Prototropic Rearrangement Research Articles

Carboxyl-Catalyzed Prototropic Rearrangements in Histidine Peptide Radicals upon Electron Transfer: Effects of Peptide Sequence and Conformation

We report an unusual prototropic rearrangement in gas-phase radicals formed by collisional electron transfer from cesium atoms to protonated peptides HAL, AHL, and ALH at 50 keV. The rearrangement depends on the peptide amino acid sequence and presence or steric accessibility of a free carboxyl group. Upon electron transfer, protonated HAL and ALH rearrange to tautomers that are detected as nondissociated anions in charge-reversal mass spectra. The isomerization is minor in protonated ALH and virtually absent in HAL amide. Electron structure calculations indicate that the gas-phase ions are preferentially protonated in the His imidazole ring and consist of multiple conformers that differ in their hydrogen bonding patterns. Electron transfer to protonated HAL and AHL triggers an exothermic and dynamically barrierless transfer of the carboxyl proton onto the C-2' position of the His ring that occurs on a 120-240 ns time scale. The kinetics of this isomerization are controlled by internal rotations in the radicals to assume conformations favoring the proton transfer. The radical conformations also affect subsequent proton migrations in zwitterionic His imidazoline intermediates that reform the COOH group and result in His ring isomerization. This autocatalytic prototropic rearrangement in gas-phase peptide radicals is analogous to enzyme catalytic reactions involving His and acidic amino acid residues. In contrast to HAL and AHL, the C-2' position is sterically inaccessible in ALH radicals. These radicals undergo proton migrations to the His ring C-5' positions that have moderate energy barriers and are less efficient. RRKM calculations on the combined B3LYP and PMP2/6-311++G(2d,p) potential energy surface of the ground doublet electronic state of the peptide radicals provided rate constants that were quantitatively consistent with the dissociations observed in the gas phase. The formation of minor sequence z(1) and z(2) fragments from AHL was interpreted as occurring in the first excited state of the radical.

The modification of acetate and propionate side chains during the biosynthesis of haem and chlorophylls: mechanistic and stereochemical studies.

In the conversion of uroporphyrinogen III into protoporphyrin IX and thence into chlorophylls, all eight carboxylic side chains, as well as the four meso positions, are modified, and four enzymes are involved. In the uroporphyrinogen decarboxylase-catalysed reaction all four acetate side chains are converted into methyl groups by the same mechanism, to produce coproporphyrinogen III. Both methylene hydrogen atoms remain undisturbed and the reaction occurs with the retention of stereochemistry. Several questions regarding the enzymology of the decarboxylase are posed. Do all the decarboxylations occur at the same active site and, if so, are the four acetate chains handled in a particular sequence? Is the decarboxylation reaction aided by the transient formation of an electron-withdrawing functionality in the pyrrole ring? Coproporphyrinogen oxidase converts the two propionate side chains of rings A and B into vinyl groups, with an overall anti-periplanar removal of the carboxyl group and the Hsi from the neighbouring position. Evidence is examined to evaluate whether a hydroxylated compound acts as an intermediate in the oxidative decarboxylation reaction. Protoporphyrinogen oxidase then converts the methylene-interrupted macrocycle of protoporphyrinogen IX into a conjugated system. The conversion has been suggested to involve three consecutive dehydrogenation reactions followed by an isomerization step. The face of the macrocycle from which the three meso hydrogen atoms are removed in the dehydrogenation reaction is thought to be opposite to that from which the fourth meso hydrogen is lost during the prototropic rearrangement. In an investigation of the in vivo mechanism for the esterification of the ring D propionic acid group with a C20 isoprenyl group 5-aminolaevulinic acid was labelled with 13C and 18O at C-1 and incorporated into bacteriochlorophyll a. The 18O-induced shift of the 13C resonance in the NMR spectrum showed that both oxygen atoms of the carboxyl group are retained in the ester bond. This and other results suggest that the reaction occurs by the nucleophilic attack of the ring D carboxylate anion on the activated form of an isoprenyl alcohol.

Conjugate Additions of Cyclic Oxygen‐Bound Nickel Enolates to α,β‐Unsaturated Ketones

The reaction of nickel enolates displaying a metallacyclic structure with the alpha,beta-unsaturated ketones methyl vinyl ketone (MVK) or methyl propenyl ketone (MPK) takes place in two stages, affording initially bicyclic adducts, which subsequently isomerize to the corresponding open-chain products. The former are generated with high stereoselectivity and can be considered as the products of the [2+4] cycloaddition of the enolate to the enone. The ring opening process involves a prototropic rearrangement that can be catalyzed by water. In the case of the reaction of the parent nickel enolate complex 1 (which displays an unsubstituted Ni-O=C(R)CH2 arrangement) with MVK, a double-addition process has been observed, consisting of two successive cycloaddition/isomerization reactions. The carbonylation of the different cyclic and noncyclic products affords the corresponding lactones that retain the stereochemistry of the organometallic precursors. This methodology allowed trapping the primary product of the reaction of 1 with MPK as the corresponding organic lactone, demonstrating that the cycloaddition process takes place with exo selectivity. DFT modeling of the latter reaction provides further support for a quasi-concerted cycloaddition mechanism, displaying a nonsymmetric transition state in which the C-C and the C-O bond are formed in an asynchronous manner.

Synthesis of 3‐Aryl‐5‐dichloromethyl‐1H‐pyrazole‐1‐carboxamides from 1‐Aryl‐3,4,4‐trichlorobut‐3‐en‐1‐ones.

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Synthesis of 3-aryl-5-dichloromethyl-1H-pyrazole-1-carboxamides from 1-aryl-3,4,4-trichlorobut-3-en-1-ones

The reaction of 1-aryl-3,4,4-trichlorobut-3-en-1-ones with semicarbazide hydrochloride in the presence of sodium acetate is accompanied by prototropic allylic rearrangement, leading to the formation of two isomeric products, semicarbazones of the initial ketones and 1-aryl-3,4,4-trichlorobut-2-en-1-one semicarbazones. The latter undergo heterocyclization in the presence of triethylamine to give the corresponding 3-aryl-5-dichloromethyl-1H-pyrazole-1-carboxamides.

Halogenation of N-substituted p-quinone imines and p-quinone oxime esters: IV. Chlorination and bromination of N-arylsulfonyl-2(3)-methyl(2-chloro)-1,4-benzoquinone monoimines

The addition of halogens to N-arylsulfonyl-1,4-benzoquinone imines, which exist in a solution as Z and E isomers, is controlled by the steric factor. Z-E Isomerization strongly affects the stability of cyclohexene structures formed by halogenation of 1,4-benzoquinone imines. The halogenation of N-arylsulfonyl-1,4-benzoquinone imines was found to be accompanied by prototropic rearrangement.

Synthesis of Indeno‐Fused Derivatives of Quinolizinium Salts, Imidazo[1,2‐a]pyridine, Pyrido[1,2‐a]indole, and 4H‐Quinolizin‐4‐one via Benzannulated Enyne—Allenes.

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First Propargyl Azides Bearing Strong Acceptor Substituents and Their Effective Conversion into Allenyl Azides: Influence of the Electronic Effects of Substituents on the Reactivity of Propargyl Azides

AbstractWe have succeeded in the synthesis of propargyl azides containing 1‐ or 3‐phenylthio functionalities. The selective oxidation of their sulfur atoms to sulfoxides and sulfones allows access to the first propargyl azides bearing acceptor substituents. Interestingly, the prototropic rearrangement of the latter propargyl azides leads to the formation of allenyl azides with relatively high stabilities and with moderate to good yields. Propargyl azides containing phenylthio functionalities react in the presence of nucleophiles to afford the expected N‐unsubstituted 1,2,3‐triazoles via short‐lived allenyl azides. These results are entirely different from those of the corresponding sulfoxides and sulfones, which react under the analogous conditions either to produce the corresponding bis(triazolo)pyrazine derivatives or to yield newly substituted vinyl azides. The latter compounds can successfully be used as starting material providing access to azirines. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2005)

Synthesis of Indeno-Fused Derivatives of Quinolizinium Salts, Imidazo[1,2-a]pyridine, Pyrido[1,2-a]indole, and 4H-Quinolizin-4-one via Benzannulated Enyne−Allenes

The benzannulated enediynyl propargylic alcohol 8 was prepared from 1-bromo-2-iodobenzene by two consecutive Sonogashira cross-coupling reactions. The subsequent transformation to mesylate 9 followed by treatment with 4-substituted pyridines 10 then furnished the benzannulated enediynes 11. On exposure of 11 to triethylamine, the indeno-fused quinolizinium salts 15 were produced in quantitative yield. Presumably the reaction proceeded through a 1,3-prototropic rearrangement to form the benzannulated enyne-allenes 12, which then underwent either a concerted Diels-Alder reaction or a two-step process involving a Schmittel cyclization reaction to form biradical 13 followed by an intramolecular radical-radical coupling to afford 14. A subsequent prototropic rearrangement then produced 15. Similarly, 21a and 21b were produced from 19a and 19b, respectively. The use of the Sonogashira reaction for cross-coupling between 1-iodo-2-(phenylethynyl)benzene (7) and 1-(2-propynyl)-1H-imidazole (25) followed by treatment of the resulting adduct with potassium tert-butoxide gave the indeno-fused imidazo[1,2-a]pyridine 24 in 98% yield. Similarly, the indeno-fused pyrido[1,2-a]indole 32 and 4H-quinolizin-4-one 35 were obtained by starting from 7 for cross-coupling with 1-(2-propynyl)-1H-indole (30) and 1-(2-propynyl)-2(1H)-pyridinone (33), respectively, followed by treatment with potassium tert-butoxide.

Unusual reactivity of 3-chloro-1-pentafluorosulfanylpropene in nucleophilic substitution reactions

Treatment of 3-chloro-1-pentafluorosulfanylprop-1-ene 1 with KCN yielded the product of prototropic rearrangement ClCH CHCH 2SF 5, whereas reactions with NaN 3 and KSCN gave the S N2 products. Ab initio calculations at MP2/6-311++G** level are used to explain the unusual behaviour of cyanide. It was found that proton transfers from both 1 to CN − and from HCN to the anion of 1 are exothermic. In contrast, azide and thiocyanate ions are too weakly basic to deprotonate 1 .

Tunneling effects of dyadic prototropic rearrangement of hypophosphorous acid

The structures and energies of the tautomeric forms of hypophosphorous acid and phosphine oxide were calculated by DFT. The tautomeric forms are in equilibrium, and intramolecular hydrogen bonding is shown to be possible in both tautomeric forms of phthalimidophosphorous acid. The equilibrium constants are estimated within a wide temperature range. The necessity to take into account the tunneling contribution to the rate constant of the rearrangement is demonstrated.

Prototropic Rearrangement of 2‐Propynyl(methyl)amino, 2‐Propynyloxy, and 2‐Propynylsulfanyl Derivatives of Hetarenes under Conditions of Phase‐Transfer Catalysis: Mechanism and Limitations.

2-Propynyl derivatives of N-methylaniline, phenol, benzenethiol, 2-pyridinethiol, 2-pyrimidinethiol, and 1,3-benzoxazole-2-thiol were synthesized. Under conditions of phase-transfer catalysis, phenyl 2-propynyl sulfide is converted into allenyl phenyl sulfide and phenyl 1-propynyl sulfide. The rearrangement mechanism was studied by the AM1 quantum-chemical method.

Functionally Substituted Amides and Esters of 3,4,4-Trichloro-3-butenoic Acid

Substituted amides and esters of 3,4,4-trichloro-3-butenoic acid were prepared by reactions of its chloride with appropriate amines and alcohols. Treatment of 3,4,4-trichloro-3-butenomorpholide and tert-butyl 3,4,4-trichloro-3-butenoate results in nucleophilic substitution of the internal chlorine atom with the morpholine residue, accompanied by prototropic allyl rearrangement.

Polycyclic Aromatic Compounds via Radical Cyclizations of Benzannulated Enyne‐Allenes Derived from Ireland—Claisen Rearrangement.

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Reactions of Heterocumulenes with Organometallic Reagents: IX. Synthesis and Rearrangements of N-Allyl-and N-[2-(Vinyloxy)ethyl]-3-butenethioamides and -1-(methylsulfanyl)-3-buten-1-imines

Reactions of allyl and 2-(vinyloxy)ethyl isothiocyanates with alyylmagnesium bromide (THF-Et2O, 20-30°C, 1-3 h) after hydrolysis or alkylation of adducts afforded respectively N-allyl- and N-[2-(vinyloxy)ethyl]-3-butenethioamides or N-allyl- and N-[2-(vinyloxy)ethyl]-1-(methylmercapto)-3-buten-1-imines. The reaction carried out in ethyl ether yielded instead of Nt-allyl-3-butenethioamide its isomer N-allyl-2-butenethioamide that cleanly isomerized in the system KOH-DMSOH2O into N-(1-propenyl)-2-butenethioamide. N-[2-(vinyloxy)ethyl]-3-butenethioamide suffers a prototropic rearrangement into N-[2-(vinyloxy)ethyl]-2-butenethioamide only in the system

Quantum Chemical Study of Spatial Structure and Stereoelectronic Properties of Iminodihydrofuran Ensembles

A quantum chemical study of structural peculiarities of iminodihydrofuran ensembles (from dimers to tetramers with individual calculations for penta- and hexamers) associated with their rotation isomerism was carried out. Three basic spatial packings of the iminodihydrofuran chains were distinguished with increasing the number of ensemble elements. The spiral and linear packings are equally probable from the standpoint of their thermodynamic stability. The third packing, exhibiting the curvature radius, is inferior to the former two, as judged from the relative stability. It was shown that ensembles in the alternating linear-spiral form are fundamentally possible to exist. Data was obtained testifying to a possibility for the intramolecular hydrogen bond forming between the imine and amine moieties in the tetramer spiral structures; activation barriers of intramolecular prototropic rearrangement were determined.

Polycyclic aromatic compounds via radical cyclizations of benzannulated enyne-allenes derived from Ireland-Claisen rearrangement.

A new synthetic sequence involving the use of Ireland-Claisen rearrangement of propargylic acetates to form the corresponding benzannulated enyne-allenes followed by Schmittel cyclization to generate benzofulvene biradicals for radical cyclizations leading to polycyclic aromatic compounds was established. Treatment of 9-fluorenone (8) with the lithium acetylide 9 followed by acetic anhydride produced the propargylic acetate 10. A sequence of reactions occurred after 10 was converted to the corresponding silyl ketene acetal 11. An initial Ireland-Claisen rearrangement produced the benzannulated enyne-allene 12, which then underwent a Schmittel cyclization reaction to generate the benzofulvene biradical 13. A subsequent intramolecular radical-radical coupling then produced the formal Diels-Alder adduct 14, which in turn underwent a prototropic rearrangement to give the silyl ester 15 and, after hydrolysis, the carboxylic acid 16 in 57% overall yield from 10 in a single operation. An intramolecular acylation reaction of 16 produced the ketone 17. The carboxylic acids 24-26 were likewise prepared from the diaryl ketones 18-20, respectively. However, the intramolecular [2 + 2] cycloaddition reaction of the benzannulated enyne-allene 33 having a tert-butyl group at the allenic terminus occurred preferentially, producing the 1H-cyclobut[a]indenyl acetic acid 35 as the predominant product.

Prototropic Rearrangement of 2-Propynyl(methyl)amino, 2-Propynyloxy, and 2-Propynylsulfanyl Derivatives of Hetarenes under Conditions of Phase-Transfer Catalysis: Mechanism and Limitations

2-Propynyl derivatives of N-methylaniline, phenol, benzenethiol, 2-pyridinethiol, 2-pyrimidinethiol, and 1,3-benzoxazole-2-thiol were synthesized. Under conditions of phase-transfer catalysis, phenyl 2-propynyl sulfide is converted into allenyl phenyl sulfide and phenyl 1-propynyl sulfide. The rearrangement mechanism was studied by the AM1 quantum-chemical method.

Sulfur Versus Oxygen in Interaction with the Double Bond: AB Initio Study of Electronic Structure and Prototropic Rearrangement of 1-Methoxy-2-propene and 1-Methylthio-2-propene

The ab initio calculations of 1-methoxy-2-propene ( 1 ), 1-methylthio-2-propene ( 2 ), and their anions are performed using the RHF/6-31+G* geometry optimization followed by MP2/6-31+G* energy calculations. Both 1 and 2 are found to rearrange toward 1-substituted 1-propenes with a comparable exothermic effect. However, the proton abstraction energies of 1 and 2 differ significantly. So, the acidity of propene is just slightly affected by the OCH 3 group while the SCH 3 group decreases its proton abstraction energy by 17.5 kcal/mol. Changes in charge distribution, bond lengths and bond orders suggest the negative hyperconjugation to stabilize anions of 2 but not that of 1 . This divergence is explained with a difference in sulfur and oxygen electronegativity. The d -functions of both sulfur and oxygen act in polarization. The Z -isomer of anion 1 is found to be by 2.9 kcal/mol more stable than its E -isomer, this could provide a predominant kinetic formation of the less stable Z -isomer of 1-methoxy-1-propene under base catalysis.

Reactivity of phosphate monoester monoanions in aqueous solution. 1. Quantum mechanical calculations support the existence of "anionic zwitterion" MeO(+)(H)PO(3)(2-) as a key intermediate in the dissociative hydrolysis of the methyl phosphate anion.

The dissociative hydrolysis reaction of the methyl phosphate monoanion has been studied for the reactant species CH(3)OPO(3)H(-) (1) and CH(3)OPO(3)H(-) x H(2)O (1a) in the gas and aqueous phases by density functional theory (B3LYP) calculations. Nonspecific solvation effects were taken into account with the polarizable continuum model PCM either by solvating the gas-phase reaction paths or by performing geometry searches directly in the presence of the solvation correction. In agreement with previous theoretical studies, our gas-phase calculations indicate that proton transfer to the methoxy group of 1 is concerted with P-O bond cleavage. In contrast, optimizations performed with the PCM solvation model establish the existence of the tautomeric form CH(3)O(+)(H)PO(3)(2-) (2) as an intermediate, indicating that proton transfer and P-O bond cleavage become uncoupled in aqueous solution. The dissociative pathway of 1a is energetically favored over the dissociative pathway of 1 only when the added water molecule plays an active catalytic role in the prototropic rearrangement 1 <--> 2. In that case, it is found that the collapse (via P-O bond cleavage) of the hydrated zwitterionic form CH(3)O(+)(H)PO(3)(2-) x H(2)O (2a) is rate-determining. This collapse may occur by a stepwise mechanism through a very short-lived metaphosphate intermediate (PO(3)(-)), or by a concerted S(N)2-like displacement through a loose metaphosphate-like transition state. The present calculations do not allow a distinction to be made between these two alternatives, which are both in excellent agreement with experiment. The present study also reveals that PO(3)(-) reacts selectively with CH(3)OH and H(2)O nucleophiles in aqueous solution. However, the observed selectivity of metaphosphate is governed by solvation effects, not nucleophilicity (water being much more effective than methanol in capturing PO(3)(-)). This arises from a better solvation of the addition product H(2)O(+)PO(3)(2-) as compared to CH(3)O(+)(H)PO(3)(2-).