Two-step nucleophilic substitution

The analogous reaction of 5-iodopyridazin-3(2H)-one led to the formation of pyridazino[4,5-6]indoles (3.82.) in a two step nucleophilic substitution, palladium catalysed intramolecular carbon-carbon bond formation sequence. The same reaction has also been carried out in one-... 

Again, as expected, pyridine A-oxides are very susceptible to nucleophilic attack. Unlike the situation usually prevalent with the quaternary pyridinium salts, the elimination stage of the two-step nucleophilic substitution can occur with relative ease, the oxide grouping serving as a good sink for the leaving hydride ion electron-pair and being itself eliminated in the process. Considerably more work has been carried out on quinoline and isoquinoline A-oxides than on pyridine A-oxide derivatives. 

The DhiA enzyme functions as a monomer ( 35 kDa) and is composed of two domains a main domain and a cap domain (Figure 2(a)). The main domain consists of a mostly parallel eight-stranded /3-sheet connected by ct-helices on both sides of the sheet. The cap domain is composed of five ct-helices with intervening loops. The active site is an occluded hydrophobic cavity located at the interface of the two domains. The overall fold of the main domain is the hallmark of the o //3-hydrolase fold superfamily of enzymes, to which lipases, esterases, carboxypeptidases, and acetylcholinesterases also belong. These superfamily members catalyze the hydrolysis of ester and amide bonds via a two-step nucleophilic substitution mechanism similar to that of serine proteases. 

For coordinativcly saturated metals, oxolation proceeds by two step nucleophilic substitution reaction involving nucleophilic addition followed by water elimination. 

It is believed that the highly important phosphoryl transfer reactions (3.92) and (3.93) involving nucleophilic displacement on a P atom (the latter acting as an electrophile), can take place either by a pure S l or a 8 2 mechanism or by a mechanism intermediate in type. The efficiency of a phosphate transfer by the more common two-step nucleophilic substitution reaction (3.92), depends on the reactivity of the nucleophile Y and on how good a leaving group X is (3.92). 

Note If this terminology seems backwards, just you wait In Part C of this activity we will encoimter two-step nucleophilic substitution reactions, which (of course) are called SnI reactions. ... 

Review) Explain why a two-step nucleophilic substitution reaction is called an SnI reaction. What does the 1 stand for (if not the number of steps) ... 

Heterocyclization based on simple acetylenes requires a catalyst to be present [33, 447-449]. Haloacetylenes with alkyl or aryl substituents also undergo heterocyclization but less effectively. However, activated electron-deficient haloacetylenes readily react with nucleophiles. With binucleophiles, this reaction often leads to the formation of heterocycles. Haloacetylene often reacts in a similar manner to acetyl chloride, differing from the latter by the absence of released water. However, sometimes an unusual reaction occurs, as was shown by the reaction of dialkyl l-chloroacetylene-2-phosphonates with specific binucleophiles. l-Chloro-2-dialkoxyphorylacetylenes 4.981 react readily with diethyl acetamidomalonate in acetonitrile in the presence of potassium carbonate as a base, to form oxazoline derivatives 4.991. The reaction has two steps nucleophilic substitution of the acetylenic chlorine atom followed by attack of the amide oxygen atom on the triple bond activated by... 

Jug and co-workers investigated the mechanism of cycloaddition reactions of indolizines to give substituted cycl[3,2,2]azines <1998JPO201>. Intermediates in this reaction are not isolated, giving evidence for a concerted [8+2] cycloaddition, which was consistent with results of previous theoretical calculations <1984CHEC(4)443>. Calculations were performed for a number of substituted ethenes <1998JPO201>. For methyl acrylate, acrylonitrile, and ethene, the concerted [8+2] mechanism seems favored. However, from both ab initio and semi-empirical calculations of transition states they concluded that reaction with nitroethene proceeded via a two-step intermolecular electrophilic addition/cyclization route, and dimethylaminoethene via an unprecedented two-step nucleophilic addition/cyclization mechanism (Equation 1). 

An examination of all papers describing the synthesis of hyperbranched poly(carbo-silanes) reveals that only two reactions have been used in the polymerization step nucleophilic substitution and hydrosilylation. 

This one-step nucleophilic substitution is an example of the SN2 mechanism. The abbreviation SN2 stands for Substitution, Nucleophilic, bimolecular. The term bimolecular means that the transition state of the rate-limiting step (the only step in this reaction) involves the collision of two molecules. Bimolecular reactions usually have rate equations that are second order overall. 

Base-catalyzed transesterification is a simple two-step nucleophilic acyl substitution ... 

The preceding discussion has generated two possible mechanisms for nucleophilic substitution a one-step mechanism in which bond breaking and bond making are simultaneous, and a two-step mechanism in which bond breaking comes before bond making. In Section 7.10 we look at data for two specific nucleophilic substitution reactions and see if those data fit either of these proposed mechanisms. 

In nucleophilic substitutions one can distinguish between two mechanisms, i.e., the two step nucleophilic substimtion (Sfj,)and the one step process (8 2). In the latter route, the highly polar intermediate species or, in the limiting case, the carbocation is stabilized by the catalyst. 

There are two general nucleophilic substitution reaction mechanisms (1) a one step process in which the nucleophile enters at the same time the leaving group exits (SN2) and (2) a two step process in which the leaving group departs and then the nucleophile enters (SN1). 

The last entry of Thble 1-1 is detailed in (1-8) a two-step nucleophilic aliphatic substitution in which the loss of the leaving group Y is concerted with cyclization involving the group Z in position 2, the latter moving in the second step to the position 1, a process that is again concerted with addition of the nucleophilic reagent X. 

This type of nucleophilic aromatic substitution for halogen has been studied extensively, and it has been determined that reaction occurs in two steps nucleophilic addition followed by elimination. For the majority of reactions of this type, addition of the nucleophile in Step 1 is the slow, rate-determining step. Elimination of halide ion in Step 2 gives the product. This reaction thus resembles reactions of carboxylic acid derivatives in that it proceeds by an addition-elimination mechanism rather than by direct substitution. 

The two identical leaving groups (X = Y) in phosgene substitutes 1002 can be consecutively replaced to prepare both symmetrical and unsymmetrical ureas. The selectivity toward the unsymmetrical N,N -disubstituted ureas is critically dependent on the relative reaction rates of the two consecutive nucleophilic substitutions. If the second step is much slower than the first one, the formation of the symmetrical urea is minimized [726]. 

A number of peptidase and esterase enzymes react covalently in substitution reactions by a two-step nucleophilic mechanism. In the first step, the enzyme is acylated in the second step, it is dea-cylated. Chymotrypsin will be discussed as an example of this reaction mechanism. Its activity is dependent on His and Ser, which are positioned in close proximity within the active site of the enzyme because of folding of the peptide chain (Fig. 2.16). 

The higjily water-soluble dienophiles 2.4f and2.4g have been synthesised as outlined in Scheme 2.5. Both compounds were prepared from p-(bromomethyl)benzaldehyde (2.8) which was synthesised by reducing p-(bromomethyl)benzonitrile (2.7) with diisobutyl aluminium hydride following a literature procedure2.4f was obtained in two steps by conversion of 2.8 to the corresponding sodium sulfonate (2.9), followed by an aldol reaction with 2-acetylpyridine. In the preparation of 2.4g the sequence of steps had to be reversed Here, the aldol condensation of 2.8 with 2-acetylpyridine was followed by nucleophilic substitution of the bromide of 2.10 by trimethylamine. Attempts to prepare 2.4f from 2.10 by treatment with sodium sulfite failed, due to decomposition of 2.10 under the conditions required for the substitution by sulfite anion. 

Section 4 9 The potential energy diagrams for separate elementary steps can be merged into a diagram for the overall process The diagram for the reac tion of a secondary or tertiary alcohol with a hydrogen halide is charac terized by two intermediates and three transition states The reaction is classified as a ummolecular nucleophilic substitution, abbreviated as SnI... 

The reaction occurs in two stages Only the first stage involves nucleophilic substitution It IS the rate determining step... 

Phosphorus ylides are prepared from alkyl halides by a two step sequence The first step is a nucleophilic substitution of the 8 2 type by triphenylphosphme on an alkyl halide to give an alkyltriphenylphosphonium salt... 

Primary and secondary alkyl halides may be converted to the next higher carboxylic acid by a two step synthetic sequence involving the preparation and hydrolysis of nitriles Nitnles also known as alkyl cyanides are prepared by nucleophilic substitution... 

Mescaline a hallucinogenic amine obtained from the peyote cactus has been synthesized in two steps from 3 4 5 trimethoxybenzyl bromide The first step is nucleophilic substitution by sodium cyanide The second step is a lithium aluminum hydnde reduction What is the structure of mescaline" ... 

The generally accepted mechanism for nucleophilic aromatic substitution m nitro substituted aryl halides illustrated for the reaction of p fluoromtrobenzene with sodium methoxide is outlined m Figure 23 3 It is a two step addition-elimination mechanism, m which addition of the nucleophile to the aryl halide is followed by elimination of the halide leaving group Figure 23 4 shows the structure of the key intermediate The mech anism is consistent with the following experimental observations... 

Substitution nucleophilic unimolecular(SNl) mechanism (Sec tions 4 9 and 8 8) Mechanism for nucleophilic substitution charactenzed by a two step process The first step is rate determining and is the ionization of an alkyl halide to a carbocation and a halide ion... 

Nucleophilic Substitution Route. Commercial synthesis of poly(arylethersulfone)s is accompHshed almost exclusively via the nucleophilic substitution polycondensation route. This synthesis route, discovered at Union Carbide in the early 1960s (3,4), involves reaction of the bisphenol of choice with 4,4 -dichlorodiphenylsulfone in a dipolar aprotic solvent in the presence of an alkaUbase. Examples of dipolar aprotic solvents include A/-methyl-2-pyrrohdinone (NMP), dimethyl acetamide (DMAc), sulfolane, and dimethyl sulfoxide (DMSO). Examples of suitable bases are sodium hydroxide, potassium hydroxide, and potassium carbonate. In the case of polysulfone (PSE) synthesis, the reaction is a two-step process in which the dialkah metal salt of bisphenol A (1) is first formed in situ from bisphenol A [80-05-7] by reaction with the base (eg, two molar equivalents of NaOH),... 

Phosphazene polymers are normally made in a two-step process. First, hexachlorocyclotriphosphazene [940-71 -6J, trimer (1), is polymerized in bulk to poly(dichlorophosphazene) [26085-02-9], chloropolymer (2). The chloropolymer is then dissolved and reprecipitated to remove unreacted trimer. After redissolving, nucleophilic substitution on (2) with alkyl or aryloxides provides the desired product (3). 

Ring expansion of haloalkyloxiranes provides a simple two-step procedure for the preparation of azetidin-3-ols (Section 5.09.2.3.2(f)) which can be extended to include 3-substituted ethers and O-esters (79CRV331 p. 341). The availability of 3-hydroxyazetidines provides access to a variety of 3-substituted azetidines, including halogeno, amino and alkylthio derivatives, by further substitution reactions (Section 5.09.2.2.4). Photolysis of phenylacylamines has also found application in the formation of azetidin-3-ols (33). Not surprisingly, few 2-0-substituted azetidines are known. The 2-methoxyazetidine (57) has been produced by an internal displacement, where the internal amide ion is generated by nucleophilic addition to an imine. 

Mechanistically the reaction can be divided into two steps. Initially the alkyl halide 1 reacts with sodium to give an organometallic species 3, that can be isolated in many cases. In a second step the carbanionic R of the organometallic compound 3 acts as nucleophile in a substitution reaction with alkyl halide 1 to replace the halide ... 

A mechanism that accounts for both the inversion of configuration and the second-order kinetics that are observed with nucleophilic substitution reactions was suggested in 1937 by E. D. Hughes and Christopher Ingold, who formulated what they called the SN2 reaction—short for substitution, nucleophilic, birnolecu-lar. (Birnolecular means that two molecules, nucleophile and alkyl halide, take part in the step whose kinetics are measured.)... 

Mechanism of nucleophilic aro-malic substitution. The reaction occurs in two steps and involves a resonance-stabilized carbanion intermediate. 

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