Direct Nucleophilic Addition Research Articles

Mechanistic Studies and Improvement of Coinage Metal-Catalyzed Transformation of Alkynyloxiranes to Furans: An Alcohol Addition−Cyclization−Elimination Cascade

In the presence of alcohol Ag or Au salts or complexes catalyze the conversion of alkynyloxiranes to substituted furans. Both catalysts are effective, and a large furan diversity can be obtained in high yield with one or the other catalyst. Mechanistic studies revealed that a cascade pathway and not the sometimes reported direct intramolecular nucleophilic addition of oxirane oxygen atom to intermediate acetylene-metal pi-complex occurs. Under the defined conditions, the intermediate formation of epoxide opening products has been identified. Depending on the catalyst, one or both of the latter cyclized to dihydrofurans, and further elimination of the alcohol led to the corresponding furans. These results highlight the duality between oxophilicity and alkynophilicity of Ag or Au salts.

How tin metal prevents verdoheme ring opening? Comparative study of various nucleophiles

The inhibitory role of tin metal in the verdoheme ring opening mechanism has been investigated using B3LYP method. Nucleophilic additions of OH −, NH 2 −, and CN − to three possibly six, five, and four coordinate verdoheme complexes of tin(IV) have been employed as model reactions. The results of calculations suggest that nucleophilic attacks to tin(IV) verdohemes does not result in the opening of the macrocycle, being in excellent agreement with experimental reports. In six coordinate tin(IV) verdoheme complex the formation of open ring helical complexes is favorable thermodynamically but not kinetically. In this coordination state, tin has no coordination role. Thus, direct addition of nucleophiles to the positive oxo-carbon centers and formation of a closed ring hydroxy compound is proposed for blocking the conversion of verdoheme to biliverdin. Contrary to zinc and iron analogues, in five and four coordinate pathways, such addition to oxo-carbons does not proceed toward stable open chain helical products. This is because formation of these complexes is unfavorable both thermodynamically and kinetically. It has been determined that in the latter pathways a closed ring compound is formed as final product by adding nucleophiles to tin atoms. It has been thus shown that high affinity of ligands for binding to both the fifth and sixth coordination sites of the highly charged Sn(IV) center is responsible for inhibiting the conversion of verdoheme complexes to biliverdin compounds. Results indicate that high tendency of tin(IV) metal to increase coordination state plays a crucial role in preventing verdoheme ring opening. These key points have been corroborated with the results obtained from molecular orbital calculations.

The Enantioselective Addition of Alkyne Nucleophiles to Carbonyl Groups.

Over the past decade, large strides have been achieved in the invention of methods for the direct enantioselective addition of alkynes and metal alkynylide nucleophiles into prochiral aldehydes, ketones, and imines. This review highlights and compares the available methods for these transformations.

Enzymatic Synthesis of Nucleoside Triphosphates. Does It Involve An Ion-Radical Path ?

Accumulation and release of energy in the nucleoside triphosphate enzymatic synthesis and hydrolysis does not limited to a routine energy consuming nucleophilic mechanism. These processes require an overcoming the large energy barrier exceeding a total value of accumulated or released energy level by at least 3 – 4 times (~10 kcal/mol). This energy is supposed to be taken from the mechanical compression of the catalytic site and used to form P–O chemical bond by a direct nucleophilic addition of phosphate to nucleoside diphosphate (ADP as an example). A new, energetically “cheap”, ion-radical mechanism of the ATP biosynthesis has been proposed due to the observation of magnetic isotope and magnetic field effects on the ATP synthesis. This mechanism is about to generate a compression energy to “spend” on a partial dehydratation of magnesium ion inside the nucleotidyl transferase catalyric site (energy cost of this process is 3-5 kcal/mol, i.e. by 2-3 times less than a total accumulated or released energy). Dehydration of this ion is to increase its electron affinity and hence to stimulate an electron transfer from ADP3- to Mg2+. This reaction is a starting point of the ion-radical mechanism considering the molecular mechanics of enzymatic machines and its quantum chemistry background as well. To the contrast of a hardly controllable nucleophilic path, the ion-radical mechanism might be turned on/off by a targeted delivery of paramagnetic magnesium ions, 25Mg2+, towards the phosphate transferring enzyme catalytic site. The magnesium isotope substitution is easily reachable by the endo-osmotic pressure techniques, which makes it attractive for further biotechnological and/or pharmacological application(s).

Catalytic Asymmetric Alkynylation and Arylation of Aldehydes by an H8‐Binaphthyl‐Based Amino Alcohol Ligand

AbstractA novel chiral H8‐1,1′‐binaphthyl‐based amino alcohol ligand (1Ra,2S,3R)‐2 has been synthesized and applied in the direct nucleophilic addition of organozincs (alkynylzinc and arylzinc prepared in situ) to aldehydes, yielding the corresponding optically active propargylic alcohols and diarylmethanols in high yields and good to excellent enantioselectivities. For the asymmetric arylation reaction, one catalyst (1Ra,2S,3R)‐2 can afford both enantiomers of many pharmaceutically interesting diarylmethanols by a proper combination of various arylzinc reagents and aldehydes.

Microstructure and thermal properties of silyl-terminated polycaprolactone–polysiloxane modified epoxy resin composites

With a direct nucleophilic addition between OH groups of polydiol and NCO of a silane, a blend of silyl-terminated polycaprolactone PCL-Si and silyl-terminated polydimethylsiloxane PDMS-Si oligomer, PCS-2Si, were firstly prepared, and then blended with a commercial epoxy resin (diglycidyl ether of bisphenol-A, DGEBA) to form a ternary composite. The formed ternary composites of different content of DGEBA were cured using a polyamidoamine as a curing agent and a sol–gel process at ambient temperature. The microstructures and properties of the cured composites were investigated by SEM, TGA, and energy dispersive spectroscopy. The results showed the compatibility between DGEBA and PDMS increased with increasing content of PCS-2Si, but higher content of PCS-2Si resulted in a slight enrichment of silicon in the surface of the cured film. TGA showed that incorporating PCS-2Si into epoxy resin altered the composites' thermal stability and degradation characteristics. © 2008 Wiley Periodicals, Inc. J Appl Polym Sci, 2008

Alkoxysilane functionalized polycaprolactone/polysiloxane modified epoxy resin through sol–gel process

Incorporating elastic polysiloxane and/or an inorganic silica network in epoxy resin could result in the enhancement of physico-chemical properties due to the existence of Si–O bonds. To improve the compatibility between polysiloxane and epoxy matrices and intensively strengthen the properties of the modified system, here polysiloxane was introduced into epoxy resin through compatibilizing epoxy-immiscible polysiloxane with epoxy-miscible polycaprolactone segments via a sol–gel process. To fulfill the process, a blend containing alkoxysilane-functionalized polycaprolactone/polydimethylsiloxane (PCS–2Si) was firstly synthesized using direct nucleophilic addition between –OH groups of polydiol and –NCO of a silane. And then a series of modified epoxy resins were prepared in different epoxy/PCS–2Si weight ratios. All the modified composites were characterized by conventional methods, and their morphological, thermal degradation and surface properties were studied. The results showed that increasing the PCS–2Si content caused the changes of miscibility between epoxy and polysiloxane. Also, the thermal stability of the modified composites was greatly improved. As for the temperature value at 5% weight loss, it reached to 308.5°C for the composite containing 50–60% (wt%) PCS–2Si, over 150°C higher than that for neat amine-cured epoxy resin. Similarly, the modified composites showed good hydrophobicity. The improvement of these properties came from the improved interaction between PCS–2Si and epoxy, the forming of Si–O–Si network and the enrichment of siloxane chains on the surface of films. Therefore, it is believed that this modified epoxy appears promising as new high performance and highly functional materials.

Direct Nucleophilic Acylation of Nitroalkenes

This paper describes the first direct nucleophilic addition of a carbonyl group to nitro­alkenes, in which a fluoride source is used to generate a carbonyl anion equivalent in situ. The application of a thiourea additive at low temperatures leads to enhanced yields of the β-nitro ketones.

Quinone-sensitized Steady-state Photolysis of Acetophenone Oximes Under Aerobic Conditions: Kinetics and Product Studies†

Oxidation of oximes via photosensitized electron transfer (PET) results in the formation of the corresponding ketones as the major product via oxime radical cations and iminoxyl radicals. The influence of electron-releasing and electron-accepting substituents on these reactions was studied. The observed substituent effect strongly supports formation of iminoxyl radicals from the oximes via an electron transfer-proton transfer sequence rather than direct hydrogen atom abstraction. Correlation of the relative conversion of the oximes with Hammett parameters shows that radical effects dominate for the meta-substituted acetophenone oximes (rho(rad)/rho(pol) = 5.4; r2 = 0.93), whereas the para-substituted oximes are influenced almost equally by radical and ionic effects (rho(rad)/rho(pol) = -1.1; r2 = 0.98). From these data sets we conclude that the follow-up reactions proceed through a number of intermediates with both radical and ionic character. This was confirmed by product studies with the use of an isotopically labeled nucleophile. In addition to the major oxidation product (ketone), a chlorine-containing product was often identified as well. Studies on the formation of this product show that the most likely pathway is either via a direct nucleophilic addition in a complex formed between the oxime radical cation and the chloranil radical anion or via a radical substitution (SH2) mechanism. These studies show that with the increasing use of oximes as drugs and pesticides, intake of these chemicals followed by enzymatic oxidation may result in the formation of a variety of reactive intermediates, which may lead to cell and tissue damage.

Direct Nucleophilic Addition versus a Single‐Electron Transfer Pathway of σH Adduct Formation in Vicarious Nucleophilic Substitution of Hydrogen.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Direct Nucleophilic Addition versus a Single‐Electron Transfer Pathway of σH Adduct Formation in Vicarious Nucleophilic Substitution of Hydrogen

AbstractTwo mechanistic pathways of formation of σH adducts, which are key intermediates in the vicarious nucleophilic substitution of hydrogen, namely direct nucleophilic addition of carbanions to nitroarenes and a two‐step mechanism involving an electron‐transfer process, are discussed on the basis of the existing data and results of the VNS reactions in which a radical probe — chloromethyl aryl sulfone bearing a 2,2‐dimethylcyclopropyl substituent — was used as the carbanion precursor. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2004)

Samarium diiodide promoted synthesis of N,N′-disubstituted amidines

An efficient one-step preparation of an N,N′-disubstituted amidine by the direct nucleophilic addition of an amine to the parent nitrile using catalytic amounts of SmI2 under relatively mild conditions is developed. Alkyl, benzyl and aryl amidines are prepared in moderate to good yields from the corresponding nitriles.

Ruthenium-Assisted Insertion of Isothiocyanates into the Silicon−Sulfur Bond: A Comparative Study on the Reactivity of the S−Si and S−H Bonds in CpRu(PPh3)2SX (X = H, SiiPr3) Complexes

CpRu(PPh3)2SSiiPr3 (1) and CpRu(PPh3)2SH (2) reacted with phenyl, p-tolyl, and 1-naphthyl isothiocyanates, as well as with 1,4-phenylene diisothiocyanate, to give the corresponding κ2S,S-dithiocarbamato complexes, CpRu(PPh3)S2CNR1R2 (R1 = SiiPr3, R2 = Ph (3a), p-Tol (3b), 1-Naphth (3c); R1 = H, R2 = Ph (3d), 1-Naphth (3e)) and 1,4-[CpRu(PPh3)S2CNR]2C6H4 (R = SiiPr3 (4a), H (4b)), the result of insertion of the isothiocyanates into the S−Si and S−H bonds, respectively. The reactions of 1 proceed via precoordination of the isothiocyanates to the ruthenium atom, followed by the formation of N-silyl κ2S,S-dithiocarbamates. The reactions of 2, at least in part, involve direct nucleophilic addition of the S−H bond to the isothiocyanates via κ1S-dithiocarbamato intermediates. Accordingly, CpRu(dppe)SSiiPr3, where ligand exchange does not occur, did not react, but CpRu(dppe)SH reacted with phenyl and 1-naphthyl isothiocyanate to give the corresponding κ1S-dithiocarbamato complexes, CpRu(dppe)SC(S)NHR (R = Ph (9a)...

Reaction between Conjugated Azoalkenes and Pyrazolinones: A Precious Entry to New Conjugated Azodiene and Asymmetric 4,4′-Bipyrazole Derivatives

Abstract The first direct nucleophilic addition under mild reaction conditions of heterocyclic compounds to conjugated azoalkenes is reported. This reaction readily gives rise to new conjugated azodiene or asymmetric 4,4′-bipyrazole derivatives by means of two independent pathways.

Theoretical Investigation of the Hydride Transfer from Formate to NAD+ and the Implications for the Catalytic Mechanism of Formate Dehydrogenase

The hydride transfer reaction between formate and NAD+ has been investigated by using molecular orbital theory in combination with continuum solvation models. The reaction in the gas phase is extremely exothermic due to the instability of the charged reactant species. The calculations reveal that during the hydride transfer the pyridine ring of NAD+ takes a quasi-boat conformation. The nitrogen atom of the pyridine ring remains planar, which is in agreement with the experimentally established 15N kinetic isotope effect (1.004 ± 0.001) of the formate dehydrogenase catalyzed oxidation of formate to carbon dioxide. The computed value at the HF/6-31+G(d,p) level of theory for the 15N kinetic isotope effect is 1.0042. In solution, however, there is a potential energy barrier for the hydride transfer. At the MP2/6-31G(d)//HF/6-31G(d) level of theory the self-consistent reaction field approach gives a barrier height of 9.0 kcal/mol in acetonitrile (e = 35.9). Direct nucleophilic addition of one of the carboxylat...

Kinetics of nucleophilic attack on coordinated organic moieties Part 29. Mechanism of addition of tertiary phosphines and phosphites to the tropylium ring of [M(CO)3(η7-C7H7]+ (M = Cr, Mo, W) cations

Kinetic studies of the addition of a wide range of tertiary phosphines and phosphites to the tropylium ring of the cation [Cr(CO) 3 ( η 7 -C 7 H 7 ] + ( 1 ) reveal the two-term raw, k obs = k 1 [PR 3 ] + k −1 . This is consistent with the reversible equilibrium process (i) which is also confirmed from IR and 1 H NMR studies. In the case of the highly basic nucleophiles PBu 3 n and PEt 2 Ph, the rate is dominated by the k 1 term and the equilibrium lies far to the right. The first-order rate constants k 1 , for addition to the tropylium ring decrease markedly down the series PBu 3 n >PEt 2 Ph>P(4-MeOC 6 H 4 ) 3 >P(4-MeC 6 H 4 ) 3 >P(C 6 H 11 3 >PPh 2 (4-MeC 6 H 4 )>PPh 3 >P(2-CNC 2 H 4 ) 3 >P(OBu n ) 3 (overall variation ∼10 4 ). This reactivity order parallels the decreasing electron availability at the phosphorus centres, as confirmed by the linear correlation between log k 1 and the Tolman Σ χ values for the nucleophiles. Excellent Hammett and Brønsted correlations are also observed for ring addition by a range of P(4-XC 6 H 4 ) 3 nucleophiles. The Brønsted slope, α, of 0.7 conirms the major importance of basicity in determining nucleophilicity towards cation 1 . Kinetic studies of the related additions of PBu 3 n to the cations [M(CO) 3 ( η 7 -C 7 H 7 ] + (M = Mo, W) reveal the rate law, Rate = k 1 [M][PBu 3 n , and show only a small dependence of k 1 on the nature of metal (Cr>W∼Mo; 2:1.1:1). These data, together with the associated activation parameters, support a mechanism involving direct addition ( k 1 ) of the phosphorus nucleophiles to the tropylium ring, and are inconsistent with initial rate-determining attack at the metal centre.

Kinetics and mechanism of addition of tertiary phosphines and phosphites to the dicarbonyl(η5-cyclopentadienyl)-(η-ethene)iron cation

Kinetic studies of the addition of a range of tertiary phosphine and phosphite nucleophiles PR3 to the cation [Fe(cp)(CO)2(η-C2H4)]+1(cp =η5-C5H5)[equation (i)] revealed the general rate law, Rate =k1[Fe][PR3]. The second-order rate constants k1 decrease markedly down the order P(C6H4OMe-2)3 > PBun3 > P(C6H4OMe-4)3 > P(C6H4Me-4)3 > P(C6H4Me-4)Ph2 > PPh3 > P(C2H4CN-2)Ph2 > P(C2H4CN-2)3 > P(C6H4Cl-4)3 > P(OBun)3. This reactivity order parallels that of decreasing electron availability at the phosphorus centre, as shown quantitatively by the good correlation between log k1 and the Tolman Σχ values. An excellent fit to the Hammett and Bronsted equations is also observed for reaction (i) with the nucleophiles P(C6H4X-4)3. The moderate Bronsted slope α of [Fe(cp)(CO)2(η-C2H4)]++ PR3→[Fe(cp)(CO)2(C2H4PR3)]+(i) 0.46 establishes the importance of phosphine basicity in determining nucleophilicity towards the ethene ligand in cation 1. These results, together with the large negative entropy of activation with PPh3(ΔS‡1=–103 J K–1 mol–1), are interpreted in terms of direct addition (k1) of the phosphorus nucleophiles to the ethene ligand in 1 and suggest a transition state in which there is build-up of positive charge on the phosphorus centre and considerable phosphorus–carbon bond formation.

Nonpeptide HIV Protease Inhibitors. Differential Introduction of Alkylamino Groups into the Two Aryl Rings of Haloperidol

In efforts to synthesize haloperidol analogues with improved properties as HIV protease inhibitors, methods were sought to introduce mono- and dialkylamino groups into the two aromatic rings of the parent structure. We report here that the reaction of haloperidol with alkylamines in the presence of a strong base (NaNH) regiospecifically introduces the alkylamino group into the chlorophenyl ring, whereas the same reaction in the presence of a weak base (KCO) results in exclusive replacement of the fluorine of the fluorophenyl ring. Different amine functions can be introduced at the two rings by sequential reactions in the presence of, respectively, a strong and a weak base. The reaction catalyzed by NaNH involves, at least in part, benzyne formation, whereas the reaction catalyzed by KCO involves direct nucleophilic addition to the aromatic ring. The regiospecificity of the reaction is due to conjugation of the fluorophenyl ring to a ketone group. The fluorophenyl ring is activated by the ketone towards nucleophilic aromatic substitution but is deactivated by the same function when it is converted by strong base to the enolate anion. Carbonyl conjugation of one of two haloaryl groups appears to be a general strategy for regiospecific introduction of alkylamino functions into complex aromatic molecules. The alkylamino derivatives actually prepared are comparable to haloperidol as inhibitors of the HIV-1 protease.

Reaction Pathway and Transition State of the Zn-Promoted Barbier-Type Reactions of Benzaldehyde and Benzophenone with Allylic Iodides

Abstract The carbonyl-14C kinetic isotope effects and the substituent effects on the reactivity of the Zn-promoted Barbier-type reaction of allyl iodide (3-iodo-1-propene) with benzaldehyde and benzophenone were determined in THF at 25 °C. The observed normal carbon isotope effects as well as positive Hammett ρ values suggest that the reactions go through a direct nucleophilic addition mechanism. No indication of the occurrence of electron transfer was obtained by enone isomerization and dehalogenation probe experiments. Diastereoselectivity in the reaction of crotyl iodide (1-iodo-2-butene) with benzaldehyde was low and independent of the substituent on aldehyde, consistent with the six-membered cyclic transition state.

Diastereoselectivity and Reaction Pathway of the Reactions of Benzaldehyde with Allylic Iodides in the Presence of Sn or Pb

The relative reactivity and stereoselectivity were determined in the Sn- or Pb-promoted reactions of substituted benzaldehydes with 3-iodo-1-propene and 1-iodo-2-butene. The reactivity data suggested that the reactions go through a direct nucleophilic addition mechanism. No indication of the occurrence of electron transfer was obtained by the dehalogenation probe experiment. The diastereoselectivity was low in the Sn/THF system but was high in Pb/DMF. Large solvent effects were observed in the erythro selectivity for the Sn-promoted reaction; erythro : threo ratio was 31 : 69 in CH2Cl2 and 84 : 16 in HMPA.