Professor David L. Van Vranken Chemistry 201: Organic Reaction Mechanisms I

Topic 18: Nucleophilic Sigma Bonds

E+ E+ E+ R Li R C R H

References: Literature cited Recall the Six Types of Canonical Frontier Orbitals

■ We’ve already discussed the interactions of 3 types of filled orbitals and 3 types of unfilled orbitals. If all things are equal then C-C and C-H sigma bonds should be the least reactive type of nucleophiles but if we replace C with Li to make a C-Li bond then the bonds became exquisitely reactive.

σ* π* Li E+

p H E+ - E n B MO H H π H H E+

σ -O

■ We need to discuss the nucleophilicity of sigma bonds more broadly. Periodic Trends - Electronegativity

■ Here are some periodic trends you should know…

electronegative rapid atom transfer pi character weaker, more nucleophilic bonds

electropositive

http://www.green-planet-solar-energy.com/electronegativity-values.html Frontier Molecular Orbital Energies Predict Reactivity

■ What happens when you replace carbon with an electropositive atom? Bonds to electropositive atoms can be highly nucleophilic.

E+ faster .. nO(Li) O Li faster nO(Be) E E+ E MO MO nO(B) E+ slower σC-Li H3C Li .. nO(C) O CH3 σC-Be σC-B E+ E+ σC-C H3C CH3 σO-Li O Li σC-N

■ For bonds to O and N, the non-bonding FMO (i.e., the lone pair) is still more reactive than the sigma bond FMO. Alkyllithiums: Frontside vs. Backside Attack

■ Frontside attack is most common for R-Li.

Et Et Still, W. C.; Sreekumar, C. O O OBn O O H H JACS 1980, 102, 1201. H3CO S Li OBn CH3 O CH3

However, electrons in the HOMO of R-Li also spend time on the back side of the carbon-lithium bond.

Li+ Ashweek, N. et. al. Li Li JACS 2005, 127, 449 + R R With Et O, k ∝ [RLi] not X X C C R 2 rac C R R 2 X R [RLi] Li Li Li+

■ Backside attack of the R—Li bond is important for [2,3]-Wittig rearrangement

R Li Li H .. R [2,3] O Verner, E. J.; Cohen, T. O H JACS 1992, 114, 375. Nucleophilic Hydrides

■ Nucleophilic hydrides are generally attached to “-ate” complexes with electropositive elements. Bonds to anionic atoms are more nucleophilic than comparable bonds to neutral atoms.

CH better H 3 CH H 3 Nu H - Li -2 - > - >> Et Si Et Li Al H B H Et .. .. H H N N N N H H OAc + + TMEDA lithiate

■ NaBH4 and LiAlH4 change with each hydride addition

H + - Li H + Li Li H Al O - O H : Al O H O etc. H H Al H H H H H

H - less reactive Al - RO OR than AlH4 OR

■ Cheap, “simple” reagents rarely involve simple reaction mechanisms. Nucleophilic Hydrides and Selectivity

■ H atoms generally move faster than C atoms. Hydrido groups undergo [1,2] migrations faster than R. Bases attack H faster than R.

faster H2O: H Cl R + Li - O B R H slower H2O: H3C Cl R

■ Ketone reduction is fast (SN2 on R-Br isn't fast)

- Jean-Claude, B. J.; Just, G. O OH H3B H Syn. Comm. 1994, 24, 1565. Na+ NaBH4

MeOH rt, 1 h Br Br 100%

■ Alkyl groups increase reactivity of anionic “ates” versus hydrogen. 4 Et3BH- is 10 more nucleophlic than BH4-. LiEt3BH = "Super Hydride" Br Li+ H Brown, H. C.; Krishnamurthy, S. H BEt - 3 THF JACS 1973, 95. 25 °C, 3 h Selectivity of Hydride Donor Reagents

■ Selectivity of hydride reagents toward π*

react fastest react slowest + H + H O RN O O O O O

R R R R R H R R R OR R NR2 R OLi

LiAlH4/THF

NaBH4/MeOH H H - - H B or H Si H H H CN OR

■ Sodium cyanoborohydride doesn’t react with carbonyls unless they are protonated.

HCl (slow addn, pH 3) O Na+ CN OH - H B CH3OH Borch, R.F., et. al. Ph H Ph H 23 °C, 1 h H JACS 1971, 93, 2897.

H +O

Ph Hydridostannates and Hydridosiliconates

■ R3SnH and R3SiH form nucleophilic hydride reagents in situ

O Shibata, I.; Yoshida, T.; Baba, A.; Matsuda, H. O Bu4N+ F- Chem. Lett. 1991, 307. + H H OH - Ph n-Bu3SnH Bu Sn Bu Ph Bu 81% OMe 0 °C, 5 h F OMe

■ NaCNBH3 reduces enamines, indoles, and pyrroles via iminium ions. This reduction works with hydridosiliconates.

O CF3 Et O2CCF3 O :O CF O2CCF3 H Si 3 Si O - Et Et EtEt Et Si Et Et Et H - Et3SiH H H H .. CF3CO2H N H N N N H H + + H

Lanzilotti, A. E., et. al. Usually with NaCNBH3 /CF3CO2H JOC 1979, 44, 4809. Electrophilic Hydride Reagents

■ BH3 and i-Bu2AlH reduce ketones. They are not nucleophilic UNTIL after they coordinate to the carbonyl

H H H B - H .. + B B O H H O H O H Al H H DIBAL-H

■ DIBAL-H reduces esters to aldehydes because it only delivers one hydride

R - R i-Bu AlH Al workup O: 2 + R Al O O H O R OEt toluene H H2O H HOEt OEt OEt

R2Al-, R2B-, and R3Si- groups reduce the nucleophilicity of oxygen l.p.

■ LiAlH4 reduces esters to alcohols via electrophilic alane (AlH3).

+ Li Li Li + Li O LiAlH4 O O :O O OEt H H + - H Al OEt THF OEt .OEt + OEt H H . H H Al H H Al - AlH3 3 - 3 C-H Weakening by Lone Pair Donation

■ Bohlmann bands occur ~ 2700 - 2850 cm-1 in the IR spectrum.

Bohlmann bands are due to donation of nitrogen lone pairs into σ*C-H

H H N .. Vapor phase IR spectrum Ferdinand Bohlmann Chem. Ber. 1958, 2157. Daly, J. W., et.al. JOC 2000, 65, 8908.

■ An extreme example of nitrogen lone pair donation affecting spectroscopy and chemical reactivity

2450 cm-1 Bohlmann bands H H 2690-2800 cm-1 Wuest, J. JACS 1980, 6365. N N Watkins, T. JACS 1980, 6363.. .. N.. -1 .. H ~2900 cm aliphatic C-H

X X- H X- H + N N 110 °C N N H + H H + 23 h N N N N nN donate into σC-H* .. N.. H .. Hydride Transfer from Carbon

■ Aldehydes without α-hydrogens can’t undergo aldol reactions. Instead, they disproportionate via hydride transfer (Cannizzaro reaction).

O NaOH OH O 2 + Geissman, T. Ph H Ph H Ph ONa Org. React. 1944, 2, 94. H H Ph O Ph Na-O.. OH.. OH

■ Formaldehyde and formate are particularly good hydride donors ■ Eschweiler-Clark methylation

CH O O 2 O N NH2 H2CO2H N + H O O O O.. - + R O N O

Dai-Ho, G., Mariano, P. S. JOC 1988, 53, 5113. Eschweiler, W. Chem. Ber. 1905, 38, 880. Awachie, P.I.; Vagwanda, V.C. Clarke, H. T., et. al. JACS 1933, 55, 4571. Tetrahedron 1990, 46, 1899 Moore, Org. React. 1949, 5, 301. Oppenauer and Meerwein-Pondorff-Verley Reactions

■ Oppenauer oxidation: (i-PrO)3Al catalyzes hydride transfer to acetone solvent

OH O Djerassi, C. cat. Al(Oi-Pr)3 Org. React. 1951, 26, 207 = oxidation ! acetone

OR + H O H O Al Al OR Al OR O OR ..O - O - OR + OR

■ The reaction is reversible and is driven by the use of solvent as a reagent ■ Meerwein-Pondorff-Verley Reduction (M-P-V): Run the reaction in i-PrOH

O OH

cat. Al(Oi-Pr)3 Wilds, A. L. isopropanol Org. React. 1944, 2, 178.