Nucleophilicity generalizations

Reaction with Sulfur Nucleophiles, Because sulfai is highly nucleophilic, reactions of aziridines with sulfur nucleophiles generally proceed rapidly (111) and with good yields. The reaction of hydrogen sulfide [7783-06S-J with ethyleneimine yields cysteamine [60-23-1] (2-mercaptoethylamine) or bis(2-aminoethyl)sulfide [871-76-1] (2,112) depending on the molar ratio of the reactants. The use of NaHS for the synthesis of cysteamine has also been described (113). 

In 2,4-disubstituted quinazolines, the 4-position reacts fastest with nucleophiles, generally even when the 4-substituent is a poorer leaving group. 2,4-Dichloroquinazoline undergoes mono-substitution at the 4-position with alcoholic alkoxides (25°, 2 hr, 80-98% yield), phenolic phenoxide (20°, 16 hr, 50% yield), aqueous hydroxide (30°, 3 hr), alcoholic methylmercaptide (20°, exothermically), alkylamines (20°, 10-60 min, 100%... 

The thermal, and more importantly, the photolytic decomposition of aryl azides in the presence of nucleophiles, generally amines or alcohols, is the commonest method for preparing 3H-azepines. In fact, jV-phenyl-3//-azepin-2-amine (32, R = Ph), the first example of a 3//-azepine, was prepared by thermal decomposition of phenyl azide in aniline.32... 

Addition of carbon nucleophiles to vinylepoxides is of particular importance, since a new carbon-carbon bond is formed. It is of considerable tactical value that conditions allowing for regiocontrolled opening of vinyloxiranes with this type of nucleophiles have been developed. Reactions that proceed through fonnation of a rr-allyl metal intermediate with subsequent external delivery of the nucleophile, or that make use of a soft carbon nucleophile, generally deliver the SN2 product. In contrast, the Sn2 variant is often the major reaction pathway when hard nucleophiles are employed. In some methods a nucleophile can be delivered selectively at either the Sn2 or SN2 positions by changing the reaction conditions. 

The reaction of an aromatic aldehyde with an aromatic nucleophile containing hydroxy or amino groups gives products with at least two identical phenyl groups79 83 e.g., 55, 56. Use of two different nucleophiles generally results in lower yield. 

In contrast to the reactivity of N-sulfonyloxy and N-acetoxy esters of arylamides and arylamines, the relative reactivity of protonated N-hydroxy arylamines with nucleophiles generally decreases in the order DNA > denatured DNA > rRNA = protein > tRNA nucleotides s nucleosides s methionine = GSH (2,13-17,30,36,40,127,129, 130). Furthermore, the rate of reaction with DNA was found to be not only first order with respect to N-hydroxy arylamine concentration, but also first order with respect to DNA concentration (127,129,131). These data suggested that the reaction mechanism was... 

The solvomercuration reaction is thought to be a two-step process. In the first step (equation 147), electrophilic attachment of mercury ion to the alkene produces a positively charged intermediate. In the second step (equation 148), a nucleophile (generally a solvent molecule) reacts with the intermediate leading to the organomercury compound. 

Fig. 10.6. Simplified representation of the postulated catalytic cycle of microsomal and cytosolic epoxide hydrolases, showing the roles played by the catalytic triad (i.e., nucleophile, general base, and charge relay acid) and some other residues, a) Nucleophilic attack of the substrate to form a /3-hydroxyalkyl ester intermediate, b) Nucleophilic attack of the /Thydroxyal-kyl ester by an activated H20 molecule, c) Tetrahedral transition state in the hydrolysis of the /f-hydroxyalkyl ester, d) Product liberation, with the enzyme poised for a further catalytic... 

Photolysis or thermolysis of 3-diazopyrazoles with nucleophiles generally led to addition to the carbene species. Thus, in diethyl ether, compounds 84 and 85 (Scheme 25) were obtained in ratio 3 2 (77JA633). This reaction, leading to 1,2- and 1,3- adducts, is quite unusual since carbenes... 

Strongly electrophilic or nucleophilic monomers will polymerize exclusively by anionic or cationic mechanisms. However, monomers that are neither strongly electrophilic nor nucleophilic generally polymerize by ionic and free radical processes. The contrast between anionic, cationic, and free radical methods of addition copolymerization is clearly illustrated by the results of copolymerization utilizing the three modes of initiation (Figure 7.1). Such results illustrate the variations of reactivities and copolymer composition that are possible from employing the different initiation modes. The free radical tie-line resides near the middle since free radical polymerizations are less dependent on the electronic nature of the comonomers relative to the ionic modes of chain propagation. 

Pyrones and thiopyrones react very readily with a variety of nucleophiles, but here the situation is complicated not only by the carbonyl group, but by the fact that these compounds show elements of both aromatic and aliphatic character. Pyran-2-one (9) can in principle react with nucleophiles at the 2-, 4- or 6-position and examples of each type of reaction are known. There is an approximate correlation with the hard and soft acid and base hypothesis, in that hard nucleophiles such as HO generally react at the 2-position while soft nucleophiles such as hydride ion generally react at the 6-position. Reactions at the 4-and 6-positions can, of course, be rationalized mechanistically simply as examples of conjugate addition. A similar situation obtains with pyran-4-ones (10), where reaction can in principle occur at the 2- or 4-position. Hard nucleophiles generally react at the 2-position,... 

The mechanism of the thermal ROP of (Cl2PN)3 has been proposed to involve a cationic mechanism (see Scheme 8.2 in Section 8.1.2.2). The unique reaction sequence involving ROP followed by nucleophilic substitution with oxygen- or nitrogen-based nucleophiles (generally alkoxides, aryloxides or primary amines) permits a diverse range of polyorganophosphazenes to be... 

Steric effects of the substrate Large groups on the electrophile hinder the approach of the nucleophile. Generally, one alkyl group slows the reaction, two alkyl groups make it difficult and three alkyl groups make it close to impossible. 

The metal-promoted reactions with nucleophiles generally yield metal complexes of the intermediate imino species and it is quite unusual to observe the carboxylate products derived from the attack of a second equivalent of nucleophile. A wide variety of products have been observed. The ligands may be monodentate O- or A-bonded species, or exhibit a didentate N,0-mode. The ligands may be in the amide or the hydroxyimine tautomeric forms, and may be neutral or deprotonated (Fig. 4-8). 

Consider now 4-fcrfbutylcyclohexanone, a configurationally rigid molecule. The carbonyl plane defines two half-spaces, the lower of which contains only the axial hydrogens at C2 and C6. Even so, the nucleophile generally arrives from above (90% in the reduction by LiAlH4). These results cannot be explained by Cram s model and other factors have been invoked. For instance, Dauben et al.56 suggested that equatorial attack is under steric approach control whereas axial attack is under product development control ... 

Epoxides directly attached to the oxetane ring in l,5-dioxaspiro[3.2]hexanes (e.g., 71) can be ring-opened by certain nucleophiles without attack on the less-strained oxetane ring <19990L825, 2003JOC1480>. However, such reactions can alternatively lead to the formation of a-substituted-/3 -hydroxyketones. It was reported that the pAla of the nucleophile generally determines the reaction outcome (Scheme 13). 

The ease of cyclization of the 3-butenyl ureas (1, R2 = H, n = 2) was dependent mainly on the steric and electronic effects of the nitrogen substituents R1 and R2 when R1 is methyl, the best results were obtained when R2 is isopropyl, cf 6 when R1 is hydrogen no cyclization occurred and methanol (solvent) acted as the nucleophile. Generally, long reaction times were necessary, and the cyclizations were often incomplete. Furthermore, cyclization fails for /V-(5-heptenyl)-amides and (3-butenyl) carbamates. 

The mechanism of the reaction has been studied in basic, acidic, and neutral media. In basic medium, the reaction is a substitution of 87 2 type, the mechanism and stereochemistry of which have been reasonably well clarified. In asymmetric oxiranes, the attack by the nucleophile generally takes place with inversion on the less-substituted carbon atom (Eq. 297). 

Semiaminal (567) reacted with nucleophiles generally by a replacement of the hydroxy group Only few exceptions were known. For example, reaction of 567 with ketene or isocyanates caused acylation and displacement of the secondary amino moiety (equation 147) cyclopropanone (84) could be detected spectroscopically in one case. A similar removal of the amino function by tosyl isocyanate (571) was observed with 570, but here compound 574 was isolated in 47% yield (equation 148). 574 resulted from a subsequent addition of the initially formed products 572 and 573 . Steric reasons led to the sequence 570 - 574 the diastereomeric endo-morpholino semiaminal reacted with 571 by displacement of the exo-hydroxy group. 

Sn2 reactions at cyclopropane rings are very difficult. Treatment of dihalocyclopro-panes with strongly basic nucleophiles generally gives rearranged products In a few... 

Although nucleophiles generally substitute allylic leaving groups with retention of configuration, the substitution of allylic carboxylates sometimes proceeds in a nonstereospecific manner due to palladium-catalyzed isomerization of the substrates (Scheme 48). ... 

In the reaction with methyloxirane in H2O at 20 C, the reactivity of the amines decreases in the order piperazine > dimethylamine > pyrrolidine > piperidine > morpholine > diethylamine > di-n-butylamine > di-n-propylamine. ° Under neutral or basic conditions, nucleophiles generally attack at the sterically less-hindered carbon atom of the oxirane ring. 

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