Inversion of configuration

Figure 3-22 shows a nucleophilic aliphatic substitution with cyanide ion as a nucleophile, i his reaction is assumed to proceed according to the S f2 mechanism with an inversion in the stereochemistry at the carbon atom of the reaction center. We have to assign a stereochemical mechanistic factor to this reaction, and, clearly, it is desirable to assign a mechanistic factor of (-i-1) to a reaction with retention of configuration and (-1) to a reaction with inversion of configuration. Thus, we want to calculate the parity of the product, of 3 reaction from the parity of the... 

Now we cany out the same reaction with thiolate as nucleophile, as shown in Figure 3-23. hlowever, we must now realize that the product has a parity of (+ 1) although we have the same mechanism as in Figure 3-22 with inversion of configuration. 

Stereochemictry of the product is related to the reactant in a mechanistically defined manner no other stereochemical outcome is mechanistically possible, i.e. SN2 reaction- inversion of configuration is required... 

In stereoselective antitheses of chiral open-chain molecules transformations into cyclic precursors should be tried. The erythro-configurated acetylenic alcohol given below, for example, is disconnected into an acetylene monoanion and a symmetrical oxirane (M. A. Adams, 1979). Since nucleophilic substitution occurs with inversion of configuration this oxirane must be trens-conilgurated its precursor is commercially available trans-2-butene. 

When the 2-hydroxy group of a monosaccharide reacts with (diethylamino)sulfur trifluoride (DAST), quantitative and stereoselective rearrangements are observed (K.C Nico-laou, 1986). This reaction may simultaneously introduce fluorine to C-1 and a new oxygen, sulfur, or nitrogen residue to C-2 with inversion of configuration. 

Benzyl bromide can be converted into ethylbenzene (731) by the reaction of Me4Sn. The use of HMPA as a solvent is important. Overall inversion of configuration takes place at the chiral center of deuterated benzyl bro-mide[598]. The cyanomethyiation[599] and methoxymethyiation[600] of aromatic rings are carried out by the reaction of cyanomethyltributyltin (732) and methoxymethyltributyltin. 

Furthermore, the catalytic allylation of malonate with optically active (S)-( )-3-acetoxy-l-phenyl-1-butene (4) yields the (S)-( )-malonates 7 and 8 in a ratio of 92 8. Thus overall retention is observed in the catalytic reaction[23]. The intermediate complex 6 is formed by inversion. Then in the catalytic reaction of (5 )-(Z)-3-acetoxy-l-phenyl-l-butene (9) with malonate, the oxidative addition generates the complex 10, which has the sterically disfavored anti form. Then the n-a ir rearrangement (rotation) of the complex 10 moves the Pd from front to the rear side to give the favored syn complex 6, which has the same configuration as that from the (5 )-( )-acetate 4. Finally the (S)-( )-mal-onates 7 and 8 are obtained in a ratio of 90 10. Thus the reaction of (Z)-acetate 9 proceeds by inversion, n-a-ir rearrangement and inversion of configuration accompanied by Z to isomerization[24]. 

Epoxides and aziridines are also capable of electrophilic subsitution of indoles. Indolylmagncsium bromide and cyclohexene oxide react to give 3-(lrans-2-hydroxycyclohexyl)indole[14]. Reaction of indoles with epoxides also occurs in the presence of Lewis acids. For example, indole reacts with methyl 2S,3R-epoxybutanoate at C3 with inversion of configuration[15]. 

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... 

Nucleophilic substitution had occurred with inversion of configuration consistent with the following transition state... 

For example the hydrolysis of optically active 2 bromooctane in the absence of added base follows a first order rate law but the resulting 2 octanol is formed with 66% inversion of configuration... 

FIGURE 8 8 Inversion of configuration predomi nates in SnI reactions because one face of the car bocation is shielded by the leaving group (red)... 

The mechanisms by which sulfonate esters undergo nucleophilic substitution are the same as those of alkyl halides Inversion of configuration is observed m 8 2 reac tions of alkyl sulfonates and predominant inversion accompanied by racemization m 8 1 processes... 

The hydrolysis of sulfonate esters of 2 octanol is stereospecific and proceeds with complete inversion of configuration Write a structural formula that shows the stereochemistry of the 2 octanol formed by hydrolysis of an opti cally pure sample of (S) (+) 1 methylheptyl p toluenesulfonate identify the prod uct as / or S and deduce its specific rotation... 

Not stereospecific racemization ac companies inversion when leaving group IS located at a chirality cen ter (Section 8 10) Stereospecific 100% inversion of configuration at reaction site Nu cleophile attacks carbon from side opposite bond to leaving group (Section 8 4)... 

The reactions of alcohols with hydrogen halides to give alkyl halides (Chapter 4) are nucleophilic substitution reactions of alkyloxonium ions m which water is the leaving group Primary alcohols react by an 8 2 like displacement of water from the alkyloxonium ion by halide Sec ondary and tertiary alcohols give alkyloxonium ions which form carbo cations m an S l like process Rearrangements are possible with secondary alcohols and substitution takes place with predominant but not complete inversion of configuration... 

Reaction of lithium diphenylcuprate with optically active 2 bromobutane yields 2 phenylbu tane with high net inversion of configuration When the 2 bromobutane used has the stereostruc ture shown will the 2 phenylbutane formed have the R or the S configuration" ... 

Nucleophilic ring opening of epoxides has many of the features of an 8 2 reac tion Inversion of configuration is observed at the carbon at which substitution occurs... 

Although nucleophilic participation at the transition state is slight it is enough to ensure that substitution proceeds with inversion of configuration... 

Inversion of configuration is observed at the carbon that is attacked by the nucleophile irrespective of whether the reaction takes place m acidic or basic solution... 

None of the bonds to the chirality center is broken when hydroxide attacks the carbonyl group Had an 8 2 reaction occurred instead inversion of configuration at the chirality center would have taken place to give (8) (—) 1 phenylethyl alcohol... 

Inversion of configuration (Section 8 4) Reversal of the three dimensional arrangement of the four bonds to sp hybridized carbon The representation shown illustrates inversion of configuration in a nucleophilic substitution where LG is the leaving group and Nu is the nucleophile... 

Stereoselective All lations. Ben2ene is stereoselectively alkylated with chiral 4-valerolactone in the presence of aluminum chloride with 50% net inversion of configuration (32). The stereoselectivity is explained by the coordination of the Lewis acid with the carbonyl oxygen of the lactone, resulting in the typ displacement at the C—O bond. Partial racemi2ation of the substrate (incomplete inversion of configuration) results by internal... 

Optically active 2-arylalkanoic acid esters have been prepared by the Friedel-Crafts alkylation of arenes with optically active a-sulfonyloxy esters (40). Friedel-Crafts alkylation of ben2ene with (5)-methyl 2-(chlorosulfonyloxy)- or 2-(mesyloxy)propionate proceeded with predorninant inversion of configuration (<97%) to give (5)-methyl 2-phenylpropionate. 

The reactions of trialkylboranes with bromine and iodine are gready accelerated by bases. The use of sodium methoxide in methanol gives good yields of the corresponding alkyl bromides or iodides. AH three primary alkyl groups are utilized in the bromination reaction and only two in the iodination reaction. Secondary groups are less reactive and the yields are lower. Both Br and I reactions proceed with predominant inversion of configuration thus, for example, tri( X(9-2-norbomyl)borane yields >75% endo product (237,238). In contrast, the dark reaction of bromine with tri( X(9-2-norbomyl)borane yields cleanly X(9-2-norbomyl bromide (239). Consequentiy, the dark bromination complements the base-induced bromination. 

Fig. 11. Proposed pathway for the biosynthesis of L-ascorbic acid (with inversion of configuration) in plants using C-l-labeled D-glucose or C-l-labeled...

Nucleophilic attack on oxirane carbon usually proceeds with inversion of configuration (Scheme 44) as expected for Sn2 reactions, even under acid conditions (Scheme 45). Scheme 45 also illustrates the fact that cyclohexene oxides open in a fran5-diaxial manner this is known as the Fiirst-Plattner rule (49HCA275) and there are very few exceptions to it. 

Inversion of configuration at carbon in hydrolysis of methyl iodide. 

Stereochemical analysis can add detail to the mechanistic picture of the Sj l substitution reaction. The ionization mechanism results in foimation of a caibocation intermediate which is planar because of its hybridization. If the caibocation is sufficiently long-lived under the reaction conditions to diffirse away from the leaving group, it becomes symmetrically solvated and gives racemic product. If this condition is not met, the solvation is dissymmetric, and product with net retention or inversion of configuration may be obtained, even though an achiral caibocation is formed. The extent of inversion or retention depends upon the details of the system. Examples of this effect will be discussed in later sections of the chapter. 

The MO picture predicts that the reaction will proceed with inversion of configuration because the development of the transition state is accompanied by rehybridization of the carbon to the trigonal bipyramidal geometry. As the reaction proceeds on to product and sp hybridization is reestablished, the product is formed with inversion of configuration. 

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