|dc.description.abstract||Thermodynamic proton dissociation constants (K_a^T) of the hydrochlorides of some α-amino acid methyl, ethyl and benzyl esters have been determined by potentiometric titration at 25, 37.1 and 50.2°C, and at I = 0.1 mol 1⁻¹. From this temperature dependence, the energetics of the reactions (ΔG˚ , ΔH˚ , ΔS0˚values) were determined and examined.
The ester hydrochlorides of the 2-amino acids have pK_a^T values that are about 2 units lower than the corresponding n-alkylammoniums. The major contributors to this large ΔG˚ lowering (acid strengthening) are the strong -I effect of the adjacent alkoxy/benzyloxy carbonyl group which produces a large decrease in ΔH˚ and a reduction in the nett solvent (H₂0) bonding for the free base form of the ester (E) which increases ΔS˚ •
pK_a^T values rise sharply from 2-aminoethanoic acid methyl ester hydrochloride (2-AE Me·HCI) to 3-aminopropanoic acid methyl ester hydrochloride (3-AP Me·HCl). There are much smaller rises with further increases in the chain length to the 4-, 5- and 6-amino acid methyl ester hydrochlorides. Similar trends occur for the corresponding ethyl and benzyl ester hydrochlorides. However, this simple increase in pK_a^T (ΔG˚) hides a complicated interplay between ΔH˚ and ΔS˚ • There is a rapid increase in ΔH˚ from 2-AE Me·HCI to 4-aminobutanoic acid methyl ester hydrochloride (4-AB Me·HCl), but a dramaticrise to 5-aminopentanoic acid methyl ester hydrochloride (5-APe Me· HCl). These large fluctuations in ΔH˚ are moderated by ΔS˚ changes to produce the observed overall increase in ΔG˚ with increasing chain length. This behaviour is probably due to intramolecular H-bonding between the ammonium and methoxycarbonyl groups in 5-APe Me· HCI which results in an 8-membered ring and stabilisation of the protonated form (EH⁺) relative to the E form, with consequent changes in solvation and ΔS˚ •
The results of N-methylation reinforce the need for ΔH˚ and ΔS˚ values if structural effects on pK_a^T values are to be understood. In going from 4-AB Me·HCI to its N, N-dimethyl analogue, pK_a^T falls. Inductive effects predict pK_a^T should rise as the weak +I effect of the two methyl groups is acid weakening and so makes a positive contribution to ΔH˚ • However, solvent bonding changes produce a much larger negative contribution to ΔH˚ • This makes the overall ΔH˚ (and ΔG˚) lower than for 4-dimethylaminobutanoic acid methyl ester hydrochloride (4-DMAB Me·HCl), however the ΔS˚ value is also compensatingly low.
Stepwise methylation at C-3 in 4-AB Me·HCl produces stepwise decreases in pK_a^T. This decrease in ΔG˚ is mainly due to a fall in ΔH˚, which apparently arises from the protonated form of 4-amino-3,3-dimethylbutanoic acid methyl ester (4-A-3,3-DMB Me) existing predominantly in the gauche conformation. Consequently, the ammonium and methoxycarbonyl groups can intramolecularly H-bond which produces the observed changes in ΔG˚ and ΔH˚ , however ΔS˚ are abnormally large and negative since this interaction is lost on deprotonation.
Changes in the ester function alone have little effect on the pK_a^T value; the methyl, ethyl and benzyl ester hydrochlorides of 4-AB have almost identical pK_a^T values. The rate constants for the alkaline hydrolysis of the ω-amino acid esters have been measured at 25, 37.1 and 50.2°C, and at I = 0.1 mol⁻¹ , using the pH-Stat method. All the reactions are pseudo first order at constant pH with a rate constant, kobs. Values of kobs /[OH⁻] vary with pH so the reaction is not simple second order. However, the data is consistent with a reaction scheme involving both forms of the ester, E and EH⁺, reacting in two parallel, second order, pathways with rate constants kE and kE8 +. The two forms of the ester are connected by a pH dependent equilibrium governed by K_a^T. Values for~ and kE8+ were separated using plots of kobs /[OH]( K_a^T + [H⁺]) vs. [H⁺] which were linear. For some esters, the E form undergoes lactamisation with a large rate constant, kL, which replaces the negligibly small kE.
The kE values for the methyl, ethyl and benzyl esters of 2-AE, 3-AP, 6-AH and 4-DMAB, and the kE8+ values for all of the esters, are consistent with a simple BAc2 reaction mechanism. This predicts changes in the reaction energetics (ΔH+, ΔH+ values), and hence changes in the rate constants, with changes in structure, that agree with those observed. These rate constant changes cannot be explained simply by the contribution made by inductive effect changes to the reaction energetics. This again emphasises the need for temperature dependence studies if a complete understanding is to be gained.
For the 2-amino acid esters, kEH+ is much larger than kE. This is due entirely to an increase in dS* associated with solvation effects. Since little difference in dW between the E and EH+ forms of the ester The differences in kEH+ and kE become smaller as the amino group is removed from the carbonyl reaction centre, as expected. The E forms of 4-AB Me and 5-APe Me undergo intramolecular aminolysis rather than simple BAc2 hydrolysis. This is because the potential 5- and 6-membered rings are energetically the optimum size for ring closure. The resulting lactams are stable under the reaction conditions. Lactamisation also occurred for the E form of the ethyl and benzyl esters of 4-AB, the ethyl ester of 5-APe, the methyl and ethyl esters of 4-(methylamino)-butanoic acid (4-MAB), 4-amino-3-methylbutanoic acid (4-A-3-MB) and 4-A-3,3-DMB. However, lactamisation was blocked for the methyl and ethyl esters of 4-DMAB because of the lack of an amino hydrogen.
The rate constant for 6-membered lactam ring formation (kL6) is about 23 times larger than for the corresponding . 5-membered Jactam (kL5). The origin of this difference is mainly the smaller dH* for k16, reflecting the smaller strain in the 6-membered ring transition state.
Single N-methylation produces a small (about 5 times) increase in kLS, with 4-MAB Me hydrolysing more rapidly than 4-AB Me. This is due to a decrease in ΔH+ associated with the increased nucleophilicity of the amino nitrogen. Stepwise methylation at C-3 in 4-AB Me produced moderate increases in kLS with the largest effect (about 6 times) for the gem-dimethyl case, associated with an increase in ΔS+, due a smaller loss of internal freedom in the transition state. The simplest reaction mechanism for the lactamisation that is consistent with all of the observations involves an initial, rate determining step, consisting of OH" deprotonating the amino nitrogen which simultaneously attacks the ester carbonyl C. The cyclic tetrahedral intermediate formed then rapidly decomposes to form the lactam, parent alcohol and OH-, probably in several steps. This mechanism can be described as "hydroxide assisted intramolecular nucleophilic catalysis."||