Oswaldo Núñez

Ring size configuration effect and the transannular intrinsic rates in bislactam macrocycles

We have synthesized compounds: N-(2-aminoacetyl)-2-pyrrolidone (1) and N-(2-aminoacetyl)-2-piperidone (2). When these compounds are dissolved in aprotic or protic solvents a fast equilibrium ca. 1:1 between the cyclol form (tetrahedral intermediate) and the bislactam macrocycle is established. The same result has been reported previously for N-(2-aminoacetyl)-2-caprolactam (3). For compounds 2 and 3, dynamic 1H-NMR (using the methylene signals α to the carbonyl and to the amino group) through spectrum simulation has been used to evaluate the exchange between the two mentioned forms at different pH. However, for compound 1 the exchange was evaluated using magnetization transfer technique. The more stable bislactam configuration of the macrocycle form in compounds 2 and 3, is the trans–cis (one lactam with the cyclic alkyl chains trans oriented and the other cis oriented). However, the same form for compound 1 has a more stable cis–cis bislactam configuration. This difference in configuration induces substantial changes in the appearance of the methylene 1H-NMR signals that precludes the use of line-shape analysis to evaluate the rates. The rate law for the proposed mechanism of exchange between the cyclol form and the macrocycle is: K = [macrocycle]/[cyclol] = kobs.f/kobs.r = Kak2[H2O]/[H+]/k−2Kw/[H+] = Kak2[H2O]/k−2Kw; where Ka is the acidity equilibrium constant of the cyclol form, Kw = 10−14 M2 and k2 and k−2 are the second order rate constants for the specific exchange catalysis. Therefore, both, the macrocycle formation (kobs.f) and the cyclol formation (kobs.r) are specific base catalyzed; however the equilibrium constant is independent of pH. Since K is ca. 1, the ΔG≠ associated with the measured rate constants represent the intrinsic barrier for this non-identical thermoneutral transformation where a cleavage of a tetrahedral intermediate is involved. The activation energies associated with the reverse rate constants then correspond to the intrinsic barrier for transannular cyclolization.

Serine Protease Mechanism-Based Mimics. Direct Evidence for a Transition State Bridge Proton in Stable Potentials

We have synthesized 1-(2-hydroxyacetyl)piperidine-2-one (2) and 1-(2-hydroxyacetyl)azepan-2-one (3). Equilibrium (K(f)) between the free alcohol (open form) and the tetrahedral intermediate (cyclol) is readily established, and both forms are observed in the D(2)O (1)H NMR spectra of 2 and 3. Therefore, their interconversion can be considered as an almost thermoneutral non-identical one. Pseudo-first-order rate constants (k(obs)) were obtained by simulating the AB (1)H NMR system observed for the cyclol. By best fitting the experimental points of a k(obs) versus pD profile to the equation k(obs) = 0.5k(0r) + 0.5k(r) K(ac)/(K(ac) + [D(+)]) + 0.5k(f)K(ao)/(K(ao)+ [D(+)]), the parameters involved were obtained: rate constants of rupture and formation (k(0r) and k(0f) = K(f)k(0r)) catalyzed by water, rate constants of rupture (k(r)) and formation (k(f)) from the conjugated bases of the cyclol form and the open form, and their acidity equilibrium constants K(ac) and K(ao). The system studied mimics the serine alcohol attack on the peptide bond and its reverse reaction in serine protease enzymes. In fact, the reaction rates are similar or perhaps even faster than the ones obtained for enzymatic reactions. The results also show the participation of water molecules forming catalytic proton bridges in stable potentials with the two interconverted forms. The position change of the bridged proton is sensitive to lactam ring size, and it is manifested by considerable change in the pKa values of both cyclol and open forms. Other evidence such as kinetics, DeltaS degrees , DeltaS, and proton inventory experiments and semiempirical molecular calculations support this proposal.

Stereochemical studies on aeromatic amino-acids. Part 4. Absolute configuration of 3-Amino-2-phenylpropionic acid

(+)-3-Amino-2-phenylpropionic acid (1) was assigned the (S)-configuration by chemical correlation with (+)-(S)-1-amino-2-phenylbutane (2). O.r.d. and molecular rotation data for this amino-acid and various derivatives are reported and discussed in the light of well known rules which have been applied to α-amino-acids previously.

N-Alkyl-N-methylacetamidinium Ions. Isomerization and Water Catalyzed Exchange Rates in D2O

We found that the sigmoided-type profile of kobs. vs. pD plot, fits the rate expression : kobs = (k1[D ] + k2Ka)/ (Ka + [D ]), where k1 and k2 are the rates of isomerization of the acetamidinium ion and the acetamidine respectively and Ka is the acidity equilibrium constant of the acetamidinium ion. These constants were evaluated by measuring the rates at each pD using dynamic NMR(H) (line shape analysis and saturation transfer). Based on the low barrier of 19.7 Kcal/mol at 25C (k1 = 0.02 s ) it was suggested that the isomerization (EZ-ZE) of the acetamidinium form procceds throw rotation of the C-N partial double bond. We argued that this relatively low barrier is due the steric repulsion of the N-benzyl group that destabilizes the ground state (planar amidinium) relative to its twisted transition state. On the other hand, our result supports that the E-syn-Z-anti isomerization of the acetamidine form proceeds via rotation about a C-N single bond as it had been proposed previously. We stated that the proposed mechanism was in agreement with the measured low barrier of 14.7 Kcal/mol at 25C (k1= 126 s). In order to test the proposed mechanisms and in view of the biological importance of the acetamidines we have undertaken a systematic study on the isomerization of N -alkyl-Nmethylacetamidines as a complementary support to our previous results on the N-benzyl.N methylacetamidine. Therefore we have prepared the following acetamidines: N-allyl-N C N

MECHANISTIC ASPECTS OF PHOTOCATALYTIC ACTIVITY OF METALLOPORPHYRIN-TITANIUM MIXTURES IN MICROEMULSIONS

Photocatalytic activity of titanium citrate and its water-in-oil microemulsions mix with zinc (II) tetraphenylporphyrin have been studied by means of adding 4-chlorophenol and following its degradation using artificial ultraviolet and visible light. 4-Chlorophenol is degraded in 71 and 86%, respectively, in 30 min with the generation of various intermediaries, whose possible formation mechanisms have been proposed based in the results of this research. The generation of benzene derivatives, different to those usually reported for this type of treatment, suggests the possibility of controlling the generation of intermediaries by simply changing the type of surfactant. In the case discussed here, we have derived a simple method for isomer generation of trimethylbenzene using a model organohalogenated compound as water contaminant and cetyltrimethylammonium bromide as surfactant.

Experimental intrinsic barriers to amide–amide interaction. Transannular cyclolization in a cyclic diamide

N-(2-Aminoacetyl)-e-caprolactam (1) was synthesized. When 1 is dissolved in aprotic solvents such as chloroform or dichloromethane and water (D2O), a ca. 1 ∶ 1 equilibrium is established between two isomeric forms: cyclol1c and macrocyclic diamide1d. The methylene protons –NHCH2CON– for both forms become diastereotopic. Therefore, the diastereotopic interconversion of 1c and 1d can be followed by dynamic 1H-NMR. In D2O, specific base catalysis is observed for both interconversions. Since the equilibrium K = kobs.f/kobs.r for the 1c = 1d transformation remains the same over the wide pD range studied (2 < pD < 11), a mechanism is proposed whereby the exchange occurs through the cyclol1c conjugate base. According to this mechanism, kobs.f and kobs.r can be measured by the diastereotopic interconversions of 1c and 1d respectively. Therefore, K = kobs.f/kobs.r = k2[H2O]Ka/k−2Kw, where k2 is the rate of cleavage of the cyclol 1c (of acidity constant Ka) conjugate base toward the macrocyclic diamide, and k−2 represents the reverse amino amide-to-carbonyl amide attack (transannular cyclolization). Values for k2 of 1.8 × 102 M−1 s−1 (ΔG‡ = 59.8 kJ mol−1 at 25 °C), and k−2 of 1 × 105 M−1 s−1 (ΔG‡ = 44.3 kJ mol−1 at 25 °C) were obtained. The uncatalyzed rates of kobs.f = ko1c and kobs.r = ko1d were also measured. These values are 2 s−1 (ΔG‡ = 71.1 kJ mol−1 at 25 °C) and 4 s−1 (ΔG‡ = 69.4 kJ mol−1 at 25 °C), respectively.