Nucleophilic Addition Step Research Articles

Redox-neutral palladium-catalyzed C-H functionalization to form isoindolinones with carboxylic acids or anhydrides as readily available starting materials.

An operationally simple, Pd-catalyzed C-H functionalization is described for the synthesis of important and useful isoindolinones from readily available carboxamides and carboxylic acids or anhydrides. The reactions proceed efficiently with a broad range of substrates under redox-neutral reaction conditions and tolerate a diversity of functional groups. The mechanistic investigation suggests that the reactions involve C-H activation, nucleophilic addition, β-O elimination, and dehydration steps.

Nucleophilic Substitution Reactions of 2‐Methoxy‐3‐X‐5‐nitrothiophenes: Effect of Substituents and Structure–Reactivity Correlations

ABSTRACTA kinetic study is reported for reactions of 2‐methoxy‐3‐X‐5‐nitrothiophenes 1a–d (X = SO2CH3, CO2CH3, CONH2, H) with piperidine in different solvents at 20°C. It is shown that the reactions take place through a SNAr mechanism with the initial nucleophilic addition step being rate limiting. The satisfactory Hammett correlations (log k1 vs. σ) obtained in the present system confirms that a 3‐X substituent exerts an effect on the 2‐position of the same type as that exerted from the 5‐position. The second‐order rate constants associated with these reactions are employed to determine the electrophilicity parameters E of the thiophenes 1a–d according to the relationship log k (20°C) = s(E + N) (Angew. Chem., Int. Ed. Engl. 1994, 33, 938–957). The E values of 1a–d are found to cover a range from −21.33 to −17.18, going from 1d, the least reactive, to 1a, the most reactive thiophene. Interestingly, a linear correlation (r2 = 0.9910) between the electrophilicity parameters E determined in this work and the Hammett's σ constants values has been observed and discussed. On the other hand, we have found that the reported rate constants of some thiophenes 1 complexation by the methoxide ion in methanol are 3.5–73.5 times higher than predicted by Mayr's approach.

Synthesis of Polycyclic Indole Skeletons by a Gold(I)‐Catalyzed Cascade Reaction

The conversion of simple, easily available urea-substituted 3-phenylpropargyl alcohols catalyzed by a simple IPr-gold(I) catalyst in a gold(I)-catalyzed cascade reaction composing of a gold-catalyzed nucleophilic addition and a subsequent gold-catalyzed substitution reaction delivers 1H-imidazo[1,5-a]indol-3(2H)-ones. Other gold(I) catalysts or silver catalysts gave lower yields and often gave other side products. Gold(III) and copper(II) catalysts decomposed the starting material. Twelve examples, including donor and acceptor substituents on the distal nitrogen of the urea substructure, are provided. An X-ray crystal structure analysis confirmed the structural assignment. The mechanistic investigation including isolation and further conversion of intermediates and reactions with enantiopure starting materials indicated that after the nucleophilic-addition step, the substrate undergoes an S(N)1-type benzylic substitution reaction at the indolyl alcohol intermediate or an intramolecular hydroamination reaction of the 2-vinylindole intermediate.

Reversal of the Stereochemical Course of 1‐Methyl‐1H‐indole Addition to Cinnamaldehyde with cis‐5‐Benzyl‐(2‐fluoromethyl)‐2,3‐dimethylimidazolidin‐4‐ones as Catalysts – a Puzzling ‘Fluorine Effect’

AbstractReplacement of the cis‐Me group by CH2F in the imidazolidinone organocatalyst specified in the title (so‐called McMillan generation‐I catalyst) leads to reversal of the product configuration in the title reaction. The topicity reversal in the nucleophilic addition step must arise either from cis‐addition with respect to the benzylic substituent of an (E)‐iminium ion intermediate or from trans‐addition to the corresponding (Z)‐iminium ion. Mechanistic investigations have not provided evidence for either one of these two possibilities, so far.

Synthesis of a Suite of Bioorthogonal Glutathione S-Transferase Substrates and Their Enzymatic Incorporation for Protein Immobilization

Label-free protein immobilization allows precise detection of biomolecular events. Preserving enzyme function is intrinsically challenging for these strategies. Considering that glutathione S-transferase (GST) is a broadly employed enzymatic fusion tag, we reported a label-free self-catalyzed immobilization for Schistosoma japonicum GST. We now report the synthesis, structure, and enzymology of a set of 20 smSNAREs (small molecule SNAr-electrophiles). These smSNAREs mimic (electronically) the canonical GST substrate 1-chloro-2,4-dinitrobenzene (CDNB), and bear a wide variety of bioorthogonal functionalities such as alkynes, aldehydes, acetals, and azides. Sixteen analogues including the chloro- and nitro-substituted 1, 3, 5, 6, 7, 11, 12, and 13 participated in the GST-catalyzed conjugation, indicating the substrate tolerance of the enzymatic H-site of SjGST. Using UV-vis spectroscopy, we estimate the efficiency of conjugation as a function of substrate diversity. Using LC-MS, we characterized the conjugates formed under each enzymatic transformation. Significant deviations from the canonical CDNB architecture are tolerated. Relative rates between nitro and chloro substituents indicate the nucleophilic addition step is rate determining. Enzyme immobilization on glass slides is affected by additional surface interactions and therefore does not reflect kinetic profiles observed in solution. This new class of heterobifunctional linkers enables a single-step and uniform protein capture on designer surfaces.

Heterogeneous versus Homogeneous Copper(II) Catalysis in Enantioselective Conjugate‐Addition Reactions of Boron in Water

We have developed Cu(II)-catalyzed enantioselective conjugate-addition reactions of boron to α,β-unsaturated carbonyl compounds and α,β,γ,δ-unsaturated carbonyl compounds in water. In contrast to the previously reported Cu(I) catalysis that required organic solvents, chiral Cu(II) catalysis was found to proceed efficiently in water. Three catalyst systems have been exploited: cat. 1: Cu(OH)2 with chiral ligand L1; cat. 2: Cu(OH)2 and acetic acid with ligand L1; and cat. 3: Cu(OAc)2 with ligand L1. Whereas cat. 1 is a heterogeneous system, cat. 2 and cat. 3 are homogeneous systems. We tested 27 α,β-unsaturated carbonyl compounds and an α,β-unsaturated nitrile compound, including acyclic and cyclic α,β-unsaturated ketones, acyclic and cyclic β,β-disubstituted enones, acyclic and cyclic α,β-unsaturated esters (including their β,β-disubstituted forms), and acyclic α,β-unsaturated amides (including their β,β-disubstituted forms). We found that cat. 2 and cat. 3 showed high yields and enantioselectivities for almost all substrates. Notably, no catalysts that can tolerate all of these substrates with high yields and high enantioselectivities have been reported for the conjugate addition of boron. Heterogeneous cat. 1 also gave high yields and enantioselectivities with some substrates and also gave the highest TOF (43,200 h(-1) ) for an asymmetric conjugate-addition reaction of boron. In addition, the catalyst systems were also applicable to the conjugate addition of boron to α,β,γ,δ-unsaturated carbonyl compounds, although such reactions have previously been very limited in the literature, even in organic solvents. 1,4-Addition products were obtained in high yields and enantioselectivities in the reactions of acyclic α,β,γ,δ-unsaturated carbonyl compounds with diboron 2 by using cat. 1, cat. 2, or cat. 3. On the other hand, in the reactions of cyclic α,β,γ,δ-unsaturated carbonyl compounds with compound 2, whereas 1,4-addition products were exclusively obtained by using cat. 2 or cat. 3, 1,6-addition products were exclusively produced by using cat. 1. Similar unique reactivities and selectivities were also shown in the reactions of cyclic trienones. Finally, the reaction mechanisms of these unique conjugate-addition reactions in water were investigated and we propose stereochemical models that are supported by X-ray crystallography and MS (ESI) analysis. Although the role of water has not been completely revealed, water is expected to be effective in the activation of a borylcopper(II) intermediate and a protonation event subsequent to the nucleophilic addition step, thereby leading to overwhelmingly high catalytic turnover.

New Delhi Metallo-β-Lactamase I: Substrate Binding and Catalytic Mechanism

Metallo-β-lactamases can hydrolyze and deactivate lactam-containing antibiotics, which is the major mechanism for causing drug resistance in the treatment of bacterial infections. This has become a global concern because of the lack of clinically approved inhibitors so far. The emergence of New Delhi metallo-β-lactamase I (NDM-1) makes the situation even more serious. In this work, first, the structure of NDM-1 in complex with the inhibitor molecule l-captopril is investigated by both density functional theory (DFT) and hybrid quantum mechanical/molecular mechanical (QM/MM) methods, and the theoretical results are in good agreement with the X-ray structure. The Michaelis structure with an antibiotic compound (ampicillin) bound in the active site is constructed from a recent X-ray structure of the NDM-1 enzyme with hydrolyzed ampicillin. It is further simulated using a QM/MM molecular dynamics method. One of the interesting binding features of ampicillin in the NDM-1 active site is that the conserved C3 carboxylate group is not ligated with Zn2 but rather is only hydrogen-bonded with N220 and K211. A bridging hydroxide ion is suggested to connect two zinc cofactors. This hydroxide ion is also hydrogen-bonded with D124. Subsequent reaction path calculations indicate that the initial step of lactam ring-opening occurs through a concerted step in which the cleavage of the C-N bond and the transfer of the hydrogen bond to D124 are nearly concerted. The ligand bond between Zn2 and the C3 carboxylate group forms after the first step of nucleophilic addition. The calculated activation energy barrier height is about 19.4 kcal/mol for the hydrolysis of ampicillin, which can be compared with the experimental value of 15.8 kcal/mol derived from kcat = 15 s(-1). The overall mechanism is finally confirmed by a subsequent DFT study of a truncated active-site model.

Light promoted aqueous phase amine synthesis via three-component coupling reactions

By applying a simple TiO2–(NH4)2S2O8 system and promoted by UV light, the three-component reactions of cyclic ether, aniline and aldehyde can be progressed efficiently. 29 substituted amines with different structures were synthesized with up to 97% isolated yields. Isotope effect study revealed that the rate-determining step might be the nucleophilic addition step but not radical generation.

Organocatalyzed straightforward synthesis of highly fluorescent 3,5-disubstituted 2,6-dicyanoanilines via domino annulation of α-enolicdithioesters with malononitrile

Piperidine mediated a robust, efficient, and selective one-pot synthesis of previously inaccessible and highly fluorescent 3,5-disubstituted 2,6-dicyanoanilines. This was achieved via the domino carboannulation of α-enolicdithioesters with malononitrile by dehydrative CO/CS bond functionalization. It is presumed that the domino sequence includes base promoted nucleophilic addition, Knoevenagel condensation and ANRORC (addition of nucleophile/ring opening/ring closure) steps. The screening for optical properties identified a strong blue emission with high fluorescence quantum yields.

Origin of Selectivity of Tsuji–Trost Allylic Alkylation of Lactones: Highly Ordered Transition States with Lithium‐Containing Enolates

We report computational investigations on the mechanism and the selectivity of Pd-catalyzed allylic alkylation of γ-valerolactone. Density functional calculations using the B3LYP functional are performed on the selectivity-determining nucleophilic addition step of this reaction. The B3LYP results of commonly assumed pathways fail to reproduce the observed selectivity of the reaction. Therefore, alternative pathways are considered for the nucleophilic addition step, to explain the experimentally established role of the additives LiCl and lithium diisopropyl amide (LDA) in the Pd-catalyzed reaction. These pathways involve different approaches of the enolate toward the η(3)-allylpalladium complex that are mainly guided by stabilizing Cl(δ-)···Li(δ+)···O(enolate) interactions in the transition state. In the calculations, the experimentally observed trans-product selectivity for the prototypical reaction with (S)-BINAP ligands is found only when assuming the addition of a "mixed" Li-enolate/LiCl adduct to the η(3)-allylpalladium complex. This mechanism provides a reasonable explanation for the experimental results and sheds light on the role of LiCl in the reaction. The analysis of the different transition-state models allows us to identify steric and electronic factors that stabilize or destabilize the relevant diastereomeric transition states. Calculations for different combinations of substrates (γ-valerolactone and δ-caprolactone) and catalysts (with (R)- and (S)-BINAP ligands) reproduce the experimentally observed selectivities well and thus provide further support for the proposed mechanism.

Carbon Nanotube Sidewall Functionalization with Carbonyl Compounds—Modified Birch Conditions vs the Organometallic Reduction Approach

Covalent addition reactions turned out to be one of the most important functionalization techniques for a structural alteration of single walled carbon nanotube (SWCNT) scaffolds. During the last years, several reaction sequences based on an electrophilic interception of intermediately generated SWCNT(n-) carbanions, obtained via Birch reduction or by a nucleophilic addition of organometallic species, have been developed. Nevertheless, the scope and the variety of potential electrophiles is limited due to the harsh reaction conditions requested for a covalent attachment of the functional entities onto the SWCNT framework. Herein, we present a significant modification of the reductive alkylation/arylation sequence, the so-called Billups reaction, which extends the portfolio of electrophiles for covalent sidewall functionalization to carbonyl compounds--ketones, esters, and even carboxylic acid chlorides. Moreover, these carbonyl-based electrophiles can also be used as secondary functionalization reagents for anionic SWCNT intermediates, derived from a primary nucleophilic addition step. This directly leads to the generation of mixed functional SWCNT architectures, equipped with hydroxyl or carbonyl anchor groups, suitable for ongoing derivatization reactions. A correlated absorption and emission spectroscopic study elucidates the influence of the covalent sidewall functionalization degree onto the excitonic transition features of carbon nanotubes. The characterization of the different SWCNT adducts has been carried out by means of Raman, UV-vis/nIR, and fluorescence spectroscopy as well as by thermogravimetric analysis combined with mass spectrometry and X-ray photoelectron spectroscopy analysis.

Kinetic Isotope Effects for RNA Cleavage by 2′-O- Transphosphorylation: Nucleophilic Activation by Specific Base

To better understand the interactions between catalysts and transition states during RNA strand cleavage, primary (18)O kinetic isotope effects (KIEs) and solvent D(2)O isotope effects were measured to probe the mechanism of base-catalyzed 2'-O-transphosphorylation of the RNA dinucleotide 5'-UpG-3'. The observed (18)O KIEs for the nucleophilic 2'-O and in the 5'-O leaving group at pH 14 are both large relative to reactions of phosphodiesters with good leaving groups, indicating that the reaction catalyzed by hydroxide has a transition state (TS) with advanced phosphorus-oxygen bond fission to the leaving group ((18)k(LG) = 1.034 +/- 0.004) and phosphorus-nucleophile bond formation ((18)k(NUC) = 0.984 +/- 0.004). A breakpoint in the pH dependence of the 2'-O-transphosphorylation rate to a pH independent phase above pH 13 has been attributed to the pK(a) of the 2'-OH nucleophile. A smaller nucleophile KIE is observed at pH 12 ((18)k(NUC) = 0.995 +/- 0.004) that is interpreted as the combined effect of the equilibrium isotope effect (ca. 1.02) on deprotonation of the 2'-hydroxyl nucleophile and the intrinsic KIE on the nucleophilic addition step (ca. 0.981). An alternative mechanism in which the hydroxide ion acts as a general base is considered unlikely given the lack of a solvent deuterium isotope effect above the breakpoint in the pH versus rate profile. These results represent the first direct analysis of the transition state for RNA strand cleavage. The primary (18)O KIE results and the lack of a kinetic solvent deuterium isotope effect together provide strong evidence for a late transition state and 2'-O nucleophile activation by specific base catalysis.

Isoprene-Mediated Lithiation of 1-Alkylimidazoles: Chiral Induction of the Alkyl Substituent

The isoprene-mediated lithiation of imidazoles bearing a secondary alkyl substituent at the nitrogen (7, 8 and 13) and the subsequent nucleophilic addition to different electrophiles allows the preparation of the corresponding 2- functionalized imidazoles 10, 11 and 14. The presence of a stereogenic center in the alkyl substituent induces diastereoselection during the nucleophilic addition step with a prochiral electrophile (i.e. pivalaldehyde), producing the expected imidazole derivative with excellent overall yield, but low de (up to 26%). Keywords: Isoprene-mediated lithiation, imidazole derivatives, nucleophilic addition, lithium

A theoretical study on the catalytic mechanism of Mus musculus adenosine deaminase

The catalytic mechanism of Mus musculus adenosine deaminase (ADA) has been studied by quantum mechanics and two-layered ONIOM calculations. Our calculations show that the previously proposed mechanism, involving His238 as the general base to activate the Zn-bound water, has a high activation barrier of about 28 kcal/mol at the proposed rate-determining nucleophilic addition step, and the corresponding calculated kinetic isotope effects are significantly different from the recent experimental observations. We propose a revised mechanism based on calculations, in which Glu217 serves as the general base to abstract the proton of the Zn-bound water, and the protonated Glu217 then activates the substrate for the subsequent nucleophilic addition. The rate-determining step is the proton transfer from Zn-OH to 6-NH(2) of the tetrahedral intermediate, in which His238 serves as a proton shuttle for the proton transfer. The calculated kinetic isotope effects agree well with the experimental data, and calculated activation energy is also consistent with the experimental reaction rate.

Magnesium Schiff Base Catalyzed Direct Asymmetric Aldol Reaction

Direct aldol reaction of ketones is a challenging problem because of their steric hindrance. This research described a highly efficient catalytic transformation to solve this problem. In order to overcome the steric effect of ketones, the authors used α-isothiocyanato esters as nucleophiles, which could react with the hydroxyl group after the first nucleophilic addition step to generate stable oxazolidinone products.

Alkylgold complexes by the intramolecular aminoauration of unactivated alkenes

Alkylgold(I) complexes were formed from the gold(I)-promoted intramolecular addition of various amine nucleophiles to alkenes. These experiments provide the first direct experimental evidence for the elementary step of gold-promoted nucleophilic addition to an alkene. Deuterium-labeling studies and X-ray crystal structures provide support for a mechanism involving anti-addition of the nucleophile to a gold-activated alkene, which is verified by DFT analysis of the mechanism. Ligand studies indicate that the rate of aminoauration can be drastically increased by use of electron-poor arylphosphines, which are also shown to be favored in ligand exchange experiments. Attempts at protodeauration lead only to recovery of the starting olefins, though the gold can be removed under reducing conditions to provide the purported hydroamination products.

The Mechanism of the Wacker Reaction: A Tale of Two Hydroxypalladations

We present a concise review on the most pertinent investigations that illuminate the complicated and elusive mechanism for the Wacker process, homogeneous olefin oxidation by palladium(II) catalysts. For more than four decades, multitudes of creative and elegant studies detailing the nucleophilic addition and other steps of the Wacker process have appeared contradictory, while in fact modern perspective has shown an intricate and colorful picture of the "textbook" organometallic reaction. A summary and critical analysis of previous studies is of great importance to explain resolved and highlight unresolved questions about this frequently misunderstood reaction.

Carbon Nucleophilicities of Indoles in SNAr Substitutions of Superelectrophilic 7-Chloro-4,6-dinitrobenzofuroxan and -benzofurazan

Superelectrophilic 7-chloro-4,6-dinitrobenzofuroxan (DNBF-Cl) and 7-chloro-4,6-dinitrobenzofurazan (DNBZ-Cl) are shown to undergo facile carbon-carbon couplings with a series of weak carbon nucleophiles consisting of a number of differently substituted indoles, 1,2,5-trimethylpyrrole and azulene, in acetonitrile. Despite the fact that steric effects preclude a coplanarity of the donor and acceptor moieties, the resulting substitution products are subject to an intense intramolecular charge transfer. A kinetic study of the various substitutions has been carried out. The absence of a significant dependence of the rates of coupling on the hydrogen or deuterium labeling at the reactive center of the nucleophiles indicates that the reactions take place through an SEAr-SNAr mechanism with the initial nucleophilic addition step being rate-limiting. A vicarious-type substitution is shown to be unreasonable. Referring to Mayr nucleophilicity parameters (N), which have become recently available for a large set of indoles, the electrophilicity of DNBF-Cl and DNBZ-Cl, could be ranked on the general electrophilicity scale E developed by this author (Acc. Chem. Res. 2003, 36, 66). With essentially similar E values of -6.1, these two compounds have an electrophilicity which approaches that of cationic stuctures such as 4-nitrobenzenediazonium cation or tropylium cations. Most important in the context of SNAr substitutions, DNBF-Cl and DNBZ-Cl are 7 orders of magnitude more electrophilic than picryl chloride, the conventional reference electrophile in this field. It is this so far unique behavior which allows the facile coupling of DNBF-Cl and DNBZ-Cl with such weak carbon nucleophiles as indoles. Based on a nice Brönsted-type correlation for 5-X-substituted indoles, the unknown pKaCH values measuring the Brönsted C-basicity of several N-benzylindoles could be readily estimated. The influence of some steric effects in 2-methylindole systems is pointed out.

Novel formation of phenylcyclopropanes from the reaction of β-cyanostyrenes and related compounds with 2-methoxyfuran: experimental and theoretical studies

As a diene, 2-methoxyfuran fails to generate a Diels–Alder adduct when it reacts with β-cyanostyrenes (cinnamonitriles). However, in the reaction with β-cyanostyrenes possessing additional electron-withdrawing groups (CN, CO2Et and SO2Ph), it yielded two new phenylcyclopropanes. We have used computational methods to investigate the mechanism and to probe the regioselectivity observed in the rearrangement reactions. We used a B3LYP/6-31G* level density functional calculation to locate the transition states (TS), and to account for the selectivity observed in these reactions, we examined the global electronic index involved. An analysis of the results for the reaction pathways of two adducts (the endo and exo isomers) shows that the reaction takes place via a polar stepwise mechanism. The first step involves a side-on nucleophilic attack by the α-carbon atom of the furan ring on the vinyl carbon of the cyanostyrene to give a zwitterionic intermediate. An intramolecular substitution within the intermediate (IN) gives the cyclopropane ring, together with fission of the furan ring. The potential energy barriers for these reactions had the following values: at the nucleophilic addition step, 14.6 and 13.7 kcal mol−1 for 2b, and 18.4 and 17.8 kcal mol−1 for 2c; at the rearrangement step, 22.3 and 22.8 kcal mol−1 for 2b, and 25.1 and 23.1 kcal mol−1 for 2c. Solvent effects in chloroform stabilized the rearrangement steps by 5–6 kcal mol−1, but the nucleophilic addition step appeared to be slightly affected. From the theoretical results, in the case of 2b, the energy of TS2-endo is lower than that of TS2-exo, so more trans-cyclopropane product from the endo form is formed under kinetic conditions. Conversely, in the case of 2c, the energy of TS2-exo is lower and more of the cis-product is formed. Density functional theory analysis of these reactions is in complete agreement with the experimental results.

Quinoline formation via a modified Combes reaction: examination of kinetics, substituent effects, and mechanistic pathways

AbstractThis is the first reported investigation of the Combes condensation employing 19F NMR spectroscopy to monitor intermediate consumption and product formation rates. The reaction was found to be first order in both the diketone and aniline. Product regioselectivity and reaction rates were found to be influenced by substituents on the diketones and anilines with rates varying as much as five fold. The consumption rate of key imine and enamine intermediates mirrored quinoline formation rates, in accord with rate determining annulation. A ρ of −0.32 was determined for this cyclization. While the sign of the reaction constant is consistent with rate limiting electrophilic aromatic substitution (EAS), the magnitude is likely a composite value, resulting from opposing substituent effects in the nucleophilic addition and EAS steps. Mechanistic details and reaction pathways supporting these findings are proposed. Copyright © 2008 John Wiley & Sons, Ltd.