Reaction mechanism of the acidic hydrolysis of highly twisted amides: Rate acceleration caused by the twist of the amide bond

We present an ab initio study of the acid hydrolysis of a highly twisted amide and a planar amide analogue. The aim of these studies is to investigate the effect that the twist of the amide bond has on the reaction barriers and mechanism of acid hydrolysis. Concerted and stepwise mechanisms were investigated using density functional theory and polarizable continuum model calculations. Remarkable differences were observed between the mechanism of twisted and planar amide, due mainly to the preference for N-protonation of the former and O-protonation of the latter. In addition, we were also able to determine that the hydrolytic mechanism of the twisted amide will be pH dependent. Thus, there is a preference for a stepwise mechanism with formation of an intermediate in the acid hydrolysis, whereas the neutral hydrolysis undergoes a concerted-type mechanism. There is a nice agreement between the characterized intermediate and available X-ray data and a good agreement with the kinetically estimated rate acceleration of hydrolysis with respect to analogous undistorted amide compounds. This work, along with previous ab initio calculations, describes a complex and rich chemistry for the hydrolysis of highly twisted amides as a function of pH. The theoretical data provided will allow for a better understanding of the available kinetic data of the rate acceleration of amides upon twisting and the relation of the observed rate acceleration with intrinsic differential reactivity upon loss of amide bond resonance.     

Acid-catalyzed reactions of twisted amides in water solution: competition between hydration and hydrolysis

The acid-catalyzed reactions of twisted amides in water solution were investigated by using cluster-continuum model calculations. In contrast to the previous widely suggested concerted hydration of the C=O group, our calculations show that the reaction proceeds in a practically stepwise manner, and that the hydration and hydrolysis channels of the C-N bond compete. The Eigen ion (H(3)O(+)) is the key species involved in the reaction, and it modulates the hydration and hydrolysis reaction pathways. The phenyl substitution in the twisted amide not only activates the N-CO bond, but also stabilizes the hydrolysis product through n(N)→π(phenyl) delocalization, leading exclusively to the hydrolysis product of the ring-opened carboxylic acid. Generally, the twisted amides are more active than the planar amides, and such a rate acceleration results mainly from the increase in exothermicity in the first N-protonation step; the second step of the nucleophilic attack is less affected by the twisting of the amide bond. The present results show good agreement with the available experimental observations.     

Modeling the reaction mechanisms of the amide hydrolysis in an N-(o-carboxybenzoyl)-L-amino acid

Reaction mechanisms of the amide hydrolysis from the protonated, neutral, and deprotonated forms of N-(o-carboxybenzoyl)-l-amino acid have been investigated by use of the B3LYP density functional method. Our calculations reveal that in the amide hydrolysis the reaction barrier is significantly lower in solution than that in the gas phase, in contrast with the mechanism for imide formation in which the solvent has little influence on the reaction barrier. In the model reactions, the water molecules function both as a catalyst and as a reactant. The reaction mechanism starting from the neutral form of N-(o-carboxybenzoyl)-l-amino acid, which corresponds to pH 0-3, is concluded to be the most favored, and a concerted mechanism is more favorable than a stepwise mechanism. This conclusion is in agreement with experimental observations that the optimal pH range for amide hydrolysis of N-(o-carboxybenzoyl)-l-leucine is pH 0-3 where N-(o-carboxybenzoyl)-l-leucine is predominantly in its neutral form. We suggest that besides the acid-catalyzed mechanism the addition-elimination mechanism is likely to be an alternative choice for cleaving an amide bond. For the reaction mechanism initiated by protonation at the amidic oxygen (hydrogen ion concentration H(0) < -1), the reaction of the model compound with two water molecules lowers the transition barrier significantly compared with that involving a single water molecule.     

Acceleration of amide bond rotation by encapsulation in the hydrophobic interior of a water-soluble supramolecular assembly

The hydrophobic interior cavity of a self-assembled supramolecular assembly exploits the hydrophobic effect for the encapsulation of tertiary amides. Variable-temperature (1)H NMR experiments reveal that the free energy barrier for rotation around the C-N amide bond is lowered by up to 3.6 kcal/mol upon encapsulation. The hydrophobic cavity of the assembly is able to stabilize the less polar transition state of the amide rotation process. Carbon-13 labeling studies showed that the (13)C NMR chemical shift of the carbonyl resonance increases with temperature for the encapsulated amides, which suggests that the assembly is able to favor a twisted form of the amide.     

Ab initio studies of the intramolecular amide hydrolysis in N-methylmaleamic acids

The intramolecular amide hydrolysis reactions of N-methylmaleamic acids (NMMA) are studied at the MP2/6-31G**//RHF/4-31G level of theory as model reactions of peptide bond cleavage by a proteolytic enzyme. In contrast to the previously reported results for a bimolecular reaction model of peptide hydrolysis, the unimolecular reactions studied here proceed via the concerted pathway in which the C–O bond formation and the release of methylamine occur simultaneously in preference to the stepwise one. The determination of an intrinsic reaction coordinate shows that the reaction is facilitated by the intramolecular proton transfer from the undissociated carboxyl group to the nitrogen of the leaving amine group. Mainly because of the increase in activation energy, methyl substitution at the 2-position retards the hydrolysis reaction rate by a factor of 14 compared to the reaction of the unsubstituted molecule. In contrast, additional methyl substitution at 3-position leads to 35-fold increase in the reaction rate. These variations of reactivity are caused by the charge redistributions in the amide group induced by methyl substitutions and the resulting changes in electrophilicity of the aminocarbonyl carbon.     

Reliable determination of amidicity in acyclic amides and lactams

Two independent computational methods have been used for determination of amide resonance stabilization and amidicities relative to N,N-dimethylacetamide for a wide range of acyclic and cyclic amides. The first method utilizes carbonyl substitution nitrogen atom replacement (COSNAR). The second, new approach involves determination of the difference in amide resonance between N,N-dimethylacetamide and the target amide using an isodesmic trans-amidation process and is calibrated relative to 1-aza-2-adamantanone with zero amidicity and N,N-dimethylacetamide with 100% amidicity. Results indicate excellent coherence between the methods, which must be regarded as more reliable than a recently reported approach to amidicities based upon enthalpies of hydrogenation. Data for acyclic planar and twisted amides are predictable on the basis of the degrees of pyramidalization at nitrogen and twisting about the C-N bonds. Monocyclic lactams are predicted to have amidicities at least as high as N,N-dimethylacetamide, and the β-lactam system is planar with greater amide resonance than that of N,N-dimethylacetamide. Bicyclic penam/em and cepham/em scaffolds lose some amidicity in line with the degree of strain-induced pyramidalization at the bridgehead nitrogen and twist about the amide bond, but the most puckered penem system still retains substantial amidicity equivalent to 73% that of N,N-dimethylacetamide.     

Facile C-N cleavage in a series of bridged lactams

A series of strained bi- and tricyclic amides has been shown to be unusually sensitive to cleavage of the C-N bond adjacent to the amide moiety. This bond undergoes facile breaking when subjected to treatment with H2/Pd(OH)2, MeI, and DDQ. In each case, the reaction is highly regioselective and mainly results in breaking the C-N bond that deviates the farthest from its natural planar state. Preliminary experiments that bear on the mechanisms of these reactions are described.     

Ab initio study of catalyzed and uncatalyzed amide bond formation as a model for peptide bond formation: Ammonia-Glycine reactions

As a model reaction for peptide and bond formation, the S_N2 reactions between glycine and ammonia have been studied with and without amine catalysis: using ab initio molecular-orbital methods. For each of the catalyzed and uncatalyzed reactions, two reaction mechanisms have been examined: a two-step and a concerted mechanism. The stationary points of each reaction, including intermediate and transition states, have been identified and free energies calculated for all geometry-optimized reaction species to determine the thermodynamics and kinetics of the reaction. The calculations demonstrate that a second ammonia molecule catalyzes amide bond formation, and that the two-step mechanism is more favorable than the concerted one for the catalyzed reaction, while for the uncatalyzed reaction both mechanisms are competitive.     

Direct hydrogenation of amides to alcohols and amines under mild conditions

The selective, direct hydrogenation of amides to the corresponding alcohols and amines with cleavage of the C-N bond was discovered. The expected products of C-O cleavage are not formed (except as traces in the case of anilides). The reaction proceeds under mild pressure and neutral, homogeneous conditions using a dearomatized, bipyridyl-based PNN Ru(II) pincer complex as a catalyst. The postulated mechanism involves metal-ligand cooperation by aromatization-dearomatization of the heteroaromatic pincer core and does not involve hydrolytic cleavage of the amide. The simplicity, generality, and efficiency of this environmentally benign process make it attractive for the direct transformations of amides to alcohols and amines in good to excellent yields.     

Structures of Highly Twisted Amides Relevant to Amide N−C Cross‐Coupling: Evidence for Ground‐State Amide Destabilization

Herein, we show that acyclic amides that have recently enabled a series of elusive transition‐metal‐catalyzed N?C activation/cross‐coupling reactions are highly twisted around the N?C(O) axis by a new destabilization mechanism of the amide bond. A unique effect of the N‐glutarimide substituent, leading to uniformly high twist (ca. 90°) irrespective of the steric effect at the carbon side of the amide bond has been found. This represents the first example of a twisted amide that does not bear significant steric hindrance at the α‐carbon atom. The ¹⁵N NMR data show linear correlations between electron density at nitrogen and amide bond twist. This study strongly supports the concept of amide bond ground‐state twist as a blueprint for activation of amides toward N?C bond cleavage. The new mechanism offers considerable opportunities for organic synthesis and biological processes involving non‐planar amide bonds.     

Regression and principal component analyses of internal coordinates for the carboxamide and carboxylate groups. Diversity of amide bonding in primary carboxamides,oligopeptides, and lactams

A new model of electronic structure of the carboxamide and carboxylate bonds is proposed to account for the diversity of the patterns of structural variation displayed by such bonds in the crystal structures. The geometries of the amide and carboxylate ester fragments retrieved from the Cambridge Crystallographic Data Centre database were examined by means of the regression and principal component analyses. Correlations of the C=O and C-O/C-N bond distances and correlations of the bond distances with the out-of-plane distortions are consistent with the predictions of Pauling's resonance model only in the more extensively substituted esters, secondary amides, and common ring lactams. Surprisingly, in the unsubstituted methyl esters and primary amides, correlations between the bond distances are positive (e.g., both C-N and C=O increase or decrease). Furthermore, for the majority of the less substituted amides and lactams, an increase in pyramidalization at the nitrogen is associated with the shortening of the C-N bond instead of the expected lengthening. Consequently, factor analyses of ther(C=O),r(C-N), ¦ _N¦coordinates for the 42 subclasses of amides and lactams reveal three patterns of coupling of structural parameters, these patterns appear to be related to the major types of the amide substitution. A hypothesis explaining this diversity is based on the assumption that structural variation observed in each of the narrowly defined subclasses of amides maps out initial stages of rehybridization accompanying internal rotation, that is, the amide bonds in the crystal structures deform along the rehybridization/rotation path. It is proposed that the positions of the minimum and the saddle point along this path depend on the alkyl substitution of the bond and the size of the embedding ring.     

An evaluation of amide group planarity in 7-azabicyclo[2.2.1]heptane amides. Low amide bond rotation barrier in solution

Here we show that amides of bicyclic 7-azabicyclo[2.2.1]heptane are intrinsically nitrogen-pyramidal. Single-crystal X-ray diffraction structures of some relevant bicyclic amides, including the prototype N-benzoyl-7-azabicyclo[2.2.1]heptane, exhibited nitrogen-pyramidalization in the solid state. We evaluated the rotational barriers about the amide bonds of various N-benzoyl-7-azabicyclo[2.2.1]heptanes in solution. The observed reduction of the rotational barriers of the bicyclic amides, as compared with those of the monocyclic pyrrolidine amides, is consistent with a nitrogen-pyramidal structure of 7-azabicyclo[2.2.1]heptane amides in solution. A good correlation was found between the magnitudes of the rotational barrier of N-benzoyl-7-azabicyclo[2.2.1]heptanes bearing para-substituents on the benzoyl group and the Hammett's sigma(p)(+) constants, and this is consistent with the similarity of the solution structures. Calculations with the density functional theory reproduced the nitrogen-pyramidal structures of these bicyclic amides as energy minima. The calculated magnitudes of electron delocalization from the nitrogen nonbonding n(N) orbital to the carbonyl pi orbital of the amide group evaluated by application of the bond model theory correlated well with the rotational barriers of a variety of amides, including amides of 7-azabicyclo[2.2.1]heptane. The nonplanarity of the amide nitrogen of 7-azabicyclo[2.2.1]heptanes would be derived from nitrogen-pyramidalization due to the CNC angle strain and twisting of the amide bond due to the allylic strain.     

Theoretical studies on the hydrolysis mechanism of N-(2-oxo-1,2-dihydro-pyrimidinyl) formamide

Density functional theory (B3LYP) and ab initio (MP2) methods with the 6-31G(d,p) basis set are used to study the mechanisms for the hydrolysis of N-(2-oxo-1,2-dihydro-pyrimidinyl) formamide (PFA) in the gas phase. The direct and the water-assisted hydrolysis processes are considered, involving one and two water molecules, respectively. Three different pathways are explored in each case. In the first pathway, the O atom of water first attacks at the C atom of amide while one H atom of water transfers toward the oxygen of amide, leading to an intermediate of tetrahedral coordinated carbon with two OH groups. In the subsequent step, the hydroxyl H atom transfers to the N atom of pyrimidine ring and the C-N covalent bond of amide dissociates simultaneously. In the second path, the O and one H of water attack at the C of amide and the N of pyrimidine ring, respectively, while the C-N bond of amide dissociates. In the third path, three processes occur simultaneously: the O of water attacks at the C of amide, one H atom attacks at the N of amide, and the C-N bond of amide is broken. It is shown that the second pathway is favored for the direct hydrolysis while the first pathway is favored for the water-assisted hydrolysis. It is also shown that the water-assisted hydrolysis is slightly more favorable than the direct hydrolysis. Moreover, solvent effects on five pathways are evaluated with Monte Carlo simulation (MC) and free energy perturbation methods. It is shown that the solvent water slightly reduces the energy barrier in each pathway. The first pathway in the water-assisted hydrolysis remains the most favorable when the solvent effects of bulk water are taken into account.     

Mechanistic insights into the hydrolysis of a nucleoside triphosphate model in neutral and acidic solution

Nucleoside triphosphate hydrolysis is an essential component of all living systems. Despite extensive research, the exact modus and mechanism of this ubiquitous reaction still remain elusive. In this work, we examined the detailed hydrolysis mechanisms of a model nucleoside triphosphate in acidic and neutral solution by means of ab initio simulations. The timescale of the reaction was accessed through use of an accelerated sampling method, metadynamics. Both hydrolyses were found to proceed via different mechanisms; the acidic system reacted by means of concerted general acid catalysis (found to be a so-called D(N)A(N)A(H)D(xh) mechanism), whereas the neutral system reacted by way of a different mechanism (namely, D(N)*A(N)D(xh)A(H)). A neighboring water molecule took on the role of a general base in both systems, which has not been seen before but is a highly plausible reaction path, meaning that substrate-assisted catalysis was not observed in the bulk water environment.     

N-Ethynylation of Anilides Decreases the Double-Bond Character of Amide Bond while Retaining trans-Conformation and Planarity

Activated amide bonds have been attracting intense attention; however, most of the studied moieties have twisted amide character. To add a new strategy to activate amide bonds while maintaining its planarity, we envisioned the introduction of an alkynyl group on the amide nitrogen to disrupt amide resonance by nN→C_sp conjugation. In this context, the conformations and properties of N-ethynyl-substituted aromatic amides were investigated by DFT calculations, crystallography, and NMR spectroscopic analysis. In contrast to the cis conformational preference of N-ethyl- and vinyl-substituted acetanilides, N-ethynyl-substituted acetanilide favors the trans conformation in the crystal and in solution. It also has a decreased double bond character of the C(O)−N bond, without twisting of the amide. N-Ethynyl-substituted acetanilides undergo selective C(O)−N bond or N−C(sp) bond cleavage reactions and have potential applications as activated amides for coupling reactions or easily cleavable tethers.     

Oxidation of organic amide ions by dioxygen

The products of base-catalyzed oxidation of secondary aromatic amines were identified by the GC-MS and EPR techniques as nitroxyls, quinone nitrones, quinone imines, and for diarylamines also as the products of C-N bond cleavage-substituted nitrobenzenes, anilines and phenols. It was shown that nitroxyl radicals are the primary paramagnetic products of the reaction and do not form by the interaction of aminyl radicals with dioxygen. A mechanism of the amide ion oxidation through the nonradical addition of dioxygen to the amide ion at the rate-limiting stage is suggested and discussed.The previous report see Ref. 1.Translated fromIzvestiya Akademii Nauk. Seriya Khimicheskaya, No. 10, pp. 1746–1751, October, 1994.     

The activation of tertiary carboxamides in metal complexes: an experimental and theoretical study on the methanolysis of acylated bispicolylamine copper(II) complexes

It is a well-established concept that the C-N bond cleavage of carboxamide functions is facilitated by the coordination of a metal ion to the carbonyl oxygen atom. In contrast, the alternative C-N bond activation by coordination of a neutral tertiary carboxamide nitrogen atom has not been studied. We present the first results on the effect of nitrogen pyramidalization in N-coordinated metal complexes on the methanolysis of tertiary carboxamide groups. An analysis of the reactions products obtained from the methanol cleavage of [(N-Acyl-bpa)Cu]2+ (bpa = N,N-bispicolylamine) complexes is presented together with experimental and high-level theoretically calculated structures. The strong effect of different anions on the amide pyramidalization and subsequent C-N-bond cleavage is evaluated. We show that dichloro complexes [(N-Acyl-bpa)CuCl2] have much less activated amide groups than the corresponding triflate species. They should therefore be less reactive. However, [(N-Acyl-bpa)CuCl2] complexes dissociate in solution to give cationic monochloro complexes [(N-Acyl-bpa)Cu(S)Cl]+ (S = solvent molecule). Theoretical calculations show that the amide pyramidalization in the monochloro complexes is equal to that in the corresponding CF3SO3- salts. Consequently, chloro and triflato complexes are cleaved with similar rates and efficiencies. Parallels to and differences in the reactivity of purely organic distorted amides are discussed.     

Transamidation of Amides and Amidation of Esters by Selective N–C(O)/O–C(O) Cleavage Mediated by Air- and Moisture-Stable Half-Sandwich Nickel(II)–NHC Complexes

The formation of amide bonds represents one of the most fundamental processes in organic synthesis. Transition-metal-catalyzed activation of acyclic twisted amides has emerged as an increasingly powerful platform in synthesis. Herein, we report the transamidation of N-activated twisted amides by selective N–C(O) cleavage mediated by air- and moisture-stable half-sandwich Ni(II)–NHC (NHC = N-heterocyclic carbenes) complexes. We demonstrate that the readily available cyclopentadienyl complex, [CpNi(IPr)Cl] (IPr = 1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene), promotes highly selective transamidation of the N–C(O) bond in twisted N-Boc amides with non-nucleophilic anilines. The reaction provides access to secondary anilides via the non-conventional amide bond-forming pathway. Furthermore, the amidation of activated phenolic and unactivated methyl esters mediated by [CpNi(IPr)Cl] is reported. This study sets the stage for the broad utilization of well-defined, air- and moisture-stable Ni(II)–NHC complexes in catalytic amide bond-forming protocols by unconventional C(acyl)–N and C(acyl)–O bond cleavage reactions.     

A comprehensive theoretical study on the hydrolysis of carbonyl sulfide in the neutral water

The detailed hydration mechanism of carbonyl sulfide (COS) in the presence of up to five water molecules has been investigated at the level of HF and MP2 with the basis set of 6-311++G(d, p). The nucleophilic addition of water molecule occurs in a concerted way across the C==S bond of COS rather than across the C==O bond. This preferential reaction mechanism could be rationalized in terms of Fukui functions for the both nucleophilic and electrophilic attacks. The activation barriers, DeltaH( not equal) (298), for the rate-determining steps of one up to five-water hydrolyses of COS across the C==S bond are 199.4, 144.4, 123.0, 115.5, and 107.9 kJ/mol in the gas phase, respectively. The most favorable hydrolysis path of COS involves a sort of eight-membered ring transition structure and other two water molecules near to the nonreactive oxygen atom but not involved in the proton transfer, suggesting that the hydrolysis of COS can be significantly mediated by the water molecule(s) and the cooperative effects of the water molecule(s) in the nonreactive region. The catalytic effect of water molecule(s) due to the alleviation of ring strain in the proton transfer process may result from the synergistic effects of rehybridization and charge reorganization from the precoordination complex to the rate-determining transition state structure induced by water molecule. The studies on the effect of temperature on the hydrolysis of COS show that the higher temperature is unfavorable for the hydrolysis of COS. PCM solvation models almost do not modify the calculated energy barriers in a significant way.