Enolates. Compare these pka s to the basicity values (as conjugate acid pka s) of common bases: Na O. MeO. OMe. ONa pk eq = = -1 K eq = 10-1

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Verity George
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1 Enolates Enolates are the conjugate anions of carbonyl compounds. Although they have been known and used since the turn of the 20 th Century, it was the development of specific enolates (see below) by.. ouse of MIT in the s that made carbanion chemistry one of the most important tools for stereo- and regio-controlled carbon-carbon bond formation in organic synthesis. That importance continues to this day. Generation of enolates by α deprotonation of carbonyls Y Y Y B Y=, alkyl,, N 2, S elevant acidity data Compound pka aldehyde ~20 ketone ~20 cyclic ketone ~17 β-dicarbonyl ester ~25 nitrile ~25 Compare these pka s to the basicity values (as conjugate acid pka s) of common s 2 N - pk a conj = 35 - pk a conj = 16 ( = Me) - 18 = t-bu) 3 N pk a conj = 9-11 Conclusion Me Me pk a = 13 NaMe Me (pk a = 16) Me Na Me pk eq = = 3 K eq = 10 3 pk a = 17 NaMe Me (pk a = 16) Na pk eq = = -1 K eq = 10-1 pk a = N(i-Pr) 2 + N(i-Pr) 2 pk a = 35 pk eq = = 18 K eq =

2 A. C- vs - Metallation Structure of Enolates M M although often drawn as resonance, this is usually tautomerism (a fast equilibrium) covalent C-M bond (true for electronegative M, e.g. g ++, Cu ++, Zn ++ ) ionic -M bond (electropositive M, e.g. +, Na +, K +, Mg ++ ) note!-diketones form cyclic chelate M B. Aggregation State 1. Although typically drawn as monomeric species, enolates in solution are usually found as higher aggregates (dimers, tetramers). 2. The exact aggregation state depends on solvent and counterion. generalized structure of solvated tetramer 3. Smaller counterions (e.g. +) favor tetramer while larger ones (e.g. K +, Cs + ) favor dimer. 4. Et 2 favors dimer, but TF and DME favor tetramer. 5. Generally speaking, tetrameric enolates react as carbon nucleophiles. 6. eferences ouse, J. rg. Chem. 1971, 36, 2361 (original suggestion) Jackman, Tetrahedron, 1977, 33, 273 (NM studies) Dunitz, elv. Chim. Acta. 1981, 64, (x-ray st udies) see also J. Am. Chem. Soc. 1985, 107, 5403; Tetrahedron Lett. 1989,

3 C. egiochemistry (which side of carbonyl deprotonates?) more stable less stable more stable less stable more stable less stable D. Stereochemistry Z-enolate E-enolate M M (M = ) E-enolate Z-enolate (M = ) Z-enolate E-enolate 211

4 Stereochemistry of Deprotonation C 3 LDA C 3 + "Z" "E" C 3 E Z Me 95 5 t-bu 95 5 Et i-pr t-bu Ph NEt Large yields Z 212

5 II. Generation of enolates A. Deprotonation of active hydrogens 1.) Thermodynamic conditions NaMe Me Na + Me K eq = 10-2 (favors s.m.) Me Me NaMe Me Me Na Me + Me essentially irreversible 0.95 eq LDA equilibrium established with s.m. Na Na Why an Equilibrium? 2.) Kinetic conditions N 2 irreversible KN 2, N 2, and NaN 2 are insoluble in organic solvents so N 2 was developed = Et, i-pr, (i-pr, cyclohexane), or t-bu development of specific enolates ouse, JC, 28, 1963, , 1965, 1341, , 1969,

6 3.) egiochemistry of deprotonation 1) LDA 2) TMS-Cl 1) Et 3 N 2) TMS-Cl TMS TMS 84% 7% 9% 13% 58% 29% TMS kinetic thermo. LDA > 95% kinetic t-buk t-bu K or K or LDA/MPA (91) thermo. + 1) Ph 3 C TMS TMS 2) TMS-Cl 13% 87% 1).95 (eq) Ph 3 C 2) MPA, TMS-Cl 53% 47% 4.) Stereochemistry of deprotonation M C 3 Z C 3 M E C 3 ouse, JC, 1963, 28,

7 ow to Determine? Make Si(C3) 3 ether 1 -NM, 13 C NM (eathcock, JACS, 1979, 44, 429) Ireland does Claisen ne (ppolzer, TL, 1983, 24, 495) [3,3] TMS TMS TMS Z syn C 2 TMS [3,3] TMS TMS TMS C 2 TMS E anti Ex C 3 C 3 + Z E N (-78 ) '', MPA 92 8 LDA (-78 ) LICA (-78 ) Why kinetic preference for E? 215

8 Look at T.S. for deprotonation JACS, 1976, 98, 2868 ' N ' not bad E N.B. e - 's abstracted proton " to! system ' N Z ' "1,3 diax." This view of the T.S accounts for both stereo- and regio- specificity b a - b ' N ' favorable b - a ' N unfavorable ' = C = Ph 991 = C = NMe

9 For acyclic ketones, we have A(1,2) strain to consider A(1,2) Me ' N Me E ' Me N' 2 Me ' N ' Z Me LDA increasing bulk of C 3 t-bu Et i-pr t-bu Ph NEt 2 EZ caveat need conditions in which coordinates (i.e., no MPA, 18C-6, polar solvents) All 3 o amides give Z-enolates Stereoselectivity of LDA/MPA w/ ketones; esters - Ireland, JC,1991, 56,

10 eactions f Enolates enolates = functionalized carbon nucleophiles (thers are CN, CC, Mg, ) react with electrophilic carbon 2 types C sp 3 First type gives enolate alkylation Enolate Alkylation M S N 2 + M (note must be Br, I, Ts, Ms or Tf to get decent reactivity) Considerations C- vs. - alkylation enolates are ambident nucleophiles; can react at C or a a b b What influences C- vs. - ratio? ouse, JC, 1973, 38,

11 a. hard/soft electrophiles "hard" anion (localized) "soft" anion (delocalized) C- alkylation with soft electrophiles (-I, -Br) M Also, -M bond affects C/ ratio (As -M covalent, is less reactive) (As -M ionic, is more reactive) So Na K NMe 4 C/ ratio covalent rate ionic cyclic β-diketones are especially hard Br vinylogous acid K 2 C 3 DMF + 37% 15% - C- Also phenolates Na PhC 2 Br Ph DMF 97% 219

12 b. Solvent polar, aprotic solvents (MPA, DMS, DMF) solvate M + ion make naked anion (very hard) favors - alkylation Na PhC 2 Br CF 3 C 2 C 2 Ph solvents which promote aggregation (e.g., TF) favor C-alkylation by making enolate less accessible c. Structure of electrophile -Br Et neat Et + Et = n-pr i-pr Br PhC 2 Br Why? indered carbon is harder Conclusion - Usually, use + enolate in TF Ex - TF also, will usually be methyl, 1, allylic, benzylic, (2 gives elimination) = -Br, -I -When reactivity is a problem, we can increase rate using K + as counterion (but run the risk of competing reactions arising from basicity of enolate) 220

Wittig Reaction - Phosphorous Ylides

Wittig Reaction - Phosphorous Ylides Wittig eaction - osphorous Ylides 3 P CC 3 3 C ylide tereoselectivity increases as the size of increases cis-olefin is derived from non-stabilized ylides Mechanism: Irreversible [22] cycloaddition P 3