N-protonated Form Research Articles

Distorted amides as models for activated peptide N-C=O units. 2. The synthesis, hydrolytic profile, and molecular structure of 3,4-dihydro-2-oxo-1,4-propanoquinoline

A distorted anilide (3,4-dihydro-2-oxo-1,4-propanoquinoline (3)) has been synthesized, its structure determined by X-ray diffraction, and its hydrolysis profile from pH 0–13 investigated. The amide unit in 3 is distorted in that the N lone pair is twisted 35° and tilted 15° out of optimum conjugation with the C=O II system. Due to this distortion, 3 hydrolyses rapidly in H2O at 25 °C. The pH/rate constant profile exhibits domains consistent with OH− attack on 3[Formula: see text] and H2O attack on a protonated form of 3[Formula: see text]; pKa (3-H+) = 0.56). The kinetic pKa is most consistent with an N-protonated form. It is also shown that this mechanism of hydrolysis is common to the series of bridged anilides consisting of 3, 3,4-dihydro-2-oxo-1,4-ethanoquinoline (1), and 2,3,4,5-tetrahydro-2-oxo-1,5-ethanobenzazepine (2). Keywords: distorted amide, hydrolysis, X-ray structure.

Reactivity of H, OH and e -aq with nicotinic acid: A pulse radiolysis study

The reactivity of aqueous nicotinic acid (NA) towards OH, e - aq and H-atoms has been investigated in the pH-range 0.3–13.8. The OH attack on NA [ k = (2.5 ± 0.2) × 10 9 M -1 s -1] and its N-protonated forms [ k = (2.2 ± 0.2) × 10 7 M -1 s -1] gives OH-adducts with pH-dependent optical spectra [NĊ 5H 4(OH)COO -:λ max = 310 nm, ϵ 310 = 1800 ± 200 M -1 cm -1; +HNĊ 5H 4(OH)COO -:λ max = 325 nm, ϵ 325 = 2000 ± 200 M -1 cm -1]. pK a = 4.5 ± 0.2 was determined for these two transients. The reaction of H-atoms with NA in the pH-range 6–12 [ k = (6.0 ± 0.5) × 10 8 M -1 s -1] results in the formation of one type of transient, the H-adducts on ring carbons (λ max = 315 nm, ϵ 315 = 4500 ± 200 M -1 s -1; pK = 6.7 ± 0.2). With the N-protonated forms of NA, however, two kinds of radicals are produced: pyridinyl (λ max = 285 nm, ϵ 285 = 7800 ± 200 M -1 cm -1; λ max = 410 nm, ϵ 410 = 3100 ± 100 M -1 cm -1) and H-adduct on ring carbons (λ max = 340 nm, ϵ 340 = 4600 ± 200 M -1 cm -1). The reaction of e - aq with NA was reinvestigated. The kinetic and spectroscopic data are in good agreement with those previously reported.

On the NO bond length in free and N-protonated hydroxylamine, and redetermination of the crystal structure of hydroxylammonium chloride, (H 3NOH)Cl

The best experimentally determined values for the NO bond length in hydroxylamine and its N-protonated form are, respectively, 1.453(3) and 1.411(2) Å, the latter being derived from a redetermination of the crystal structure of hydroxylammonium chloride. The data are mutually consistent and in good agreement with those from ab initio MO calculations reported in the literature. The chloride salt crystallizes in space group P2 1/ n, with a = 6.954(2), b = 5.943(1), c = 7.286(2) Å, β = 114.12(2)° and Z = 4. The structure has been refined to R = 0.036 for 979 observed Mo K α reflections.

A molecular orbital study of protonated N 2O

The structures of isomers of protonated N 2O in the ground state are determined by the ab initio MP2 gradient method with a 6-31 G ∗ basis set. Calculations at the MP4SDQ/6-311 G ★★ level predict that the O-protonated N 2O is the most stable isomer and is lower in energy by 7.1 kcal mol than the N-protonated form. The singlet and triplet biradical intermediates, which connect the two isomers, are found ≈ 80 kcal/mol higher than the N-protonated N 2O, suggesting that both isomers are experimentally observable.

Acid deuterium exchange in methoxyquinolines and their N-oxides

Kinetic studies of acid deuterium exchange have been carried out for a series of isomeric 6-, 7-, and 8-methoxyquinolines and their N-oxides, in comparison with the analogous carbocyclic compounds. It has been found that methoxyquinolines are deuterated in the N-protonated form, whereas the N-oxides are reactive in their neutral forms. In full agreement with data for the reactivity of these heterocycles in nitration, quantum chemical calculations show that in exchange in 6-methoxyquinoline and its N-oxide the preferred site for electrophilic attack is the 5-position, and in the 7-isomers the 8-position is preferred. The rate is lower in the 8-isomer, owing to the presence in the latter of intramolecular hydrogen bonding. The probable structure of the transition state in the reaction is discussed.

Theoretical studies on the acid hydrolysis of acetamide

The mechanism of the A2 hydrolysis of acetamide has been investigated theoretically using MNDO Method. Fully optimized geometries of all species at the stationary points corresponding to energy minima and energy maxima along the reaction coordinate are determined for the two reaction paths: the rate-determining nucleophilic attack of water on the carbonyl carbon (i) of the O-protonated tautomer and (ii) of the N-protonated form. Results show that the latter provides a lower energy path by 7.5 Kcal Mol compared to the former.Tetrahedral species' found were not at the energy minima but at or near the saddle points. Optimizied structures and formal charges on heavy atoms showed that the bond interchange with the concurrent proton interchange takes place at the rate-determining step. The negative charge on N atom was found to increase in the rate-determining step relative to that of the ground state, the O-protonated acetamide, and hence substitution of electron withdrowing group on N is predicted to depress the activation energy in agreement with the experimental results.

Ab-initio calculations on the retinal Schiff base – formic acid and allylimine – formic acid hydrogen bonds

The proton potential functions of Schiff base – formic acid complexes were calculated in the ab-initio scheme with STO-3G and 4-31G basis sets without and with the inclusion of a perturbing charge. The comparison of the curves with the retinal Schiff base and allylimine obtained by using the short base encouraged further calculations with the longer base on the truncated system only. The curve obtained with the 4-31G set on the allylimine – formic acid complex is of a double minimum type with the deeper well still at the formyl oxygen. Inclusion of a perturbing negative charge near the hydrogen bond reverses the depth of the wells making the N-protonated form more stable.

Reversible reduction of an alpha-imino acid to an alpha-amino acid catalyzed by glutamate dehydrogenase: effect of ionizable functional groups.

The glutamate dehydrogenase catalyzed reduction of delta 1-pyrroline-2-carboxylic acid (PCA; an alpha-imino acid) with reduced nicotinamide adenine dinucleotide phosphate (NADPH) to give L-proline and NADP+ is employed as a model for the redox step of the corresponding enzyme-catalyzed reductive amination of alpha-ketoglutarate. We demonstrate the reversibility of the model reaction and measure its equilibrium constant. The pH profiles for the model reactions show that the active substrates are the N-protonated imino acid in one direction and the proline anion with a neutral amino group in the other. The V/K value for the imino acid reduction is enhanced by a group Z of pK = 8.6 in the enzyme-NADPH complex, while that for the proline reaction is unaffected by any such group in the enzyme-NADP+ complex. The following conclusions emerge from a comparison of the pH dependence of the rates for the model reactions with that for the oxidative deamination of L-glutamate [Rife, J. E., & Cleland, W. W. (1980) Biochemistry 19, 2328]. The N-protonated form of alpha-iminoglutarate and the conjugate base of glutamate are the active substrates. The redox step is not sensitive to the protonation state of the groups that catalyze the hydrolysis of bound alpha-iminoglutarate. The group Z, which facilitates the PCA reaction, plays no role in the binding of alpha-ketoglutarate. We propose a chemical mechanism for the glutamate reaction where an unprotonated enzyme group of pK = 5.2 in enzyme-NADPH catalyzes the conversion of the alpha-iminoglutarate to the carbinolamine.(ABSTRACT TRUNCATED AT 250 WORDS)

The structure and reactivity of dipyrido[1,2-a : 1′,2′-d]pyrazinium cations

The crystal structure of 6,12-dihydrodipyrido[1,2-a : 1′,2′-d]pyrazinium dibromide (1) has been determined by X-ray crystallography. In aqueous or methanolic solution (1) behaves as a strong acid and is in equilibrium with the monocation (2); the proton-transfer kinetics have been studied using stopped-flow methods and the N-protonated form of (2) has been isolated as the di-iodide. Reduction of (1) with borohydride yields a mixture of isomeric octahydro derivatives which do not appear to re-aromatise to compound (3). The relative enthalpies of formation of (1) and (3) have been calculated using MNDO and are compared to related heteroaromatic compounds.

Heterogeneous catalysis and electrosorption phenomena in the cathodic reduction of acetylpyridines: Part II. Electrode kinetic investigations

The mechanism of the cathodic reduction of three isomeric acetylpyridines has been evaluated by electrode kinetic and preparative measurements at the DME and rotating rod electrodes of different solid metal electrode materials. The influence of electrosorbed molecules, which may either act as proton donors and asymmetric inductors (strychnine, camphoric acid) or are chemically inert surfactants (tetraalkylammonium ions) on the electrode kinetics, has been studied. Up to pH 10, acetylpyridines are reduced from their N-protonated form. If the strongly pH-dependent reduction potential of the ketone is close to the E pzc of the electrode, electrosorbed ketyl radicals are formed in a 1 e −/1 H + EC reaction sequence and the pinacol is formed by heterogeneous dimerization of these adsorbed radicals. This holds for the 2- and 4-acetylpyridine reduction at low pH (1<pH<3.5). At higher pH (pH>4) and in the absence of electrosorbed proton donors, the alcohol formation proceeds by eventual irreversible protonation of the pyridyl-benzylic carbanion which is formed at more negative potentials in a fast and reversible (2 e −/H +)-reduction step. Reduction of 2- and 4-acetylpyridine in the presence of adsorbed proton donors (1<pH<7) is speeded up due to the participation of the adsorbed proton donor in the initial 2 e −/H + equilibrium. Heterogeneous protonation of the ketyl radical brought about by adsorbed chiral proton donors (inductor acid) is one of the key steps in cathodic asymmetric electro-organic synthesis. The ketyl radicals formed by a 1 e −/1 H + protonation reduction step from the three ketones possess relatively different basicities: for 2-acetylpyridine the radical is a 10 7 times stronger base, and for 4-acetylpyridine a 10 5 times stronger base than for 3-acetylpyridine. For the least basic ketyl radical of 3-acetylpyridine, only surfactants which are stronger acids, such as camphoric acid, show a decrease in lifetime and a speeding up of electrode kinetics which yields an optical induction.

1H and 13C NMR and infrared spectroscopic study of the conformational equilibria in S-methyl dithiocarbazate

Analysis of the variable temperature 1H and 13C and ambient temperature 2H NMR spectra coupled with IR spectra of S-methyl dithiocarbazate shows that the results can be best rationalized in terms of a mixture of cis-cis and trans-cis conformers. The assignment of the proton chemical shifts has been supported by utilizing lanthanide induced shifts. The torsional barrier about the CN bond has been determined; a full line shape analysis of the 1H spectra at different temperatures has been made. The rotational behaviour in the N-protonated form relative to the free base is also noted.

NMR (1H, 13C) and MO (ab initio, CNDO/2, EHT) studies on basic and N-protonated hydrazinecarbothioamide

The conformational preferences of hydrazinecarbothioamide (HCTA, H2NNHCSNH2) in its basic and N-protonated (PHCTA, H3NNNHCSNH2) forms have been studied by 1H and 13C NMR spectroscopy and by theoretical LCAO-MO methods (ab initio, CNDO/2 and EHT). The hindered rotation around the CN bond has been investigated by a total line shape analysis for the thioamide protons and by the three MO methods. Changes in the molecular conformation and electronic structure on protonation are briefly discussed.

The temperature variation of the H A acidity function for sulphuric acid and the thermodyanamics of protonation of amides

The anchoring of the HA acidity function to 4- and 2-nitroaniline indicators at low acid concentrations has been reexamined and found to be satisfactory. The HA function has been determined up to 45% sulphuric acid over the temperature range 15–40 °C. As found earlier for the HO function, the HA values become less negative with increasing temperature. The thermodynamic functions of protonation for pyrrole-2-carboxamide, 4-methoxybenzamide, and methacrylamide have been derived. The protonations are slightly endothermic and occur with a decrease in entropy. The thermodynamic functions, ΔG° and ΔH°, follow the same correlation as those for the protonation of alkylamines and arylamines, and therefore indicate that the predominant form of amide cations in aqueous acid is the N-protonated form. The entropy changes, ΔS°, indicate that restricted rotation about the C–N bonds in the amide molecules also makes a contribution.

Effects ofN-protonation on the electronic structure of morphine and naloxone

The FSGO molecular fragment technique has been employed to perform ab-initio SCF-MO calculations on morphine and naloxone in the free-base and N-protonated forms. Particular features of electronic structure which have been investigated are molecular-orbital (MO) density distributions, energies and ordering, as well as the correlation of specific orbitals between different molecular species. It has been found that high-energy occupied and low-energy unoccupied MOS are centered on the aromatic moiety of both drugs, enabling the ring to act either as an electron donor or as an acceptor in a charge-transfer interaction. Comparison of corresponding MOs in the free base and the acid cation of both morphine and naloxone demonstrates that the field of the cationic head causes a dramatic downward shift in orbital energies. Thus in the N-protonated drugs the acceptor capability of the benzene ring is greatly enhanced at the expense of its suitability as a donor. Furthermore, the allyl group of naloxone becomes highly activated as an electron acceptor through N-protonation. Investigation of the molecular electrostatic potential of the free-base species has revealed preferred avenues of approach for electrophilic and nucleophilic entities. However, the N-protonated species shows no regions of attraction for electrophiles. In both the free base and the acid cation, the vicinities of the nitrogen atom and the 3-hydroxy group are found to be favorably disposed for electrostatic interactions with receptor entities possessing the proper charge or polarity. Based on the findings with regard to electronic structure, a simple model has been suggested to explain the binding of morphine and naloxone at the opioid receptor.

The products, kinetics, and mechanisms of metal ion-promoted hydrolyses of thioimidate esters and the effects of hydrogen ions on thioimidate ester hydrolyses

A kinetic study shows that the hydrolysis of thiomidate esters in the presence of hyrogen ions at pH ≲ 2 is promoted by mercury(II) ions. Methyl thiobenzimidate leads to benzonitrile and methyl N-cyclohexyl thiobenzimidate to N-cyclohexylbenzamide. The N-protonated forms of the esters, like their analogue the 1-[α-(methylthio)-benzylidene]piperidinium ion, are unreactive towards mercury(II) ions: the rate of reaction therefore falls as [H3O+] rises. Mechanisms of the mercury-promoted reactions are given which are compatible with the observed reaction orders. The hydrolysis of the imidate esters at pH ≲ 2, in the absence of heavy metal ions, which leads predominantly to the thiol ester, is also inhibited by an increase in [H3O+] and the explanation of this effect is disscussed. Unlike mercury(II) ions, silver ions have no detectable effect on the rate of hydrolysis of thioimidate esters at pH ≲ 2, but do affect the isolable products since they rapidly convert the thiol ester to the carboxylic acid.

Theoretical studies of aromatic substitution. Part I. Pyrrole and its protonated species

The MINDO/2 method has been applied to pyrrole and its α-, β-, and N-protonated forms. The geometries of the various species have been varied so that the energy of each may approach a minimum. It is found that there are substantial geometrical changes on protonation, and that these changes differ for the different cations. The sequence of reactivity is found to be α < β < N, in accordance with experimental findings. The calculations on pyrrole are compared with the results of other all valence electron calculations.

Acylation of phenol with the hydrochlorides of carboxylic acid amides

1. A study was made of the acylation of phenol with the hydrochlorides of carboxylic acid amides in nitrobenzene solution. 2. The hydrochlorides of the N,N-dialkyl-substituted amides of carboxylic acids possess the highest acylating capacity. 3. The formation of the N-protonated form of the amide is apparently one of the possible paths for progress of the acylation reaction.