Nucleophilic addition phase

Walden, Paul, 360 Walden inversion. 359-360 Wang resin, solid-phase peptide synthesis and. 1037 Water, acid-base behavior of, 50 dipole moment of, 39 electrostatic potential map of. 53 nucleophilic addition reactions of, 705-706 pKaof, 51-52... 

Generally, in the nucleophilic addition to carbonyl groups, either magnesium compounds or alkali metal compounds (such as the Li, Na and K derivatives) are used. In some cases even potassium carbonate or piperidine were used as the base for condensation with sulfones. Good results were obtained when concentrated aqueous NaOH was used under phase-transfer conditions288,297,333. 

The HX compounds are electrophilic reagents, and many polyhalo and polycyano alkenes, (e.g., Cl2C=CHCl) do not react with them at all in the absence of free-radical conditions. When such reactions do occur, however, they take place by a nucleophilic addition mechanism, (i.e., initial attack is by X ). This type of mechanism also occurs with Michael-type substrates C=C—Z, where the orientation is always such that the halogen goes to the carbon that does not bear the Z, so the product is of the form X—C—CH—Z, even in the presence of free-radical initiators. Hydrogen iodide adds 1,4 to conjugated dienes in the gas phase by a pericyclic mechanism ... 

The iminophosphenium cation was also of interest for more physical investigations. It was noted to be a stable entity in gas phase experiments [52], the parameters were investigated in detail [53] and a systematic study of the nucleophilic addition of CH, NH and OH bonds was performed [54] with a concomitant interpretation of the chemical shifts (at the dicoordinate phosphorus centres). The latter authors also confirmed the loose interaction of a triphenylphosphine with the iminophosphenium cation (PP = 2.625 A). 

Hydrolysis of diphenyl phosphorochloridate (DPPC) in 2.0 M aqueous sodium carbonate is also believed to be a two-phase process. DPPC is quite insoluble in water and forms an insoluble second phase at the concentration employed (i.e. 0.10 M). It seems highly significant that the hydrophobic silicon-substituted pyridine 1-oxides (4,6,7) are much more effective catalysts than hydrophilic 8 and 9. In fact, 4 is clearly the most effective catalyst we have examined for this reaction (ti/2 < 10 min). Since derivatives of phosphoric acids are known to undergo substitution reactions via nucleophilic addition-elimination sequences 1201 (Equation 5), we believe that the initial step in hydrolysis of DPPC occurs in the organic phase. Moreover, the... 

This aldol condensation is assumed to proceed via nucleophilic addition of a ruthenium enolate intermediate to the corresponding carbonyl compound, followed by protonation of the resultant alkoxide with the G-H acidic starting nitrile, hence regenerating the catalyst and releasing the aldol adduct, which can easily dehydrate to afford the desired a,/3-unsaturated nitriles 157 in almost quantitative yields. Another example of this reaction type was reported by Lin and co-workers,352 whereas an application to solid-phase synthesis with polymer-supported nitriles has been published only recently.353... 

Nucleophilic addition of phenolic nucleophiles to l,l-dicyano-2-arylethenes in the gas phase and in water has been studied theoretically" using the semiempirical AMI method and the Cramer-Truhlar solvation model SM2.1. The difference between the Brpnsted coefficients (a" = 0.81 and P" =0.65) determined for the gas-phase reaction is indicative of a small positive transition state imbalance of / = 0.16. For reaction in water the estimates (a" = 0.61 and P" = 0.36, giving I = 0.25) are close to the experimental values (a" = 0.55 and P" = 0.35) obtained with amine bases, and the small imbalance is as expected for a reaction involving no hybridization change at the incipient carbanion site. 

To conclude this section on the effect of solvent on a-nucleophilicity, we refer to the current, rather controversial, situation pertaining to gas-phase smdies and the a-effect. As reported in our review on the a-effect and its modulation by solvent the gas-phase reaction of methyl formate with HOO and HO , which proceeds via three competitive pathways proton abstraction, nucleophilic addition to the carbonyl group and Sat2 displacement on the methyl group, showed no enhanced nucleophilic reactivity for HOO relative to This was consistent with gas-phase calculational work... 

Y. Ali and W. A. Szarek, Synthetic approaches to gem-di-C-alkyl derivatives of carbohydrates Nucleophilic addition reactions of 3-C-methylene compounds derived from l,2 5,6-di-0-isopropylidene-ot-D-rifto-hexofuranos-3-ulose using phase transfer catalysis, Carbohydr. Res. 67 Cll (1978). 

Step 2 Beginning of addition phase. Amide ion acts as a nucleophile and adds to one of the carbons of the triple bond. The product of this step is a carbanion. 

A series of rapid microwave-mediated ester syntheses using Mo(CO)6 as the carbon monoxide source were published in 200374. In this paper, a range of valuable ester-protected acids (butyl-, benzyl- and trimethylsilylethyl esters) were smoothly produced both in solution (Scheme 2.32) and on solid phase (TentaGel S RAM-resin, Scheme 2.33) after 15-20 min of single-mode microwave irradiation. The use of DMAP as a nucleophilic additive increased the product yields slightly. Unfortunately, the sterically hindered ferf-butanol furnished little or no product formation at all. 

The salient feature of le as a chiral phase-transfer catalyst is its ability to catalyze the asymmetric alkylation of glycine methyl and ethyl ester derivatives 4 and 5 with excellent enantioselectivities. Since methyl and ethyl esters are certainly more susceptible towards nucleophilic additions than tert-butyl ester, the synthetic advantage of this process is clear, and highlighted by the facile transformation of the alkylation products (Scheme 5.3) [8],... 

Asymmetric nucleophilic addition to C=C double bonds (see also Chapter 4) can also proceed highly stereoselectively. Several examples of enantio- and diastereo-selective Michael additions with 99% ee for the resulting products have been described by the Corey group [19]. A cinchonidine-derived phase-transfer organo-catalyst (10 mol%) was used. 

The enantio-determining step of nucleophilic additions to a-bromo-a,y -unsaturated ketones is mechanistically similar to those of nucleophilic epoxidations of enones, and asymmetry has also been induced in these processes using chiral phase-transfer catalysts [20]. The addition of the enolate of benzyl a-cyanoacetate to the enone 31, catalysed by the chiral ammonium salt 32, was highly diastereoselective and gave the cyclopropane 33 in 83% ee (Scheme 12). Good enantiomeric excesses have also been observed in reactions involving the anions of nitromethane and an a-cyanosulfone [20]. 

The next phase of the synthesis was installation of the dimethylamino-oxazoline ring system. This was constructed from the oxazolidinone precursor 19. Oxazolidinone formation occurred when 25 was reacted with thionyl chloride. The more nucleophilic carbonyl of 19 was then O-alkylated with the Meerwein reagent to give an iminium ion that readily participated in a nucleophilic addition/elimination reaction with dime-thylamine to give 26. The final step of the synthesis was O-deacetylation of 26 with sodium methoxide to provide (—)-allosamizoline hydrochloride in 98% yield after acidification. 

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