Carbanions As Nucleophiles in SN2 Reactions (C&S A, P

Chemistry 730, Au 2005

Carbanions as Nucleophiles (C&S A, p. 432-439; 290-298)

Structure of enolates:

• ambident anion

• An enolate be alkylated either at C or O

Reactivity can be explained using Hard and Soft Acid and Base (HSAB) principle

(CSA p. 292-293); CSA p. 22

R. G. Pearson, J. Chem. Ed. 1968, 45, 581, 643.; Chem. Rev. 1975, 75, 1.; J. Am. Chem. Soc. 1967, 89, 1827.

• “Reactions occur best between species that are matched in hardness or softness”

e.g., Hard nucleophiles prefer hard electrophiles and soft nucleophiles prefer soft electrophiles.

Definitions:

Soft base (or nucleophile): Donor atom of high polarizability, low electronegativity, easily oxidized, has empty low-lying orbitals

Hard Base (nucleophile): Donor atom of low polarizability, high electronegativity, difficult to oxidize, has empty orbitals of high energy.

Soft acid (electrophile): Acceptor of low positive charge, large size, has several easily excited outer electrons

Hard Acid (electrophile): Acceptor of high positive charge, small size, does not have easily excited electrons.

Examples

Bases (nucleophiles)

Soft: RSH, RS–, I–, R3P, CN–, CO, Olefins, ambident enolate carbanion

Borderline: Br–, N3–

Hard: H2O, OH–, ROH, RO–, RCO2–, F–, Cl–, NO3–, NH3, RNH2, ambident enolate oxyanion

Acids (electrophiles)

Soft: I2, Br2, RCH2X, RSX, RSeX, Cu(I), Ag(I), Pd(II), Pt(II)

Borderline: Cu(II), Zn(II), Sn(II), R3C+, R3B

Hard: H–X, H+, Li+, Na+, K+, Mg2+, Ca2+, Sn(IV), Ti(IV), R3SiX

Examples

(a) Nucleophilic substitution versus elimination in alkyl halides

(b) C vs O Alkylation of enolates

(c) C vs O Alkylation and leaving group ability

Important:

• Hard-hard combination is driven by coloumbic attraction, usually through has early transition state leading to O-alkylation (not much covalent bond formation)

• Soft-soft combination has late TS, partial bond formation is important leading to C-alkylation

• Consider covalent bond energies in this context: energetically C-alkylation is better, other things being equal:

{C=O + C–C ([–173 + (–)81] = –254 kcal/mol)} is better than {C–O + C=C ([–79 + (–)145] = –224 kcal/mol)}

Another interesting effect is alpha effect: (p. , CS A)

e. g., HOO– is more nucleohilic than HO– and

H2NNH2 and HONH2 mor enucleophilic than NH3 (WHY ?)

Medium effects in alkylation of enolates: Dielectric constants

DMSO - 47; DMF - 37; NMP - 32; HMPT -30

• Polar medium facilitates breaking up of aggregates

• Nucleophilicity of anions depends on degree of solvation

• Protic hydrogen-bonding solvents tend to solvate anions, especially hard nucleophiles: therefore soft nucleophiles are more nucleophilic in such media.

• Best nucleophilic substitutions proceed in polar aprotic solvents. They tend to coordinate to the cation , increasing the reactivity of the anion.

• Maximum rate for enolate alkylation is seen in polar medium; Li+, Na+, K+ are all solvated under these conditions.

In a given solvent order of cationic reactivity is:

BrMg+ < Li+< Na+<K+<NR4+

13C chemical shifts confirm the difference of electronegativity of the carbanions in various solvents.

• Electron density of a given carbanion increases in the following order for various solvents:

• THF/HMPA. DME>THF>Ether (House, J. Org. Chem. 1976, 41, 1209.)

• For various metal ions the order is: K+ > Na+. >Li+

EXPLAIN:

• Also the trends seen in Table p. 438, CS A C vs O alkylation of K-salt of ethyl acetoacetate as a function of the leaving group)

Summary

• To maximize O-alkylation use highly polar aprotic solvent (HMPA/THF, DMF, NMP) , with a hard leaving group (tosylate or mesylate).

• To maximize C-alkylation, use aprotic solvent of low dielectric constant and dipole moment (THF, DME) with soft leaving group (e. g., a halide)

• Solvents like THF and DME are extensively used: low bp, easy to remove after reaction, enhanced reactivity upon mixing with HMPA or TMEDA or crown-ethers

• To maximize O-alkylation use dissociting counte r ions: R4N, K+, Na+ etc.

• Crown ethers also enhance reactivity of nucleophiles:

• 12-crown-4 (small cavity) - for sequestering Li

• 18-crown-6 (large cavity) - for sequestering K and Na

READ: X-Ray structures of enolates (unsolvated vs solvated (p. 436, CS B)

LOOK UP THE X-RAY STRUCTURES OF ENOLATES

Generation and alkylation of aldehydes esters amides and nitriles

• Ketones most common

• But equaly viable for other realtively acidic compounds except aldehydes (see for this substrate work with the imines)

OVERHEAD SCHEME 1. 8

Alkylation of Dianions (CS B, p. 19 and Handout)

HANDOUT - READ, READ, CAREFULLY WORKOUT THE EXAMPLES!!!

Diastereoselective synthesis: Alkylation of chiral enolates (Evans enolates)

Lookup the synthesis of the starting oxazolidinones (JACS 1982, 104, 1737)

HANDOUT - READ, CAREFULLY WORKOUT THE EXAMPLES!!

8