Sites For Nucleophilic Attack Research Articles

First-Principles Investigation of Enantioselective Catalysis: Asymmetric Allylic Amination with Pd Complexes Bearing P,N-Ligands

Site selectivity for nucleophilic attack of a π-allyl−Pd(II) complex with a bidentate phosphine−pyrazole ligand by an amine has been investigated with first-principles density functional calculations using the projector augmented wave method. The interplay between steric and electronic effects, namely the trans influence, is elucidated. While the trans influence favors nucleophilic attack at the carbon in a pseudo-trans position to the phosphine, site selectivity is dominated by steric effects between the allyl group and a groove in the catalyst surface, which prescribe an orientation of the allyl out of the P−Pd−N plane. The direction of this out-of-plane orientation determines the site of nucleophilic attack for a given isomer of the allyl complex, irrespective of whether this site is cis or trans to the phosphine. Our results provide insight into the observed relation between isomeric distributions of the allyl complexes and the resulting selectivities.

Molecular modeling of substrate-enzyme reactions for the cysteine protease papain

AM1 quantum mechanical reaction coordinate (RC) calculations were run to simulate the rate-limiting deacylation (hydrolysis) reaction for a series of para- X-PhC(O)NHCH 2C( Y)S-papain intermediates, where X = OCH 3, CH 3, H, Cl, NO 2 and Y = O (thioester) or S (dithioester), for which a large body of structural, kinetic, and spectroscopic data is available. Several reaction zones, in particular the so-designated Large Zone and Small Zone, were extracted for these RC simulations from the fully solvated and energy-minimized X-ray crystal structure of papain ( pdb9pap) bound to the appropriate substrate moiety. The major structural difference between these two zones was the absence of the oxyanion hole in the latter. For both the thioester and dithioester cases, the calculated E a value associated with the parent ( X = H) acyl-enzyme intermediate was lower by ca. 10 kcal/mol for the Large Zone than for the Small Zone. The magnitude of this difference suggests that the oxyanion hole plays a functional if not essential role in stabilizing the anionic tetrahedral intermediate with the cysteine proteases. The calculated E a value was lower by ca. 10 kcal/mol for the thioester [C(O)S] than for the corresponding dithioester [C(S)S], in qualitative agreement with kinetic data for this series of substrates which reveal that the specific rate constant for deacylation k 3 is ca. 60 times larger for the former. This difference is also consistent with both AM1 and 6-31G ∗ calculations on model intermediates, which indicate that the weaker polarity of the dithioester compared with the thioester [i.e., C(←S)S versus C(→O)S] renders the former a much poorer site for nucleophilic attack. The anionic tetrahedral intermediate is energetically more stable for the dithioester than for the corresponding thioester, a finding that is discussed in terms of its kinetic and mechanistic implications. The mode of attack by the H 2O nucleophile is “concerted” rather than “sequential” in terms of the order of proton abstraction by His-159 and nucleophilic attack on the acyl-enzyme intermediate. While the presumably key S thiol ··· N nonbonded contact remained almost constant (ca. 2.90 Å) up to formation of the [TS] structure, the substrate torsion angles φ and ψ rotated significantly as the hybridization around the reaction site transforms from sp 2 to sp 3 during formation of the tetrahedral intermediate. The AM1-calculated frontier molecular orbitals for model thioester and dithioester acyl-enzyme intermediates generally associate the HOMOs with the reaction site and the LUMOs with the benzamide moiety. Computer graphics images corroborate our view that, in relation to the S thiol ··· N interaction, the HOMOs and LUMOs should be identified, respectively, with S thiol and N rather than the reverse, as suggested by other workers.

ChemInform Abstract: Reactions of Cyclic Oxalyl Compounds. Part 37. Substituent Effects on the Site of Nucleophilic Attack at 1H‐Pyrrole‐2,3‐diones.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

The influence of 4-alkyl substituents on the formation and reactivity of 2-methoxy-quinone methides: evidence that extended π-conjugation dramatically stabilizes the quinone methide formed from eugenol

The effects of para-alkyl substituents on both the cytochrome P450-catalyzed oxidation of phenols to quinone methides (QMs; 4-methylene-2,5-cyclohexadien-1-ones), and on the rates of nucleophilic additions to the QMs were investigated. The derivatives of 4-alkyl-2-methoxyphenol studied were 4-methyl (creosol), 4-ethyl, 4-propyl, 4-isopropyl, and 4-allyl (eugenol). The relative reactivities of QMs derived from these phenols with water were 4-methyl > 4-ethyl = 4-propyl > 4-isopropyl > 4-allyl. These variations in rate were rationalized by differences in stabilization of positive charge density at the site of nucleophilic attack. In particular, saturation of the vinyl substituent on eugenol-QM increases the solvolysis rate 100-fold. This effect is presumably due to the loss of the contribution of an additional aromatic resonance structure to the overall resonance hybrid of the QM from 2-methoxy-4-propylphenol. Finally, the kinetic results show that there is a 472-fold difference in reactivity within this series of QMs. The QM glutathione conjugates were synthesized and characterized by 1H-NMR and electrospray mass spectrometry and a HPLC assay was developed to quantify QM formation in rat liver microsomes. The general trend is increasing alkyl substitution at the para position results in more QM; however, in contrast to the large range of reactivities of the QMs observed in the kinetic experiments, the amounts of P450-derived QM GSH adducts varied only by a factor of 3. In particular, similar amounts of the QMs from eugenol and 2-methoxy-4-propylphenol were produced which suggests that the lack of reported hepatotoxicity for the latter phenol in mice depleted of GSH, may be due to the extreme reactivity of 4-propyl-QM that would be rapidly detoxified by hydrolysis. These data suggest that there may be a threshold cytotoxicity level for QMs related to their reactivity which may affect the relative toxicities of 4-alkyl-2-methoxyphenols.

Reactions of cyclic oxalyl compounds, 37. Substituent effects on the site of nucleophilic attack at 1H‐pyrrole‐2,3‐diones

AbstractReactions of 1H‐pyrrole‐2,3‐diones 2a‐i with N‐ and O‐nucleophiles proceed by initial attack at C‐2 or/and C‐5. Consequently, earlier results suggesting structures of type A (attack at C‐3) have to be revised (5, 13, 17, 18b). In general, electron‐withdrawing substituents at C‐4 favor attack at C‐5 with formation of 2‐pyrrolones 5, 6, 10, 13, 17, and 20. Alternatively, attack at C‐2 leads to α‐oxobutenoic acid derivatives 3, 7, 11, 12, 15, and 18. IR and 13C‐NMR spectroscopic techniques were employed to differentiate between the possible isomeric addition products formed. The structure of methyl α‐oxobutenoate 15 was established by an X‐ray crystallo‐graphic analysis.

Associative substitution mechanisms of clusters: the relationship between sites of nucleophilic attack and leaving group dissociation

The associative substitution mechanism of [Fe4S4Cl4]2– with 4-RC6H4S– involves initial, rapid binding of the thiolate to an iron atom (Fea), followed by rate-limiting dissociation of a chloro-ligand; however, the origin of the leaving group changes with the electron-releasing capability of the thiolate and when R = Cl, F, H or Me, the chloro-group at Fea is labilised, whereas when R = Me, MeO or NH2 the chloro-group at a remote iron site (Fer) is labilised.

Theoretical Investigation of Reaction Pathways of 3-Methyloxadiazolinium Ion and 1,2,3-Oxadiazoline: Correlation with Experimental Findings

Quantum mechanical calculations were used to investigate the stability of the 3-methyloxadiazolinium ion and 1,2,3-oxadiazoline and to deter- mine the most probable thermal decomposition pathway of the oxadiazoli- ne. Ab initio RHF calculations were carried out at the 3-21G and 6-31G * basis set level to obtain the optimized SCF energies and geometries of these molecules, as well as that of the protonated 4,5-dihydro-2,3-oxa- diazoline. Only the N2-protonated oxadiazoline was found to be stable; the N1- and O-protonated oxadiazolines underwent immediate decomposi- tion. Calculations on the oxadiazolinium ion confirmed experimental re- sults regarding the most likely site of nucleophilic attack on the mo- lecule. Optimized geometries and energies for the reactant, transition state, and product molecules were obtained at post Hartree-Fock using MP2 and QCISD, as well as the density functional code, DGauss. Compari- son of the optimized geometries of the transition states from the three different bond-breakage processes revealed minor differences in these structures at the various levels of theory

Reaction studies on heterodinuclear alkanediyl complexes: some examples of metalloselectivity

The reactions of some heterobimetallic alkanediyl complexes of the type [(η-C5R5)(OC)2Fe(CnH2n)MLy][R = H, n= 3–6, MLy= Mo(CO)3(cp), W(CO)3(cp), Ru(CO)2(cp) or Re(CO)5; R = Me, n= 3, MLy= Ru(CO)2(cp); cp =η-C5H5] with tertiary phosphines, trityl hexafluorophosphate (Ph3CPF6) and halogens were investigated. The reactions of [(cp)(CO)2Fe(C3H6)MLy] with PPh3 were metalloselective, with the phosphine always attacking the expected metal site, which could be predicted from the reactivities of the corresponding monometallic alkyl or homodinuclear alkanediyl species. The alkanediyl chain length was found not to influence the site of nucleophilic attack. The reactions of [(cp)(OC)2Fe(C3H6)MLy][MLy= Ru(CO)2(cp), Mo(CO)3(cp) or W(CO)3(cp)] with Ph3CPF6 gave the complexes [(cp)(OC)2Fe(C3H5)MLy]PF6, where the β-CH unit is believed to be weakly bonded to both metal centres. The reaction of [(cp)(OC)2Fe(CnH2n)Ru(CO)2(cp)](n= 4 or 6) with the trityl salt was not metalloselective, and gave a mixture of equal amounts of [(cp)(OC)2Fe{CH2CH(CH2)n–2}Ru(CO)2(cp)]PF6 and [(cp)(OC)2Fe{(CH2)n–2CHCH2}Ru(CO)2(cp)]PF6. In contrast, [(cp)(OC)2Fe(C4H8)W(CO)3(cp)] gave only [(cp)(OC)2Fe{CH2CH(CH2)2}W(CO)3(cp)]PF6. Metalloselectivity was observed for the reaction of [(cp)(OC)2Fe(C6H12)W(CO)3(cp)] with HCl, which gave cleavage of the W–C bond. In contrast, the reaction of [(cp)(OC)2Fe(C5H10)Ru(CO)2(cp)] with I2 resulted in cleavage of both metal–alkyl bonds. The reactions of [(cp)(OC)3Mo(C4H8)Mo(CO)3(cp)] with PPh3 to give [(cp)(OC)2-(Ph3P)Mo{C(O)(CH2)4}Mo(CO)3(cp)] and [(cp)(OC)2(Ph3P)Mo{C(O)(CH2)4C(O)}Mo(PPh3)(CO)2-(cp)] are also reported.

The enzymic formation and chemical reactivity of quinone methides correlate with alkylphenol-induced toxicity in rat hepatocytes

The effects of o-alkyl substituents on both the cytochrome P450-catalyzed oxidation of phenols to p-quinone methides (QM's; 4-methylene-2,5-cyclohexadien-1-ones), and on the rates of nucleophilic additions to the 4-methylene carbon of QM's were investigated. The derivatives of 4-methylphenol studied were BHT (2,6-di-tert-butyl), BHTOH [6-tert-butyl-2-(hydroxy-tert-butyl)], BDMP (2-tert-butyl-6-methyl), BMP (2-tert-butyl), TMP (2,6-dimethyl), and DMP (2-methyl). QM formation was estimated to be in the range 0.17-0.70 nmol/(nmol of P450.min) in rat liver microsomes and 16-62 pmol/(10(6) cells.min) in isolated rat hepatocytes. QM's derived from BHT (BHT-QM), BHTOH (BHTOH-QM), BDMP (BDMP-QM), and TMP (TMP-QM) were synthesized and their rates of reaction with water and reduced glutathione (GSH) determined. BDMP-QM and TMP-QM were the most reactive, BHT-QM was consumed relatively slowly, and BHTOH-QM displayed intermediate reactivity. These variations in rate were rationalized by differences in hydrogen bonding with the carbonyl oxygen, which affects positive charge density at the site of nucleophilic attack. The loss of hepatocyte viability during incubations with BMP, BDMP, and BHTOH was preceded by GSH depletion. Pretreatment of hepatocytes with diethyl maleate exacerbated alkylphenol toxicity, and metyrapone protected the cells. These data, together with information on the formation and reactivity of QM's, strongly support the proposal that QM's mediate the toxicity of alkylated 4-methylphenols in rat hepatocytes.

Reactions of (η6-arene)(η6-[2.2]paracyclophane)ruthenium(II) complexes with nucleophiles

Single addition of the nucleophiles X–= H–, CN– or OH– to (η6-arene)(η6-[2.2]paracyclophane)ruthenium(II) tetrafluoroborate (arene = benzene, p-cymene, 1,4-diisopropylbenzene or hexamethylbenzene) and the osmium(II)η6-C6H6 analogue produces the (η5-cyclohexadienyl)(η6-[2.2]paracyclophane)metal(II) complexes as the sole products. These compounds have been identified by 1H NMR and by infrared spectroscopy. The expected isotope shift is observed when Na[BD4] is used in place of Na[BH4]. The steric factors influencing the site of nucleophilic attack are discussed and nucleophilic addition to [Ru(η6-C16H16)2][BF4]2 is also examined.

The C-terminal half of UvrC protein is sufficient to reconstitute (A)BC excinuclease.

The UvrC protein is one of three subunits of the Escherichia coli repair enzyme (A)BC excinuclease. This subunit is thought to have at least one of the active sites for nucleophilic attack on the phosphodiester bonds of damaged DNA. To localize the active site, mutant UvrC proteins were constructed by linker-scanning and deletion mutagenesis. In vivo studies revealed that the C-terminal 314 amino acids of the 610-amino acid UvrC protein were sufficient to confer UV resistance to cells lacking the uvrC gene. The portion of the uvrC gene encoding the C-terminal half of the protein was fused to the 3' end of the E. coli malE gene (which encodes maltose binding protein), and the fusion protein MBP-C314C was purified and characterized. The fusion protein, in combination with UvrA and UvrB subunits, reconstituted the excinuclease activity that incised the eighth phosphodiester bond 5' and the fourth phosphodiester bond 3' to a psoralen-thymine adduct. These results suggest that the C-terminal 314 amino acids of UvrC constitute a functional domain capable of interacting with the UvrB-damaged DNA complex and of inducing the two phosphodiester bond incisions characteristic of (A)BC excinuclease.

Fluorine-19 NMR spectroscopy of polyhalonaphthalenes. Part II polychloropolyfluoronaphthalenes via nucleophilic fluoride dechlorination

Six new polychloropolyfluoronaphthalenes have been identified by F-19 NMR whose empirical formulae are C 10 Cl 8−n F n where n is 5 and 6 i.e. two trichloropentafluoronaphthalenes and four dichlorohexafluoronaphthalenes:- • 1,3,8-trichloro-2,4,5,6,7-pentafluoronaphthalene, • 1,3,6-trichloro-2,4,5,7,8-pentafluoronaphthalene, • 1,3-dichloro-2,4,5,6,7,8-hexafluoronaphthalene, • 1,8-dichloro-2,3,4,5,6,7-hexafluoronaphthalene, • 1,6-dichloro-2,3,4,5,7,8-hexafluoronaphthalene and • 2,7-dichloro-1,3,4,5,6,8-hexafluoronaphthalene. In the partly fluorinated compounds such as 1,3,6,8-tetrachloro- 2,4,5,7-tetrafluoronaphthalene, nucleophilic fluoride dechlorination occurs at both α and β positions. Initial substitution in octachloronaphthalene is more selective and occurs predominantly at the α-position; both subsequent exchanges occur at sites two carbons away from the initial site. The results support the idea that the transition state is stabilised by chlorine at the sites of electron density, ortho and para to the site of nucleophilic attack.

Preparation of β‐hydroxysulfides from 1,2,3‐thiadiazoles. Comparison of the effect of phenylmagnesium bromide on α‐Thio‐ and α‐selenoketones

AbstractBase decomposition of 4‐substituted‐phenyl‐1,2,3‐thiadiazoles at 78° resulted in 2‐(4‐substituted‐phenyl)‐ethynylthiolate anions which were immediately reacted with α‐bromoketones to give a series of α‐(2‐[4‐substituted‐phenyf]ethynyl) thioketones. Unlike the selenophilic reaction of the Grignard reagents with α‐selenoketones, the carbonyl group was the site of nucleophilic attack and the reaction of the α‐thioketones with phenylmagnesium bromide gave the corresponding β‐hydroxysulfides. The difference in mode of action toward the Grignard reagents was attributed to the difference in the bond strengths between carbon and the heteroatoms.

ChemInform Abstract: Electrostatic Potentials and Relative Bond Strengths of Some Nitro‐ and Nitrosoacetylene Derivatives

Abstract : A computational analysis of the structures and properties of a group of substituted acetylenes has been carried out by means of an ab initio self-consistent-field molecular orbital procedure (GAUSSIAN 82). The molecules studied were acetylene, its singly and doubly substituted nitro and nitroso derivatives, methylnitroacetylene, and aminonitroacetylene. The properties computed were the molecular electrostatic potentials and the bond orders, used as measures of relative bond strengths. Among the interesting structural features found for these molecules are a slight nonlinearity of the mono- and dinitrosoacetylene and the fact that the two substituents in dinitro- and dinitrosoacetylene are not coplanar but rather lie in perpendicular planes. The presence of nitrile is observed to strengthen the carbon triple bond carbon, whereas nitrous oxide substitution weakens it. The combination of nitrogen dioxide and NH2 (a strong electron donor) has an overall weakening effect, relative to acetylene. The carbon nitrogen dioxide bonds are found to be stronger than the nitrile bonds. The electrostatic potential analyses show that the introduction of NO2 completely eliminates the negative regions associated with the triple bond, thus rendering it less susceptible to electrophilic attack. There are found to be buildups of positive potential above the C-NO bonds, indicating that these can serve as initial sites for nucleophilic attack.

The synthesis, properties and reactivity of model systems for protonated chromophores in biliproteins

AbstractThree 2,3,22,23,24‐pentahydro‐21H‐biline‐1,19‐dion‐10‐enium salts have been prepared: 17,18,22,23‐tetramethyl‐2,3,22,23,24‐pentahydro‐21H‐biline‐1,19‐dion‐10‐enium methanesulphonate (1) with a central flexible structure, its 10‐syn‐locked 22,23‐methylene homologue (2) with a central Z‐syn structure and its 8,12‐isopropylidene homologue (3), the first bile pigment with a central E‐anti structure. For comparison, the corresponding E‐anti 22,23,24‐trihydrobilinedionium salt 3a was also prepared. The 2,3 single bond induces a more delocalized charged system, having higher fluorescence quantum yields than observed for the fully conjugated systems. The flexible systems 1, 1a, which adopt an E‐anti conformation, do not show fluorescence. The E‐anti systems have a larger Stokes shift than do the Z‐syn systems. In the pentahydrobilinedionium salts, the highest positive charge resides on the central C10 atom as apparent from 1H NMR spectroscopy and as was corroborated by the finding that the site of nucleophilic attack is invariably at C10. The pentahydro salts also undergo electrophilic H‐D exchange at positions 5, 7 and 12. From the spectral data presented it would appear that the chromophore in (allo)phycocyanine will occur as a protonated system in a rigid protein environment in the E‐anti conformation.

Syntheses of β‐hydroxyselenides and selenides from 1,2,3‐selenadiazoles: Selenophilic reaction of phenylmagnesium bromide on α‐selenoketones

Abstractα‐Selenoketones were prepared starting from 1,2,3‐selenadiazoles and α‐haloketones and were reduced to corresponding β‐hydroxyselenides. The action of phenylmagnesium bromide on α‐selenoketones was studied. Selenium was the site of nucleophilic attack by Grignard reagent.

The aromatic CNO 2 bond as a site for nucleophilic attack

The significance of the recently discovered buildup of positive electrostatic potential above and below nitroaromatic CNO 2 bonds is investigated by computing electric field lines of force and by studying the possible interaction of an OH − ion with the CNO 2 portion of nitrobenzene. Both kinds of evidence - the paths found for the lines of force and the attractive interaction with OH − support the conclusion that the CNO 2 bond in nitrobenzene can serve as an initial site for nucleophilic attack. Some nitroaromatic reactions in which this may play a role are mentioned briefly.

Electrochemistry of anilines Part II. Oxidation to dications, electrochemical and uv/vis spectroelectrochemical investigation

The electrochemical oxidation of 2,6-di- tert -butyl-4-R-anilines (R=C 6 H 5 , p -CH 3 O−C 6 H 4 and p -(CH 3)2 N−C 6 H 4 ) at the potentials of the second peak has been investigated. Dications could be observed and characterized by electroanalytical and spectroelectrochemical means. The cyclic voltammogram of the methoxy compound has been simulated by the orthogonal collocation method. Products of bulk electrolysis have been identified. We found two different sites of nucleophilic attack in the case of the methoxy compound.

Electrochemistry of anilines: Part II. Oxidation to dications, electrochemical and UV/VIS spectroelectrochemical investigation

The electrochemical oxidation of 2,6-di- tert-butyl-4-R-anilines (R=C 6H 5, p-CH 3O−C 6H 4 and p-(CH 3)2N−C 6H 4) at the potentials of the second peak has been investigated. Dications could be observed and characterized by electroanalytical and spectroelectrochemical means. The cyclic voltammogram of the methoxy compound has been simulated by the orthogonal collocation method. Products of bulk electrolysis have been identified. We found two different sites of nucleophilic attack in the case of the methoxy compound.

Reactivity of nucleophiles toward and the site of nucleophilic attack on bis(alkylthio) selenides

Reactivity of nucleophiles toward and the site of nucleophilic attack on bis(alkylthio) selenides