 to prediction of rates of iodomethane removal appears to be more reliable than the predicted rate from the diffusion-reaction model.Treatment of the data in Table I11 according to the Arrhenius relationship yields an energy of activation of between 5 and 6 kcal. per mole. The energy of activation second-'. appears to increase as the temperature is increased. Winning (1 1 ), in studying the heterogeneous reaction of hydrazine and oxygen, found an energy of activation of 6.4 kcal. per mole which increased as the temperature was increased. Winning suggested that this effect, the increase in energy of activation, was due to the increasing importance of the gas phase reaction. Bowen has reported the energy of activation of the gas phase reaction of hydrazine and oxygen to be 38 kcal. per mole ( 2 ) . This reasoning could be applied to the reaction between hydrazine and iodomethane, and the rate of the gas phase reaction would be predicted to become an increasingly important term as the temperature is increased. (If 5 and 38 kcal. per mole are assumed to be the energy of activation of the first and second terms, and if a t 50"C., the cont...

Potent HIV Protease Inhibitors Containing a Novel (Hydroxyethyl)amide Isostere

“…The amide groups of the inhibitor are hydrogen-bonded to the protease dimer either directly or through water molecules. The critical hydroxyl group of the transition state mimic ((R)-configuration at the carbinol atom) is located in close proximity to the catalytic Asp 25 and Asp 25′ residues. The P 3 to P 1 groups of the inhibitor are similar to those for the pipecolic series, and their binding modes and interactions with the protease are similar.…”

“…The right-hand side of our inhibitors was readily constructed by condensation of succinic anhydrides with amines. cis-Succinamic derivative 26 25 was prepared in racemic form from 25, as shown in eq 1, and used as such. Homochiral tertbutylsuccinic amides 28-34 were prepared from the corresponding anhydrides (R)-and (S)-27 as depicted in Scheme 1 for the (R)-enantiomers.…”

“…Synthesis of Inhibitors. (±)- cis -2-( tert -Butylcarbamoyl)cyclohexanecarboxylic Acid (26): prepared from cis -1,2-cyclohexanedicarboxylic anhydride and tert -butylamine; mp 130−132 °C (lit . mp 128.5−130 °C); IR (KBr) ν 3360, 3200−2400, 1711, 1625, 1551 cm -1 ; 1 H NMR (400 MHz, DMSO- d 6 ) δ 11.25 (broad s, 1 H), 7.06 (broad s, 1 H), 2.64 (broad m, 1 H), 2.44 (dt, J = 8.7, 4.3 Hz, 1 H), 2.07−1.96 (m, 1 H), 1.90−1.82 (m, 1 H), 1.65−1.15 (m, 6 H), 1.22 (s, 9 H); 13 C NMR (50 MHz, DMSO- d 6 ) δ 175.0, 173.3, 49.7, 42.4, 42.0, 28.5, 27.9, 25.5, 23.7, 22.7; MS (FAB) m / z 228 (MH + ).…”

“…26): prepared from cis-1,2-cyclohexanedicarboxylic anhydride and tert-butylamine; 25 mp 130-132 °C (lit. 25 C NMR (50 MHz, DMSO-d6) δ 175.0, 173. 3, 49.7, 42.4, 42.0, 28.5, 27.9, 25.5, 23.7, 22.7 (R/S)-2-tert-Butylsuccinic Acid.…”

“…The title succinamic acid derivative (S)-38 was obtained as a white solid (0.562 g, 88% yield): mp 185-189 °C. [R] 25 0, 172.4, 50.8, 49.9, 32.6, 32.1, 28.5, 27.7; MS (FAB) m/z 230 (MH + ). Anal.…”