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.     

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.     

Total syntheses of the thiopeptides amythiamicin C and D

The thiopeptides amythiamicin C and D were synthesized by employing amide bond formation, a Stille cross-coupling reaction, and two Negishi cross-coupling reactions as key transformations. The central 2,3,6-trisubstituted pyridine ring of the target compounds was introduced as a 2,6-dibromo-3-iodopyridine, which was selectively metalated at the 3-position and connected to the complete Southern fragment of the amythiamicins by a Negishi cross-coupling. For the synthesis of amythiamicin C, this step was followed by a Negishi cross-coupling at C-6 of the pyridine core. Subsequent attachment of the Eastern fragment was achieved by amide bond formation and macrolactam ring closure by a Stille cross-coupling at C-2. The Eastern bithiazole fragment of the amythiamins was constructed also by regioselective metalation and cross-coupling reactions. The pivotal step involved the diastereoselective addition of 4-bromothiazole-2-magnesium bromide to a chiral sulfinyl imine. For the synthesis of amythiamicin D, the order of cross-coupling at C-6, amide bond formation, and cross-coupling at C-2 was changed. The amide bond formation to the Eastern fragment was performed first and it was subsequently attempted to close the macrolactam by an intramolecular regioselective Stille cross-coupling at C-2. Despite the low regioselectivity of this reaction it paved the way to the immediate completion of the amythiamicin D synthesis when followed by a Negishi cross-coupling at C-6 with 2-zincated methyl thiazole-5-carboxylate.     

Gas-phase SN2 reactivity of dicoordinated borinium cations using pentaquadrupole mass spectrometry

We report gas phase ion/molecule reactions between dialkoxyborinium cations (RO-B+-OR) and small organic amides, such as N,N-dimethylformamide and N,N-diethylpropionamide. Besides direct addition at boron, the results show efficient SN2 methyl transfer from the borinium ion to the amide. Isotopic labeling and collision-induced dissociation (CID) of the methyl transfer products demonstrate O-methylation of the amide. Methyl substitution at the alpha-carbon of the amide affects the degree of alkylation and adduct formation. Direct proton abstraction via beta-elimination is a major competitive reaction for substituents other than methyl. Ab initio calculations at the B3LYP/6-31G(d) level indicate that SN2 transmethylation is highly exothermic with O-methylation favored over N-methylation by 14.8 kcal/mol.     

Kinetik der Bromierung von Phenolen und phenolischen Mekrkernverbindungen

The bromination of 15 dinuclear phenolic compounds (dihydroxydiphenylmethanes, methylene bisphenols) by molecular bromine in acetic acid was studied kinetically at 22°C. In all compounds the electrophilic substitution occurred inortho-position to the phenolic hydroxy group of the methyl phenol unit while the non reacting neighboring unit was differently substituted by H, CH₃,t-Bu and NO₂. A decrease in the reaction rate was observed in 2,2′-dihydroxydiphenylmethanes, where the +M-effect of the hydroxy group is diminished by an intramolecular hydrogen bond. The strength of this hydrogen bond may be influenced mainly by steric factors. Strong electron withdrawing substituents like NO₂ show a rate decreasing influence on the reactivity of the neighboring unit also in 2,4′- and 4,4′-dihydroxydiphenylmethanes.     

CX_2(X=H,F,Cl)与甲基异丙基醚C-H键插入反应的理论研究

用从头计算方法在MP2 /6 31G(d)水平上研究了CX2 (X =H ,F ,Cl)与甲基异丙基醚的C -H键插入反应。CCl2 与甲基异丙基醚两个不同的α C的C -H键插入势垒分别为 117.2kJ/mol (甲基 )和 2 0 .6kJ/mol (异丙基 )。CF2 与异丙基α C的C -H键上插入势垒为 12 0 .0kJ/mol,在插入甲基上C -H键时会引起C -O键的断裂。CH2 的插入反应则不需要势垒。对CX2 与二甲醚、甲乙醚、甲基异丙基醚、甲基苄基醚上各种不同的C -H键插入势垒进行了比较 ,甲基和苯基都促使其毗邻的C -H键更容易被CX2 所插入     

乙酰胆碱水解反应的从头算研究

本文对乙酰胆碱水解反应历程进行了从头算分子轨道研究。首先, 我们在RHF/6-31G级别上研究了乙酰胆碱的水解反应的势能面, 找到了反应过程中的两个过渡态和连接这两个过渡态的中间体。然后进行了RHF/6-31G**级别上的单点能量计算。优化结果表明在两个过渡态中都包含有四元环状结构, 而且, 两个过渡态的四元环中存在着不同的分子内氢键。计算结果还表明,乙酰胆碱最终分解成胆碱和乙酸盐部分时, 酯键的断裂发生在羰基碳和酯基氧之间。最后, 进一步考虑溶剂化效应, 我们还运用量子Onsager模型, 在RHF/6-31G**级别上对整个水解反应的反应物、产物、中间体和过渡态分别进行了从头算自洽反应场能量计算, 求出了包含溶剂化效应在内的反应的能垒及总反应热。     

Peptide bond vibrational coupling

Neutral trialanine (Ala3), which is geometrically constrained to have its peptide bond at Phi and Psi angles of alpha-helix and PPII-like conformers, are studied at the B3LYP/6-31+G(d,p) level of theory to examine vibrational interactions between adjacent peptide units. Delocalization of the amide I, amide II, and amide III3 vibrations are analyzed by calculating their potential energy distributions (PED). The vibrational coupling strengths are estimated from the frequency shifts between the amide vibrations of Ala3 and the local amide bond vibrations of isotopically substituted Ala3 derivatives. Our calculations show the absence of vibrational coupling of the amide I and amide II bands in the PPII conformations. In contrast, the alpha-helical conformation shows strong coupling between the amide I vibrations due to the favorable orientation of the C=O bonds and the strong transitional dipole coupling. The amide III3 vibration shows weak coupling in both the alpha-helix and PPII conformations; this band can be treated as a local independent vibration. Our calculated results in general agree with our previous experimental UV Raman studies of a 21-residue mainly alanine-based peptide (AP).     

Amide bond cleavage: acceleration due to a 1,3-diaxial interaction with a carboxylic acid

To independently assess the contribution of ground-state pseudoallylic strain to the enormous rates of amide bond cleavage in tertiary amide derivatives of Kemp's triacid, we have studied four amide derivatives of (1alpha-3alpha-5beta)-5-tert-butyl-1,3-cyclohexanedicarboxylic acid. Our results demonstrate that absent pseudoallylic strain, a 1,3-diaxial interaction of an amide with a carboxylic acid leads to only a 2400-fold increase in the rate of amide bond cleavage as compared with the rate of hydrolysis of an unactivated peptide bond.     

An efficient approach to azirino and pyrrolo-fused dibenzazepines. Conformations of substituted dibenzo[c,f]pyrrolo[1,2-a]azepines

An effective approach to azepino-fused heterocycles is described. trans-1-Aryl-7,11b-dihydro-1H-azirino[1,2-a]dibenzo[c,f]azepines were synthesised via a domino sequence: isomerization of gem-dichloroaziridine-intramolecular Friedel-Crafts acylation of the tethered benzene ring catalysed by SnCl(4) and subsequent hydride induced intramolecular cyclization. Cycloaddition of dibenzazepinium ylides, generated by heating these aziridines, to activated C[double bond]C, C[triple bond]C dipolarophiles and fullerene C(60), leads to derivatives of dibenzo[c,f]pyrrolo[1,2-a]azepine. The reaction proceeds with complete stereoselectivity via cycloaddition of only W-ylide, which due to the high barrier does not undergo E,Z-isomerization under the reaction conditions. It was found that 2,3,9,13b-tetrahydro-1H-dibenzo[c,f]pyrrolo[1,2-a]azepine systems can exist in conformations of two types depending on the substituents at the pyrrolidine carbons in β-position with respect to nitrogen. Details of cycloaddition reactions and the conformational behavior of cycloadducts were studied by DFT calculations at the B3LYP/6-31G(d) level.     

Computational study on nonenzymatic peptide bond cleavage at asparagine and aspartic acid

Nonenzymatic peptide bond cleavage at asparagine (Asn) and glutamine (Gln) residues has been observed during peptide deamidation experiments; cleavage has also been reported at aspartic acid (Asp) and glutamic acid (Glu) residues. Although peptide backbone cleavage at Asn is known to be slower than deamidation, fragmentation products are often observed during peptide deamidation experiments. In this study, mechanisms leading to the cleavage of the carboxyl-side peptide bond of Asn and Asp residues were investigated using computational methods (B3LYP/6-31+G**). Single-point solvent calculations at the B3LYP/6-31++G** level were carried out in water, utilizing the integral equation formalism-polarizable continuum (IEF-PCM) model. Mechanism and energetics of peptide fragmentation at Asn were comparatively analyzed with previous calculations on deamidation of Asn. When deamidation proceeds through direct hydrolysis of the Asn side chain or through cyclic imide formationvia a tautomerization routeit exhibits lower activation barriers than peptide bond cleavage at Asn. The fundamental distinction between the mechanisms leading to deamidationvia a succinimideand backbone cleavage was found to be the difference in nucleophilic entities involved in the cyclization process (backbone versus side-chain amide nitrogen). If deamidation is prevented by protein three-dimensional structure, cleavage may become a competing pathway. Fragmentation of the peptide backbone at Asp was also computationally studied to understand the likelihood of Asn deamidation preceding backbone cleavage. The activation barrier for backbone cleavage at Asp residues is much lower (approximately 10 kcal/mol) than that at Asn. This suggests that peptide bond cleavage at Asn residues is more likely to take place after it has deamidated into Asp.     

The reaction mechanism of the gas‐phase thermal decomposition kinetics of neopentyl halides: A DFT study

The kinetics and mechanisms of the gas‐phase elimination reactions of neopentyl chloride and neopentyl bromide have been studied by means of electronic structure calculations using density functional methods: B3LYP/6‐31G(d,p), B3LYP/ 6‐31++G(d,p), MPW1PW91/6‐31G(d,p), MPW1PW91/6‐31++G(d,p), PBEPBE/6‐31G(d,p), PBEPBE /6‐31++G(d,p). The reaction channels that account in products formation have a common first step involving a Wagner‐Meerwein rearrangement. The migration of the halide from the terminal carbon to the more substituted carbon is followed by beta‐elimination of HCl or HBr to give two olefins: the Sayzeff and Hoffmann products. Theoretical calculations demonstrated that these eliminations proceed through concerted asynchronous process. The transition state (TS) located for the rate‐determining step shows the halide detached and bridging between the terminal carbon and the quaternary carbon, while the methyl group is also migrating in a concerted fashion. The TS is described as an intimate ion‐pair with a large negative charge at the halide atom. The concerted migration of methyl group provides stabilization of the TS by delocalizing the electron density between the terminal carbon and the quaternary carbon. The B3LYP/6‐31++G(d,p) allows to obtain reasonable energies and enthalpies of activation. The nature of these reactions is examined in terms of geometrical parameters, electron distribution, and bond order analysis. © 2011 Wiley Periodicals, Inc. Int J Quantum Chem, 2011     

A mass spectrometric and ab initio study of the pathways for dehydration of simple glycine and cysteine-containing peptide [M+H]+ ions

The gas phase fragmentation reactions of the [M+H]⁺ and [M+H?H²O]⁺ ions of glycylglycine, glycylcysteine, N-acetylglycine, N-acetylcysteine, their corresponding methyl esters, as well as several other related model systems have been examined by electrospray ionization (ESI) tandem mass spectrometry (MS ⁿ ) using triple quadrupole and quadrupole ion trap mass spectrometers. Two discrete gas phase fragmentation pathways for the loss of water from glycine-containing peptides, corresponding to retro-Koch and retro-Ritter type reactions were observed. Two pathways were also observed for the loss of water from C-terminal cysteine-containing peptides: a retro-Koch type reaction and an intramolecular nucleophilic attack at the carbonyl of the amide bond by the cysteinyl side chain thiol. Various intermediates involved in these reactions, derived from the [M+H?H²O]⁺ ions of N-formylglycine and N-formylcysteine, were modeled using ab initio calculations at the MP2(FC)/6-31G*//HF/6-31G* level of theory. These calculations indicate that: (i) the retro-Koch reaction product is predicted to be more stable than the product from the retro-Ritter reaction for N-formylglycine, and (ii) the intramolecular nucleophilic attack product is preferred over the retro-Koch and retro-Ritter reaction products for N-formylcysteine. The results from these ab initio calculations are in good agreement with the experimentally determined ion abundances for these processes.     

Some Aspects of the Reaction of Polyacrylamide with Formaldehyde

The reaction of polyacrylamide with formaldehyde was studied in a neutral aqueous medium at equal initial molar concentrations of amide groups and of formaldehyde (0.05 mol/L) and in a range of temperatures from 45 to 75°C. The process was investigated by measuring the loss of free formaldehyde in the reaction mixture and the changes of the sum of free formaldehyde and methylol groups versus time. The addition of HCHO to an amide function of the polymer leads to its N-methylol derivative which may transform into the product of condensation between the latter and another amide group. Because of high dilution of polyacrylamide macromolecules in the reaction mixtures studied, cross-linking of the polymer chains with formaldehyde is rather unlikely. Therefore the disappearance of the N-methylols formed is probably due to some intramolecular reactions. It is believed that they involve the condensation of N-hydroxymethyls with neighboring amide groups which results in cyclic structures containing methylenediamide sequences. The occurrence of intramolecular reactions was confirmed by applying Flory's theory of gelation. The addition of HCHO to amide functions is a rate-determining stage in the case of polyacrylamide. For this reaction the rate constants were estimated and the corresponding activation energy was found to be 62 kJ/mol.     

X-ray crystallographic analysis of N,N-diallylcoumarincarboxamides and the solid-state photochemical reaction

X-ray crystallographic analysis and the photochemical aspects of N,N-diallylcoumarincarboxamides were investigated. Irradiation of the corresponding amides promoted stereoselective intramolecular cyclobutane formation exclusively. The solid-state photoreaction of the coumarinamide without substituent on the 4-position proceeded in a crystal-to-crystal manner. On the other hand, photolysis of the amide possessing a methyl group at the 4-position also effected 2+2 cycloaddition; however, the reaction proceeded much slower. The difference in the reactivity was explainable on the basis of the molecular conformation in the crystal lattice.     

Probing the electronic structure of peptide bonds using methyl groups

The observed V3 torsional barriers measured by microwave spectroscopy for nine methyl groups attached alpha to peptide bond linkages in five gas-phase biomimetics have been found to differ considerably from one molecule to the next and even depend on the position of substitution, being sensitive to structural changes at the other end of the peptide bond. In the search for an explanation for these results, ab initio calculations have been performed at the HF/6-311++G(d,p) level of theory and interpreted in terms of the natural bond orbitals and resonance structures of the peptide bond. These calculations reveal that resonance delocalization in peptide bonds is influenced by methyl conformation through the coupling of vicinal sigma to sigma* orbital interactions with the n to pi*. Thus, CN double-bond character increases (and CO double-bond character decreases) as the methyl group is rotated from the syn to the anti position. A quasilinear correlation exists between the barriers to internal rotation of attached methyl groups and the relative importance of the two principal resonance structures that contribute to the peptide bond.     

分子内氮原子上亲核取代反应的理论研究

Using the -CHR-(CH2)3-NFCH3(R=H, CH3, CH2CF3, CHO, COCH3) as the computational model, the two possible intramolecular reactions, nucleophilic substitution on nitrogen and elimination reaction, were studied at the theoretical level of MP2(full)/6-31+G(d,p). The results indicate that the elimination mechanism, when the -CHR radical is more basic (R=H, CH3, CH2CF3) leading to linear products R-CH2-(CH2)3N=CH2 is preferred. In contrast, electro-withdrawing groups CHO and COCH3 on the attacking site will favor the intramolecular nucleophilic substitution of nitrogen and form 5-membered heterocyclic compounds. These theoretical predictions agree with the available experiments.     

Hydrogen/deuterium exchange in gas phase reactions of anions with some alkyl phenyl ethers

The gas phase reactions of anions with methyl and ethyl phenyl ether have been studied by Fourier Transform Ion Cyclotron Resonance Mass Spectrometry. ¹⁸O-Labelling has shown that part of the reactions of OH^- with methyl phenyl ether proceed via ipso-substitution, the main reaction channel being S_N2 substitution. Deuterium labelling has shown that extensive inter- and intramolecular hydrogen/deuterium exchange can precede the final substitution reaction. Hydrogen atoms originating from the methoxy substituent are involved in this exchange process. The reactions of anions with ethyl phenyl ether proceed mainly via an elimination mechanism. Deuterium labelling has shown that in some cases hydrogen/deuterium exchange takes place prior to elimination.     

Synthetic transformations of higher terpenoids: XVII. Intramolecular cyclization of N-furfuryl amides of the labdane series

16-(Benzylaminomethyl)lambertianic acid methyl ester reacts with 2-methylprop-2-enoyl chloride to give unsaturated amide which readily undergoes intramolecular [4 + 2]-cycloaddition with formation of terpenoid derivatives of 10-oxa-3-azatricyclo[5.2.1.0^1,5]decenone. Acetylation of lambertianic acid methyl ester with acetic anhydride occurs preferentially at the 2-position of the furan ring and is accompanied by migration of the exocyclic double bond. Reductive amination of 16-acetyl-15,16-epoxylabda-8(9),13,14-triene and subsequent reaction of the resulting amine with 2-methylprop-2-enoyl chloride give intramolecular cyclization products in high yield without isolation of intermediate furfurylacryloyl derivative. Reactions of methyl 16-(benzylaminomethyl)-15,16-epoxylabda-8(9),13,14- and -8(17),13,14-trien-18-oates with maleic anhydride lead to the formation of the corresponding 10-oxa-3-azatricyclo[5.2.1.0^1,5]dec-8-ene-6-carboxylic acid derivatives as mixtures of diastereoisomers.     

Theoretical study on the pyrolysis mechanism and kinetics of β-hydroxyketones

The mechanism and kinetics for the decomposition of β-hydroxypropaldehyde, primary and secondary β-hydroxyketones, were studied by using ab initio RHF/6–31G and RHF/6–31G^* methods. The activation barriers of these reactions were refined to be 39.57, 40.10, and 36.80 kcal mol⁻¹ at the MP2/ /RHF/6–31G^* level, respectively. The calculated results show that each decomposition is a concerted process with hydrogen transferring and bond breaking via a six-membered cyclic transition state. The thermal rate constants of the decomposition of primary and secondary β-hydroxyketones were obtained by calculating microcanonical probability fluxes through each transition state. It is theoretically confirmed that methyl substitution at the hydroxyl carbon of β-hydroxyketones causes a small enhancement in rates. The theoretical investigations of the mechanism and the rate constants are in agreement with the experimental results. © 1997 John Wiley & Sons, Inc.