Mechanism Of Substitution Reactions Research Articles

Attachment of Docetaxel to Multiwalled Carbon Nanotubes for Drug Delivery Applications

In this manuscript we report the development of multiwalled carbon nanotubes-docetaxel conjugate by covalent interaction, involving nucleophilic substitution reaction mechanism. The surface functionalization of nanotubes was carried out by enrichment of carboxylic groups with optimized oxidation treatment. The carboxyl groups were converted to acyl groups followed by covalent attachment of docetaxel to multiwalled carbon nanotubes with a cleavable ester linkage. The drug carbon nanotube conjugate was characterized by Fourier Transform Infra red, UV-Visible, Raman spectroscopy, Scanning and Transmission electron microscopy. The drug release from the conjugate was studied in vitro in phosphate buffers having pH 5, 6.8 and 7.4. It was demonstrated that conjugate showed drug release faster in acidic pH, which resembles the pH of cancerous cells, as compared to buffer of normal cell pH. This property would reduce the drug dosage thereby substantially benefit the antitumor effect and would boost significantly the applications of carbon nanotubes in the biomedicine field.

The chemistry of group-VIb metal carbonyls

The special interest attached to the chemistry of metal carbonyls arises from several causes. While quite distinct from the metal carbonyls in the organometallic compounds, they differ in physical properties (e.g., their volatility) from all other compounds of the transition metals. Chemically, they constitute a group of compounds in which the formal valency of the metal atoms is zero, and in this respect (apart, perhaps, from the ammoniates of the alkali metals) they are comparable only with the recently discovered compounds. As a class, the carbonyls are reactive compounds, and a number of new types of inorganic compounds have been discovered. In the concepts for new products, performance, product safety, and product economy criteria are equally important. They are taken into account already when the raw material base for a new industrial product development is defined. Since the discovery of nickel carbonyl by Mond and Langer in 1888, the carbonyls of the iron group and of chromium, molybdenum and tungsten have found important technical applications, e.g., in the Mond nickel process, and for the preparation of the metals in a state of subdivision and of purity suitable for powder metallurgy, for catalysts, etc. The reaction mechanism of the processes developed for producing the carbonyls technically has only recently received its interpretations. Within the space of review it is necessary to limit discussion to a few topics. Particular stress has accordingly laid upon (a) the chemical bonding in metal carbonyls, (b) importance of IR and NMR spectroscopy in characterization of metal carbonyls, (c) substitution reactions of G-VIb metal carbonyls, (d) kinetics and mechanism of substitution reactions in metal carbonyls, (e) substituted complexes of G-VIb metal carbonyl, (f) chelate complexes of G-VIb metal carbonyls, (g) uses of G-VIb metal carbonyl complexes and (h) studies done on G-VIb metal carbonyls.

The chemistry of group-VIb metal carbonyls

The special interest attached to the chemistry of metal carbonyls arises from several causes. While quite distinct from the metal carbonyls in the organometallic compounds, they differ in physical properties (e.g., their volatility) from all other compounds of the transition metals. Chemically, they constitute a group of compounds in which the formal valency of the metal atoms is zero, and in this respect (apart, perhaps, from the ammoniates of the alkali metals) they are comparable only with the recently discovered compounds. As a class, the carbonyls are reactive compounds, and a number of new types of inorganic compounds have been discovered. In the concepts for new products, performance, product safety, and product economy criteria are equally important. They are taken into account already when the raw material base for a new industrial product development is defined. Since the discovery of nickel carbonyl by Mond and Langer in 1888, the carbonyls of the iron group and of chromium, molybdenum and tungsten have found important technical applications, e.g., in the Mond nickel process, and for the preparation of the metals in a state of subdivision and of purity suitable for powder metallurgy, for catalysts, etc. The reaction mechanism of the processes developed for producing the carbonyls technically has only recently received its interpretations. Within the space of review it is necessary to limit discussion to a few topics. Particular stress has accordingly laid upon (a) the chemical bonding in metal carbonyls, (b) importance of IR and NMR spectroscopy in characterization of metal carbonyls, (c) substitution reactions of G-VIb metal carbonyls, (d) kinetics and mechanism of substitution reactions in metal carbonyls, (e) substituted complexes of G-VIb metal carbonyl, (f) chelate complexes of G-VIb metal carbonyls, (g) uses of G-VIb metal carbonyl complexes and (h) studies done on G-VIb metal carbonyls.

A detailed quantum chemical study of the interactions of [Pt(dien)Cl]+ with a series of S-donor ligands: A computational approach

The mechanism of substitution reaction of [Pt(dien)Cl]+ (dien=diethylenetriamine) with a series of endogenous and exogenous S-containing ligands such as H2S, sodium methanethiolate (NaSMe), dimethylsulfane (Me2S), diethylsulfane (Et2S), thiourea (TU), 1,3-dimethylthiourea (DMTU), 1,3-diethylthiourea (DMTU), sodium-2-mercaptoethanesulfonate (mesna), sodium diethyldithiocarbamate (Naddtc), l-methionine (Met) and l-cysteine (Cys) were studied by computational methods. Within the framework of transition state theory, DFT-based calculations were performed in gas phase using the B3LYP exchange–correlation functionals as implemented in the Gaussian 09 program. Pentacoordinated square pyramidal (SP) and trigonal–bipyramidal (TBP)-like structure transition states (TS) along with other stationary points on potential energy surface were optimized and characterized. Results led us to conclude that for platination of S-ligands as protecting agents Naddtc, mesna and TU are more suitable than thiol and thioether ligands. Natural bond orbital (NBO) analysis method was performed for the investigation of major stabilizing orbital interactions. To obtain accurate energies for the reaction surfaces, single-point energies were calculated by conductor-like polarisable calculation model (CPCM) using larger basis sets at MP2 and B3LYP levels of theory. The sequence of rate constants found in our study in aqueous phase is: Naddtc>mesna>TU>Met>Cys>Me2S>Et2S≈MeSH>H2S≈DETU>NaSMe>DMTU.

Role of π-Acceptor Effects in Controlling the Lability of Novel Monofunctional Pt(II) and Pd(II) Complexes: Crystal Structure of [Pt(tripyridinedimethane)Cl]Cl

The kinetics and mechanism of substitution reactions of novel monofunctional [Pt(tpdm)Cl](+) and [Pd(tpdm)Cl](+) complexes (where tpdm = tripyridinedimethane) and their aqua analogues with thiourea (tu), L-methionine (L-met), glutathione (GSH), and guanosine-5'-monophosphate (5'-GMP) were studied in 0.1 M NaClO(4) at pH = 2.5 (in the presence of 10 mM NaCl for reactions of the chlorido complexes). The reactivity of the investigated nucleophiles follows the order tu > l-met > GSH > 5'-GMP. The reported rate constants showed the higher reactivity of the Pd(II) complexes as well as the higher reactivity of the aqua complex than the corresponding chlorido complex. The negative values reported for the activation entropy as well as the activation volume confirmed an associative substitution mode. In addition, the molecular and crystal structure of [Pt(tpdm)Cl]Cl was determined by X-ray crystallography. The compound crystallizes in a monoclinic space group C2/c with two independent molecules of the complex and unit cell dimensions of a = 38.303(2) Å, b = 9.2555(5) Å, c = 27.586(2) Å, β = 133.573(1)°, and V = 7058.3(8) Å(3). The cationic complex [Pt(tpdm)Cl](+) exhibits square-planar coordination around the Pt(II) center. The lability of the [Pt(tpdm)Cl](+) complex is orders of magnitude lower than that of [Pt(terpyridine)Cl](+). Quantum chemical calculations were performed on the [Pt(tpdm)Cl](+) and [Pt(terpyridine)Cl](+) complexes and their reactions with thiourea. Theoretical computations for the corresponding Ni(II) complexes clearly demonstrated that π-back-bonding properties of the terpyridine chelate can account for acceleration of the nucleophilic substitution process as compared to the tpdm chelate, where introduction of two methylene groups prevents such an effective π-back bonding.

Alan McLeod Sargeson FAA. 13 October 1930 — 29 December 2008

Alan Sargeson was an extraordinarily gifted inorganic chemist who consistently made important and lasting contributions to his discipline. His lifelong interests were in the area of coordination chemistry, especially in the stereochemistry and reactivity of complexes involving the transition element cobalt. Notable discoveries included the elucidation of the mechanisms of substitution reactions of cobalt complexes, the demonstration that amino acid amides and their esters and phosphate esters incorporated in properly designed metal complexes could achieve the high rates of hydrolysis displayed by enzyme reactions, and perhaps most notably the discovery of the ready formation of cage complexes in which the metal is fully encapsulated. His impact on his field was far reaching, his achievements were at the highest level and for more than 30 years he was among the few who dominated the field.

A highly selective wavelength-ratiometric and colorimetric probe for cysteine

Based on the nucleophilic aromatic substitution reaction mechanism, a new highly selective probe for cysteine (Cys), N-butyl-4-bromo-3-nitro-1,8-naphthalimide (1), was designed and synthesized. The probe displayed a remarkable (58 nm) red-shift in the absorption spectra and the color changes from colorless to yellow upon reaction with Cys. The probe could detect Cys quantitatively in the range of 0–0.9 mM by both normal and ratiometric absorption spectrometry methods. Moreover, 1 could also serve as a “naked-eye” probe for Cys with a minimum detectable concentration of approximately 50 μM.

The Structural Basis for Substrate Recognition by Mammalian Polynucleotide Kinase 3′ Phosphatase

Mammalian polynucleotide kinase 3' phosphatase (PNK) plays a key role in the repair of DNA damage, functioning as part of both the nonhomologous end-joining (NHEJ) and base excision repair (BER) pathways. Through its two catalytic activities, PNK ensures that DNA termini are compatible with extension and ligation by either removing 3'-phosphates from, or by phosphorylating 5'-hydroxyl groups on, the ribose sugar of the DNA backbone. We have now determined crystal structures of murine PNK with DNA molecules bound to both of its active sites. The structure of ssDNA engaged with the 3'-phosphatase domain suggests a mechanism of substrate interaction that assists DNA end seeking. The structure of dsDNA bound to the 5'-kinase domain reveals a mechanism of DNA bending that facilitates recognition of DNA ends in the context of single-strand and double-strand breaks and suggests a close functional cooperation in substrate recognition between the kinase and phosphatase active sites.

Perfluoro Allyl Fluorosulfate (FAFS): A Versatile Building Block for New Fluoroallylic Compounds

In this study we will present and discuss both the synthesis of CF2=CFCF2OSO2F (perfluoroallyl fluorosulfate, FAFS), focusing in particular on the important role of C3F6/SO3 ratio, reaction temperature and boron catalyst/SO3 ratio on FAFS’ yield and selectivity, as well as a wide variety of ionic and radical reactions possible with FAFS. We focused our attention on reactions of FAFS with aliphatic and aromatic alcohols, acyl halides, halides, H2O2, ketones and radicals whose synthesis and reaction mechanisms will be presented and discussed. Particular attention will be devoted to the novel diallyl-fluoroalkyl peroxide obtained. Factors such as pKa and Lowry and Pearson’s Hard/Soft Acid-Base Theory which determine the selectivity between Addition/Elimination vs. Nucleophilic Substitution reaction mechanisms on FAFS will also be presented and discussed.

The Kinetics and Mechanisms of Aromatic Nucleophilic Substitution Reactions in Liquid Ammonia

The rates of aromatic nucleophilic substitution reactions in liquid ammonia are much faster than those in protic solvents indicating that liquid ammonia behaves like a typical dipolar aprotic solvent in its solvent effects on organic reactions. Nitrofluorobenzenes (NFBs) readily undergo solvolysis in liquid ammonia and 2-nitrofluorobenzene is about 30 times more reactive than the 4-substituted isomer. Oxygen nucleophiles, such as alkoxide and phenoxide ions, readily displace fluorine of 4-NFB in liquid ammonia to give the corresponding substitution product with little or no competing solvolysis product. Using the pK(a) of the substituted phenols in liquid ammonia, the Brønsted β(nuc) for the reaction of 4-NFB with para-substituted phenoxides is 0.91, indicative of the removal of most of the negative charge on the oxygen anion and complete bond formation in the transition state and therefore suggests that the decomposition of the Meisenheimer σ-intermediate is rate limiting. The aminolysis of 4-NFB occurs without general base catalysis by the amine and the second-order rate constants generate a Brønsted β(nuc) of 0.36 using either the pK(a) of aminium ion in acetonitrile or in water, which is also interpreted in terms of rate limiting breakdown of the Meisenheimer σ-intermediate. Nitrobenzene and diazene are formed as unusual products from the reaction between sodium azide and 4-NFB, which may be due to the initially formed 4-nitroazidobenzene decomposing to give a nitrene intermediate, which may then give diazene or be trapped by ammonia to give the unstable hydrazine which then yields nitrobenzene.

Alan McLeod Sargeson 1930 - 2008

Alan Sargeson was an extraordinarily gifted inorganic chemist who consistently made important and lasting contributions to his discipline. His lifelong interests were in the area of coordination chemistry, especially in the stereochemistry and reactivity of complexes involving the transition element cobalt. Notable discoveries included the elucidation of the mechanisms of substitution reactions of cobalt complexes, and the demonstration that amino acid amides and their esters and phosphate esters incorporated in properly designed metal complexes could achieve the high rates of hydrolysis displayed by enzyme reactions. Perhaps most notable was the discovery of the ready formation of cage complexes where the metal is fully encapsulated. His impact on his field was far-reaching, his achievements were at the highest level and for over thirty years he was among the few who dominated the field.

The mechanism of aromatic nucleophilic substitution reaction between ethanolamine and fluoro‐nitrobenzenes: an investigation by kinetic measurements and DFT calculations

AbstractWe have studied the kinetics and elucidated the mechanism by DFT calculation of the reaction between ethanolamine (EOA) and 1‐fluoro‐2,4‐dinitrobenzene (DNFB) in acetonitrile and toluene. To determine the contribution of the nitro group, the activation energy of the reaction between ethanolamine and 1‐fluoro‐2‐nitrobenzene (MNFB) vs. DNFB was determined in acetonitrile and calculated by DFT method. Kinetic measurements reveal that the reaction is faster in acetonitrile than in toluene. The reaction follows overall second‐order kinetics: first order with respect to both EOA and DNFB which is similar to the results reported for reaction between other primary amines and 1‐substituted‐2,4‐dinitrobenzenes. The calculations by using DFT methods reveal that the mechanism of the reaction involves the formation and decomposition of a Meisenheimer complex (MC). DFT calculations also reveal that the activation energy of the reaction is highest in vacuum and decreases with increasing polarity of the solvent reaching a minimum in acetonitrile. In addition, activation energies obtained by both DFT calculations and experiments show that the reactivity of MNFB is less than that of DNFB showing the effect of the 4‐nitro group. Copyright © 2010 John Wiley & Sons, Ltd.

Kinetics and Mechanism of Nucleophilic Substitution Reaction of 4-Substituted-2,6-dinitrochlorobenzene with Benzylamines in MeOH-MeCN Mixtures

The reaction rates of 4-X-2,6-dinitrochlorobenzenes (X = <TEX>$NO_2$</TEX>, CN, <TEX>$CF_3$</TEX>) with Y-substituted benzylamines (Y = p-<TEX>$OCH_3$</TEX>, p-<TEX>$CH_3$</TEX>, H, p-Cl) in MeOH-MeCN mixtures were measured by conductometry at <TEX>$25^{\circ}C$</TEX>. It was observed that the rate constant increased in the order of X = <TEX>$NO_2$</TEX> > CN > <TEX>$CF_3$</TEX> and in the order of Y = p-<TEX>$OCH_3$</TEX> > p-<TEX>$CH_3$</TEX> > H > p-Cl. When the solvent composition was varied, the rate constant increased in the order of 100% MeOH < 50% (v/v) MeOH-MeCN < 100% MeCN. These results may be ascribed to the formation of hydrogen bonds between the alcoholic hydrogen and nitrogen of benzylamines in groud state (GS). We conclude that the reaction takes place via <TEX>$S_NAr$</TEX> base on the transition state parameters <TEX>${\rho}x$</TEX>, <TEX>${\rho}Y$</TEX>, <TEX>$\beta_{nuc}$</TEX>, and solvent effects.

Physical organic chemistry

Physical organic chemistry – the study of the interplay between structure and reactivity in organic molecules – underpins organic chemistry, and we cannot imagine organic chemistry as a subject without knowledge of mechanism and reactivity. It is sometimes thought that the golden age of ‘physical organic chemistry’ was in the 20th century, when systematic information about mechanism first burst onto the scene. Certainly the impact of early knowledge of mechanism of fundamental aliphatic substitution reactions, among others, was enormous, but our knowledge of reactivity and mechanism has continued to progress and deepen enormously ever since and this has been reflected in a number of Nobel Prizes in Chemistry. In an area of particular interest to me, the transformation of radical chemistry from being an almost impenetrable area to one that can be usefully harnessed even in synthetic applications, has been extraordinary – this transformation has been relatively recent and has been principally dependent on the accurate determination of kinetics of radical reactions. Applications to complex reactions in biology, polymer chemistry and electronic materials are ever more prevalent, and add to contributions in ‘small molecule’ chemistry. Novel experimental techniques combined with the revolution in computational chemistry give new impetus to physical organic chemistry and contribute to its continuing importance, an importance that is reflected in the large number of international meetings in physical organic chemistry in the past two years. I am privileged to act as Guest Editor for this Thematic Series of the Beilstein Journal of Organic Chemistry, and hope that you enjoy the papers that form this issue. I am grateful to the contributors for their contributions. John A. Murphy Glasgow, November 2010

The kinetics and mechanism of the substitution reactions of the aquapentacyanoruthenate(II) ion with naphthalene‐substituted ligands in aqueous medium

AbstractThe kinetics and mechanism of substitution reaction of [Ru(CN)5H2O]3− anion with two naphthalene‐substituted ligands viz. Ln = nitroso‐R‐salt (NRS) and α‐nitroso‐β‐naphthol (αNβN) have been studied spectrophotometrically by monitoring an increase in absorbance at λmax = 525 nm corresponding to metal to ligand charge transfer (MLCT) transitions due to formation of substituted [Ru(CN)5L]n−3 as a function of pH, ionic strength, temperature, a wide range of ligands concentration, and [Ru(CN)5H2O3−] under pseudo‐first‐order conditions. The experimental observation suggests that [Ru(CN)5H2O]3− ion interacts with both ligands, which finally get converted into corresponding, [Ru(CN)5L]n−3 complexes as a final reaction product. The reaction is found to obey first‐order dependence each in [Ru(CN)5H2O3−] and [Ln]. The substituted products, viz. [Ru(CN)5L]n−3, in each case have strong MLCT transitions in visible region. The substitutional lability of [Ru(CN)5H2O]3− has been discussed in terms of electronic effect on the MOH2 bond interactions. The kinetic observation suggests that the complexation reaction of [Ru(CN)5H2O]3− with both the ligands, i.e., NRS and αNβN, follows an ion pair dissociative mechanism. The thermal activation parameters ΔH≠ and ΔS≠ have been calculated using Eyring's equation and provided in support for the proposed mechanistic scheme. © 2010 Wiley Periodicals, Inc. Int J Chem Kinet 43: 21–30, 2011

ChemInform Abstract: The Mechanisms of Nucleophilic Substitution Reactions of Aromatic Ethers with Amines in Benzene.

The variation of the second-order rate constants with nucleophile concentration has been determined for the following reactions of some aromatic ethers with primary and secondary amines in benzene: 6-methyl-2,4-dinitrophenyl- and 2,6-dinitrophenyl phenyl ethers with piperidine, n-butylamine, morpholine and benzylamine; 2-phenoxy-3,5-dinitropyridine with these four nucleophiles and aniline; and 2,4,6-trinitrophenyl 4-nitrophenyl ether with N-methylaniline. An attempt has been made to rationalise the kinetic forms of these and similar reactions of other aromatic ethers in benzene.

ChemInform Abstract: Single Electron Transfer in Aliphatic Nucleophilic Substitution

Since the classical studies by Ingold in the nineteen thirties the mechanism of the aliphatic nucleophilic substitution reaction has been described as a polar two-electron mechanism in which the nucleophile transfers two electrons to the new bond which is established to the electrophilic center. Depending on the reaction order the abbreviations SN1 and SN2 were used for first-order and second-order reactions, respectively.

ChemInform Abstract: Recent Developments on the Mechanisms of Substitution Reactions of Octahedral Coordination Complexes

ChemInform 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 Formation and Stability of Alkylthiol Monolayers on Carbon Substrates.

The formation and stability of alkylthiol monolayers on amorphous carbon thin films are investigated. Alkylthiol monolayers were prepared via a two-step, wet chemical process in which the carbon surface was first halogenated and then incubated with (4-(trifluoromethyl)phenyl)methanethiol (4tBM). The 4tBM covalently attaches to the surface in a substitution reaction in which the 4tBM thiol replaces the surface halogen. Studies of the substitution mechanism showed that monolayer formation is affected by the nature of the surface-bound halogen as well as the concentration and nucleophilicity of the 4tBM sulfur atom, consistent with a bimolecular (S(N)2) substitution reaction mechanism. The alkylthiol monolayers are stable over a wide range of solvent, pH, and temperature conditions.

ChemInform Abstract: The Reactivity of β-Lactams, the Mechanism of Catalysis and the Inhibition of β-Lactamases

Four membered b-Lactam rings do not show unusual reactivity compared with their acyclic amide analogues and there is no evidence of concerted mechanisms for nucleophilic substitution reactions at the carbonyl centre. The identity of the general base/acid catalyst in the serine b-Lactamases, which catalyse the hydrolysis of b-Lactams, is unknown. There are no ideal transition state analogue inhibitors for these enzymes which involve several intermediates and transition states. The class C serine b-Lactamase enhances the rate of phosphonylation of its active site serine residue by a similar magnitude to the enzyme rate enhancement factor for the hydrolysis of b-Lactams. Comparisons are made between the stereochemical consequences of tetrahedral and trigonal bipyramidal intermediates for hydrolysis and phosphonylation respectively. Class B zinc b-Lactamases are inhibited by thiol dipeptides with a D configuration at the cysteine centre analogous to the L configuration at C6 in penicillins. The mechanism of hydrolysis catalysed by the metallo-b-Lactamases probably involves a di-anionic tetrahedral intermediate stabilised by zinc(II).