Water-promoted hydrolysis of a highly twisted amide: rate acceleration caused by the twist of the amide bond

The water-promoted hydrolysis of a highly twisted amide is studied using density functional theory in conjunction with a continuum dielectric method to introduce bulk solvent effects. The aim of these studies is to reveal how the twisting of the C-N bond affects the neutral hydrolysis of amides. To do so, both concerted and stepwise mechanisms are studied and the results compared to the ones from the hydrolysis of an undistorted amide used as reference. In addition, an extra explicit water molecule that assists in the required proton-transfer processes is taken into account. Our results predict important rate accelerations of the neutral hydrolysis of amides when the C-N bond is highly twisted, the corresponding barrier relaxation depending on the specific reaction pathway and transition state involved. Moreover, our calculations strongly suggest a change in reaction mechanism with degree of amide bond twist, and clearly point to a concerted mechanism at neutral pH for the hydrolysis of highly twisted amides. In addition, the twisting of the amide bond also provokes a higher dependence on an auxiliary water molecule for the concerted mechanism, due to the orthogonality of the lone pair of the nitrogen and the carbonyl pi orbital. There is a direct implication of these findings for biological catalytic mechanism of peptide cleavage reactions that undergoes ground-state destabilization of the peptide.     

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.     

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.     

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.     

Electrophilicity Scale of Activated Amides: 17O NMR and 15N NMR Chemical Shifts of Acyclic Twisted Amides in N−C(O) Cross-Coupling

The structure and properties of amides are of tremendous interest in organic synthesis and biochemistry. Traditional amides are planar and the carbonyl group non-electrophilic due to n_N→π*_C=O conjugation. In this study, we report electrophilicity scale by exploiting ¹⁷O NMR and ¹⁵N NMR chemical shifts of acyclic twisted and destabilized acyclic amides that have recently received major attention as precursors in N-C(O) cross-coupling by selective oxidative addition as well as precursors in electrophilic activation of N-C(O) bonds. Most crucially, we demonstrate that acyclic twisted amides feature electrophilicity of the carbonyl group that ranges between that of acid anhydrides and acid chlorides. Furthermore, a wide range of electrophilic amides is possible with gradually varying carbonyl electrophilicity by steric and electronic tuning of amide bond properties. Overall, the study quantifies for the first time that steric and electronic destabilization of the amide bond in common acyclic amides renders the amide bond as electrophilic as acid anhydrides and chlorides. These findings should have major implications on the fundamental properties of amide bonds.     

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.     

Structural Characterization of N‐Alkylated Twisted Amides: Consequences for Amide Bond Resonance and N−C Cleavage

Herein, we describe the first structural characterization of N‐alkylated twisted amides prepared directly by N‐alkylation of the corresponding non‐planar lactams. This study provides the first experimental evidence that N‐alkylation results in a dramatic increase of non‐planarity around the amide N?C(O) bond. Moreover, we report a rare example of a molecular wire supported by the same amide C=O‐Ag bonds. Reactivity studies demonstrate rapid nucleophilic addition to the N?C(O) moiety of N‐alkylated amides, indicating the lack of n_N to π^*_C=O conjugation. Most crucially, we demonstrate that N‐alkylation activates the otherwise unreactive amide bond towards σ N?C cleavage by switchable coordination.     

酰胺水化作用的富里埃红外光谱研究及其SCFPPP计算

本文用富里埃红外光谱仪研究了酰胺水化作用引起的红外光谱变化。用SCFPPP方法对五种酰胺进行了计算。含水酰胺的羰基伸缩振动频率向低波数的位移与酰胺和水分子间的氢键强度成正比。其氢键强度与羰基上氧原子的净电荷密度成正比,与酰胺分子的HOMO轨道能量成反比。     

The catalytic hydration of nitriles to amides using a homogeneous platinum phosphinito catalyst

New homogeneous catalysts for the hydration of nitriles to amides are described. The catalyst precursors are coordination compounds of Pt(II) with secondary phosphine oxides. They contain a hydrogen bridged mono-anionic didentate phosphinito group, together with a third phosphine oxide ligand and a monodentate anionic ligand, either hydride or chloride. Reacting the chloride with silver ion, or the hydride with water gives a cationic species which is the active catalyst. On coordination to the cation the nitrile becomes susceptible to nucleophilic attack. The hydrolysis gives the amide as the sole product, and there is no tendency towards further hydrolysis to the acid. The effects of substituents on phosphorus are investigated, and a reaction mechanism is suggested. The most active catalyst, [PtH(PMe₂OH)(PMe₂O)₂H], 2a, is derived from dimethylphosphine oxide, and this precursor catalyses the hydration of acrylonitrile to acrylamide with a turnover number of 77,000, without addition to the C=C double bond.     

Synthesis of a novel diarylphosphinic acid: a distorted ground state mimic and transition state analogue for amide hydrolysis

We describe herein the synthesis of a new unsymmetrical diarylphosphinic acid, a hapten aimed to produce catalytic antibodies for the hydrolysis of heterocyclic amides. The phosphinate functionality was selected as a mimic both of the tetrahedral intermediate and the transition state of higher energy along the reaction profile. The phenyl and 2,4,6-(trimethyl)-phenyl groups flanking the phosphinate were chosen in order to impose rotation around the P–C bond, a choice supported by ab initio calculations. This new hapten should elicit catalytic antibodies whose binding site could affect the distortion at nitrogen as well as the twist along the N–C(O) bond for heterocyclic amides. This hapten along with a series of new sterically hindered unsymmetrical phosphinic acid derivatives was prepared by a key palladium-catalysed step.     

Are the enolates of amides and esters stabilized by electrostatics?

The fact that amides and esters form less stable enolates than ketones might be seen as evidence that electrostatic stabilization is unimportant in these anions. However, ab initio molecular orbital calculations show that electrostatic stabilization does in fact lie beneath the competing resonance effect that causes the decrease in acidity. The electrostatic contribution is revealed by examining torsionally twisted amide and ester structures in which the pi resonance interactions are largely inhibited. These twisted amides and esters have greater enolate acidity than the corresponding ketones. Qualitatively similar behavior is observed with respect to protonation, such that twisted amides and esters are generally less basic than the reference ketones, in striking contrast to their behavior in the normal geometries.     

无痕施陶丁格连接反应机理的理论研究

叠氮化合物和膦硫酯的无痕施陶丁格连接反应是一种有效生成酰胺键的方法. 通过密度泛函方法研究了无痕施陶丁格连接的反应机理. 计算结果表明反应的决速步为反应的第一步, 即膦进攻叠氮的端基氮, 形成膦基叠氮化物的过程. 膦亚胺中间体形成之后, 向不同方向转化(酰基迁移后水解或者直接水解)的难易程度决定了最终产物的组成. 对几种不同偶联试剂介导的无痕施陶丁格连接反应的计算结果, 都与实验数据相吻合.     

Sialic acid biosynthesis: stereochemistry and mechanism of the reaction catalyzed by the mammalian UDP-N-acetylglucosamine 2-epimerase

The bifunctional enzyme, UDP-N-acetylglucosamine 2-epimerase/ManNAc kinase, catalyzes the first two steps in the biosynthesis of the sialic acids in mammals. The epimerase domain converts UDP-GlcNAc into ManNAc and UDP. This paper demonstrates that alpha-ManNAc is the first formed anomer and therefore the reaction proceeds with a net retention of configuration at C-1. Studies in deuterated buffer show that solvent-derived deuterium is quantitatively incorporated into the C-2 position of the product during catalysis, but it is not incorporated into the remaining pool of substrate. This indicates that the inversion of stereochemistry is ultimately brought about by the removal and replacement of a proton at C-2 and is consistent with a two-base mechanism. Studies with (18)O-labeled UDP-GlcNAc show that the anomeric oxygen of the glycosyl phosphate bond departs with the UDP product and therefore the net hydrolysis reaction involves C-O bond cleavage. Incubation of the putative intermediate, 2-acetamidoglucal, with the enzyme resulted in a slow hydration reaction to give the product, ManNAc. Additional kinetic isotope effect and positional isotope exchange (PIX) experiments address the nature of the rate-determining step of the reaction and show that C-H bond cleavage is not rate limiting. Overall, these results support a reaction mechanism involving an anti-elimination of UDP to give 2-acetamidoglucal, followed by a syn-addition of water.     

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.     

How Strong is Hydrogen Bonding to Amide Nitrogen?

The protonation of the carboxamide nitrogen atom is an essential part of in vivo and in vitro processes (cis-trans isomerization, amides hydrolysis etc). This phenomenon is well studied in geometrically strongly distorted amides, although there is little data concerning the protonation of undistorted amides. In the latter case, the participation of amide nitrogen in hydrogen bonding (which can be regarded as the incipient state of a proton transfer process) is less well-studied. Thus, it would be a worthy goal to investigate the enthalpy of this interaction. We prepared and investigated a set of peri-substituted naphthalenes containing the protonated dimethylamino group next to the amide nitrogen atom (“amide proton sponges”), which could serve as models for the study of an intramolecular hydrogen bond with the amide nitrogen atom. X-Ray analysis, NMR spectra, basicity values as well as quantum chemical calculations revealed the existence of a hydrogen bond with the amide nitrogen, that should be attributed to the borderline between moderate and weak intramolecular hydrogen bonds (2–7 kcal ⋅ mol⁻¹).     

Highly enantioselective synthesis of glycidic amides using camphor-derived sulfonium salts. Mechanism and applications in synthesis

The reactions of a range of amide-stabilized sulfur ylides derived from readily available camphor-derived sulfonium salts for the synthesis of glycidic amides have been studied. Primary, secondary, and tertiary amides were tested, and it was found that the highest enantioselectivities were observed with tertiary amides, which provided glycidic amides in good to excellent yields, exclusive trans selectivity, and excellent enantioselectivities. The reaction was general for aromatic aldehydes, but aliphatic aldehydes gave more variable enantioselectivities. The epoxy amides could be converted cleanly into epoxy ketones by treatment with organolithium reagents. We were also able to effect selective ring opening of the epoxy amides with a variety of nucleophiles, followed by hydrolysis of the amide to yield the corresponding carboxylic acid. This methodology was applied to the total synthesis of the target compound SK&F 104353. A combination of crossover experiments and theoretical calculations has revealed that the rate- and selectivity-determining step is ring closure, not betaine formation as was the case for phenyl-stabilized ylides.     

Hydrolysis of fluorosilanes: a theoretical study

Hydrolysis and condensation of simple trifluorosilanes, HSiF3 and MeSiF3, was studied by quantum mechanical methods. Hydrolysis of fluorosilanes is highly endothermic. The Gibbs free energy of the first reaction step in the gas phase is 31.4 kJ/mol, which corresponds to an equilibrium constant of 10(-6). Hydrolysis of the subsequent fluorine atoms in trifluorosilanes is thermodynamically more unfavorable than the first step of substitution. No significant difference in thermodynamics of hydrolysis was found between HSiF3 and MeSiF3. The activation energy for hydrolysis by a water dimer is significantly lower than that for hydrolysis by a water monomer. The former reaction is also less unfavorable thermodynamically, due to a high binding energy of the HF-H2O complex formed as a product of hydrolysis. Self-consistent reaction field (SCRF) calculations show that hydrolysis of trifluorosilanes in aqueous medium has lower activation energy than in the gas phase. It is also thermodynamically less unfavorable, due to better solvation of the products. Homofunctional condensation of HSiF2OH is thermodynamically favored. The equilibrium mixture for hydrolysis/condensation of RSiF3 in water is predicted to contain ca. 2.3% disiloxane (HF2Si)2O, if 100-fold excess of water relative to silane is assumed. Further hydrolysis of (HF2Si)2O is negligible. The thermodynamics of fluorosilane hydrolysis contrasts with that of chlorosilanes, where both hydrolysis and condensation are strongly favorable. Moreover, in the case of trichlorosilanes each subsequent hydrolysis step is more facile, leading to the product of full hydrolysis, RSi(OH)3.     

Unraveling the Role of Water in the Stereoselective Step of Aqueous Proline‐Catalyzed Aldol Reactions

A multiscale computational study was performed with the aim of tracing the source of stereoselectivity and disclosing the role of water in the stereoselective step of propionaldehyde aldol self‐condensation catalyzed by proline amide in water, a reaction that serves as a model for aqueous organocatalytic aldol condensations. Solvent mixing and hydration behavior were assessed by classical molecular dynamics simulations, which show that the reaction between propanal and the corresponding enamine takes place in a fully hydrated environment. First‐principles molecular dynamics simulations were used to study the free‐energy profile of four possible reaction paths, each of which yields a different stereoisomer, and high‐level static first‐principles calculations were employed to characterize the transition states for microsolvated species. The first solvation shell of the oxygen atom of the electrophilic aldehyde at the transition states contains two water molecules, each of which donates one hydrogen bond to the nascent alkoxide and thereby largely stabilizes its excess electron density. The stereoselectivity originates in an extra hydrogen bond donated by the amido group of proline amide in two reaction paths.     

Hydration of simple amides. FTIR spectra of HDO and theoretical studies

The hydration of formamide (F), N-methylformamide (NMF), N,N-dimethylformamide (DMF), acetamide (A), N-methylacetamide (NMA), and N,N-dimethylacetamide (DMA) has been studied in aqueous solutions by means of FTIR spectra of HDO isotopically diluted in H2O. The difference spectra procedure has been applied to remove the contribution of bulk water and thus to separate the spectra of solute-affected HDO. To facilitate the interpretation of obtained spectral results, DFT calculations of aqueous amide clusters were performed. Molecular dynamics (MD) simulation for the cis and trans forms of NMA was also carried out for the SPC model of water. Infrared spectra reveal that only two to three water molecules from the surrounding of the amides are statistically affected, from among ca. 30 molecules present in the first hydration sphere. The structural-energetic characteristic of these solute-affected water molecules differs only slightly from that in the bulk and corresponds to the clathrate-like hydrogen-bonded cage typical for hydrophobic hydration, with the possible exception of F. MD simulations confirm such organization of water molecules in the first hydration sphere of NMA and indicate a practical lack of orientation and energetic effects beyond this sphere. The geometry of hydrogen-bonded water molecules in the first hydration sphere is very similar to that in the bulk phase, but MD simulations have affirmed subtle differences recognized by the spectral method and enabled their understanding. The spectral data and simulations results are highly compatible. In the case of F, NMF, and A, there is a visible spectral effect of water interactions with N-H groups, which have destabilizing influence on the amides hydration shell. There is no spectral sign of such interaction for NMA as the solute. The energetic stability of water H-bonds in the amide hydration sphere and in the bulk fulfills the order: NMA > DMA > A > NMF > bulk > DMF > F. Microscopic parameters of water organization around the amides obtained from the spectra, which have been used in the hydration model based on volumetric data, confirm the more hydrophobic character of the first three amides in this sequence. The increased stability of the hydration sphere of NMA relative to DMA and of NMF relative to DMF seems to have its origin in different geometries, and so the stability, of water cages containing the amides.