Leaving groups substitution

When the nucleophile (base) attacks the carbon atom bearing the leaving group, substitution results. 

The triphenylphosphine combines with DEAD to generate a phosphonium intermediate that binds to the alcohol oxygen, activating it as a leaving group. Substitution by the carboxylate, mercaptyl, or other nucleophile completes the process. 

We believe (5.) that pseudorotations, or other ligand reorganisation processes, in TBP reaction intermediates are limited to the pairwise exchange of apical and equatorial ligands, with the constraint that P-X 0 remains equatorial. Thus if nucleophilic attack occurs opposite the eventual leaving group substitution occurs with inversion where this is not the case substitution occurs, after pseudorotation, with retention. When mixed stereochemistry is observed we believe it results from competitive attack opposite more than one substrate ligand. The factors that determine the direction of nucleophilic attack are not yet... 

Thiadiazole 1-monoxides react analogously <8iH(l6)i56i, 81H(16)1565). When alkythio is the leaving group, substitution with carbon nucleophiles can be accomplished. Thus, the methylthio analog (33) reacts smoothly with malonate anion to form (34). Analogous... 

S vj2 and E2 reactions are both favored by a high concentration of a strong nucleophile or base. When the nucleophile (base) attacks a j8 hydrogen atom, elimination occurs. When the nucleophile attacks the carbon atom bearing the leaving group, substitution results ... 

Reactions of simple primary haUdes with strongly basic nucleophiles give mostly Sn2 products. As steric bulk is increased around the carbon bearing the leaving group, substitution is retarded relative to elimination because an attack at carbon is subject to more steric hindrance than is an attack on hydrogen. Thus, branched primary substrates give about equal amounts of Sn2 and E2 reaction, whereas E2 is the major outcome with secondary substrates. 

OCHs-reasonable leaving group substitution reactions... 

Allylic acetoxy groups can be substituted by amines in the presence of Pd(0) catalysts. At substituted cyclohexene derivatives the diastereoselectivity depends largely on the structure of the palladium catalyst. Polymer-bound palladium often leads to amination at the same face as the aoetoxy leaving group with regioselective attack at the sterically less hindered site of the intermediate ri -allyl complex (B.M. Trost, 1978). 

Unsymmetrically substituted dipyrromethanes are obtained from n-unsubstitued pyrroles and fl(-(bromomethyl)pyiToIes in hot acetic acid within a few minutes. These reaction conditions are relatively mild and the o-unsubstituted pyrrole may even bear an electron withdrawing carboxylic ester function. It is still sufficiently nucleophilic to substitute bromine or acetoxy groups on an a-pyrrolic methyl group. Hetero atoms in this position are extremely reactive leaving groups since the a-pyrrolylmethenium( = azafulvenium ) cation formed as an intermediate is highly resonance-stabilized. 

TosOH 4-methylbenzenesulfonic acid = p toluenesiilfonic acid, tosic acid X, Y leaving groups. e.g., halogen, RSOj, in substitution and elimination reactions... 

The wM-diacetate 363 can be transformed into either enantiomer of the 4-substituted 2-cyclohexen-l-ol 364 via the enzymatic hydrolysis. By changing the relative reactivity of the allylic leaving groups (acetate and the more reactive carbonate), either enantiomer of 4-substituted cyclohexenyl acetate is accessible by choice. Then the enantioselective synthesis of (7 )- and (S)-5-substituted 1,3-cyclohexadienes 365 and 367 can be achieved. The Pd(II)-cat-alyzed acetoxylactonization of the diene acids affords the lactones 366 and 368 of different stereochemistry[310]. The tropane alkaloid skeletons 370 and 371 have been constructed based on this chemoselective Pd-catalyzed reactions of 6-benzyloxy-l,3-cycloheptadiene (369)[311]. 

An important method for construction of functionalized 3-alkyl substituents involves introduction of a nucleophilic carbon synthon by displacement of an a-substituent. This corresponds to formation of a benzylic bond but the ability of the indole ring to act as an electron donor strongly influences the reaction pattern. Under many conditions displacement takes place by an elimination-addition sequence[l]. Substituents that are normally poor leaving groups, e.g. alkoxy or dialkylamino, exhibit a convenient level of reactivity. Conversely, the 3-(halomethyl)indoles are too reactive to be synthetically useful unless stabilized by a ring EW substituent. 3-(Dimethylaminomethyl)indoles (gramine derivatives) prepared by Mannich reactions or the derived quaternary salts are often the preferred starting material for the nucleophilic substitution reactions. 

Nucleophilic substitution reactions of alkyl halides are related to elimination reactions m that the halogen acts as a leaving group on carbon and is lost as an anion The... 

The order of alkyl halide reactivity in nucleophilic substitutions is the same as their order m eliminations Iodine has the weakest bond to carbon and iodide is the best leaving group Alkyl iodides are several times more reactive than alkyl bromides and from 50 to 100 times more reactive than alkyl chlorides Fluorine has the strongest bond to car bon and fluonde is the poorest leaving group Alkyl fluorides are rarely used as sub states m nucleophilic substitution because they are several thousand times less reactive than alkyl chlorides... 

Two stereochemical possibilities present themselves In the pathway shown in Fig ure 8 la the nucleophile simply assumes the position occupied by the leaving group It attacks the substrate at the same face from which the leaving group departs This is called front side displacement or substitution with retention of configuration... 

In a second possibility illustrated in Figure 8 Ih the nucleophile attacks the sub state from the side opposite the bond to the leaving group This is called back side dis placement or substitution with inversion of configuration... 

FIGURE 8 1 Two contrast mg stereochemical pathways for substitution of a leaving group (red) by a nucleophile (blue) In (a) the nucleophile attacks carbon at the same side from which the leaving group departs In (b) nude ophilic attack occurs at the side opposite the bond to the leaving group... 

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