Inversion of configuration reactions

The synthetic utility of the chloral ene adducts has been extensively explored. Reaction with NaOR in ROH gives the a-alkoxy ester with inversion of configuration. Reaction of the corresponding tosyl-ate with sodium ethoxide in ethanol affords ethyl alka-2,4-dienoates (Scheme 9). 

These observations contrast with those of Shoppee and co-workers in a study of the epimeric 3-chloro-A -compounds which were believed to solvolyse via a single allylic carbocation. A re-examination of the solvolysis of the chloro-compounds appeared to confirm the intermediacy of two carbocations since the product ratios were very similar to those from the trifluoroacetates. Treatment of the trifluoroacetates with NaNs-HMPA resulted in substitution at C-3 with inversion of configuration. Reaction of the 17j8-trifluoroacetoxy-17a-vinyl compounds (7) and (8) under similar conditions gave the JB -17(20)-dehydro-21-azido-compounds (9). These reactions are not regarded as pure 5n2 processes since the compounds (7) and (8) may rearrange to compounds (10) in HMPA. Solvolysis of compounds (7) and (8) in MeOH-NaOAc gave product distributions... 

An important observation has been made recently by Brosch and Kirmse. They showed that the nitrous acid deamination of optically active [1- H] butylamine and [1- H] methyl propylamine both proceed with complete ( 2%) inversion of configuration. Reaction via a carbocation is unlikely to proceed with complete inversion of configuration reaction of a diazonium ion with a nucleophile must proceed with complete inversion of configuration. Although ion pairs would be involved in the carbocation reaction it is unlikely that they would give a completely inverted product. 

A particular value of thionyl halides is that their reaction with alcohols is stereoselective it occurs with inversion of configuration. Reaction of thionyl chloride with (S)-2-octanol, for example, in the presence of a tertiary amine occurs with inversion of configuration and gives (R)-2-chlorooctane. 

Methylation of t-butyl-l-dimethylphosphono-2-p-tolylsulfinyl cyclopropanecar-boxylic ester has been shown to occur with inversion of configuration. Reaction of cyclopropyl sulfoxide with Pr MgCl leads to 1,2-migration of the phosphoryl group (Scheme ( )... 

The trichloroacetimidates are readily displaced to give substitution at C-1. They react with hydrogen halides to give chlorides, bromides, and fluorides, with retention of configurations (reaction 4.64). Carboxylic acids, being relatively weak acids, react to give inversion of configuration (reaction 4.65). 

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... 

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]. 

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)... 

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" ... 

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... 

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. 

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. 

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. 

Attack by a nucleophile or the solvent can occur at either of the ion pairs. Nucleophilic attack on the intimate ion pair would be expected to occur with inversion of configuration, since the leaving group would still shield the fiont side of the caibocation. At the solvent-separated ion pair stage, the nucleophile might approach fiom either fece, particularly in the case where solvent is the nucleophile. Reactions through dissociated carbocations should occur with complete lacemization. According to this interpretation, the identity and stereochemistry of the reaction products will be determined by the extent to which reaction occurs on the un-ionized reactant, the intimate ion pair, the solvent-separated ion pair, or the dissociated caibocation. 

Studies of the stereochemical course of rmcleophilic substitution reactions are a powerful tool for investigation of the mechanisms of these reactions. Bimolecular direct displacement reactions by the limSj.j2 meohanism are expected to result in 100% inversion of configuration. The stereochemical outcome of the lirnSj l ionization mechanism is less predictable because it depends on whether reaction occurs via one of the ion-pair intermediates or through a completely dissociated ion. Borderline mechanisms may also show variable stereochemistry, depending upon the lifetime of the intermediates and the extent of internal return. It is important to dissect the overall stereochemical outcome into the various steps of such reactions. 

Neopentyl (2,2-dimethylpropyl) systems are resistant to nucleo diilic substitution reactions. They are primary and do not form caibocation intermediates, but the /-butyl substituent efiTectively hinders back-side attack. The rate of reaction of neopent>i bromide with iodide ion is 470 times slower than that of n-butyl bromide. Usually, tiie ner rentyl system reacts with rearrangement to the /-pentyl system, aldiough use of good nucleophiles in polar aprotic solvents permits direct displacement to occur. Entry 2 shows that such a reaction with azide ion as the nucleophile proceeds with complete inversion of configuration. The primary beiuyl system in entry 3 exhibits high, but not complete, inversiotL This is attributed to racemization of the reactant by ionization and internal return. 

The reaction is stereospecific and can be described as a [tz2 + mechanism requires that inversion of configuration occur at C-4 as the new [Pg.760]

Mechanism On the basis of the available evidence a mechanism has been proposed which envisions rapid formation of the intermediate (25), which may undergo an SNj reaction to form fluoro products with inversion of configuration, as is the case with 3a- and 15a-ols. More frequently this substitution reaction is accompanied by decomposition of (25) to the steroidal cation Sf ", which in turn may undergo rearrangement or elimination as discussed above. 

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