Nucleophilic Substitution Pentavalent Carbon in SN2? E2, SN1, E1 Chemistry 125: Lecture 46 January 31, 2011 Nucleophilic Substitution Pentavalent Carbon in SN2? E2, SN1, E1 This For copyright notice see final page of this file

Tools for Testing (i.e. Excluding) Mechanisms: Stereochemistry Rate Law Rate Constant Structure X-Ray and Quantum Mechanics

Problem: Neither Transition State nor Intermediate would hold together long enough to study. Pentavalent Intermediate Nu L C Transition State

Held in place by molecular framework HOYWAT + Nu L C Held in place by molecular framework JACS 4354-4371 (2005)

Powerful alkylating agent like “Meerwein’s . Reagent” CH3 O C OCH3 + + CH3-O(CH3)2 BF4- NOT elongated to reflect superposed average of two “bell-clapper” structures. HOYWAT Powerful alkylating agent like “Meerwein’s . Reagent” Et3O+ BF4- + : ARE THERE BONDS HERE? F3BF - BF3 2.64 Å Calcd. JACS 4354-4371 (2005)

Pentavalence seemed to be a safe inference BUT without central C+ etc. shortened by 0.21 Å! etc. Eclipsed repulsion 4.96 Å 4.75 Å 4.86 Å shortened by 0.16 Å bent in bent in Pentavalent C attraction? 125° 113° 125° 114° 5.02 Å

Central O only slightly repulsive compared to C+. SiO2 CF3 Eclipsed repulsion 5.02 Å 4.86 Å 5.08 Å 5.00 Å 124° 116° 125° 113°

BF2 does seem to suck in CH3O groups. Eclipsed repulsion 4.92 Å 4.56 Å 126° 112°

Double minimum with stronger nucleophile O-(higher HOMO and . nearby K+ Double minimum with stronger nucleophile O-(higher HOMO & lower LUMO) CF3 - O 5.02 Å 4.86 Å 127° 109° 4.84 Å 1.47 Å 2.99 Å 125° 113° 1.88 Å

Range Bonded O (or S) seems to “use up” the vacant AO. For F CH3O OCH3 + Bonded O (or S) seems to “use up” the vacant AO. Range For F withdrawal dominates  donation. Compared to what? Higher neighbor HOMOs favor tetravalence.

Short & Long X A X Distances Pressed in by HCH3 repulsion C+ A-X distances (Å) No sign of stability for pentavalent SN2 “intermediate ”  transistion state H nonbond reference ~ equal symmetrical very different unsymmetrical B “loose” like H B “tight” Bonded?  transistion state B tetracoordinate (as calculated by q. mech.) A X Compound

For copyright notice see final page of this file E2, SN1, E1 This For copyright notice see final page of this file

E2 -Elimination (e.g. J&F sec. 7.9) Rate influenced by: [base]  attack occurs during (or before) rate-determining-step nature of leaving group  it leaves during (or before) rds H isotope (kinetic isotope effect)  C-H broken during rds Heavier atom, lower ZPE see Lecture 8: frames 21-22 F CH2 CH2 H :OH "E2 Elimination" ABN AON F H OH CH2 C H C H O H O kH > kD ZPE (kinetic) but only if bond is weakened in rate-determining transition state D

E2 -Elimination (e.g. J&F sec. 7.9) Anti Stereochemistry (J&F sec 7.9c) but not dogmatic How to test experimentally? Which should be better? CH3 C Ph OTs H H3C syn (R) (S) CH3 C Ph OTs H H3C F CH2 CH2 H :OH "E2 Elimination" ABN AON F H OH CH2 (eclipsing strain) C Ph H3C CH3 H (Z) syn R Maybe (E) is just more stable than (Z). trans anti C Ph H3C H CH3 OTs R anti C Ph H3C CH3 H (E) cis (S) (S) (anti hybrids overlap better)

E2 -Elimination (e.g. J&F sec. 7.9) Anti Stereochemistry (J&F sec 7.9c) but not dogmatic H 98% yield OTs D RO- Na+ starting material is already eclipsed Loses syn DOTs, not HOTs despite kinetic isotope effect. H OTs Note that in this rigid, eclipsed case overlap with s*C-OTs is better for eclipsed syn D than for anticlinal H. D

E2 -Elimination (e.g. J&F sec. 7.9) Regiochemistry H “Saytzeff” “Hofmann” NaOCH3 HOCH3 L (cis + trans) I 81 19 Br 72 28 Cl 67 33 ~4:1 ~1:50 Range: 200 x 102.3 3 kcal/mole (subtle) F 30 70 (CH3)3N+ 2 98

E2 -Elimination (e.g. J&F sec. 7.9) E2 vs. SN2 Methyl Ethyl iso-Propyl t-Butyl Steric Hindrance favors E2 as does a nucleophile that is weak compared to its basicity (e.g. OH-)

Synthesis Games - + Exchange Ions + Create + Destroy MTBE (e.g. J&F sec. 7.10) Williamson Ether Synthesis (1852) O- Na+ EtBr + OEt Br- Exchange Ions (Double Decomposition) Finkelstein Reaction (1910) Na+ Cl- I- + RCl RI also RBr Br- Menschutkin Reaction (1890) Et3N + RI Et3N-R + I- Create Destroy Breaking apart by solvent Solvolysis (CH3)3C-Br EtOH HBr (CH3)3C-OEt Meerwein Reagent (1940s) RO- (CH3)3O BF4 ROCH3 + Na+ BF4 + (CH3)3O - () acetone C OH CH3 NaH -H2 O- + CH3Br C Br CH3 + CH3 C O MTBE CH3OH CH3O- NaH -H2 strong base favors E2 too hindered for SN2 actually made a different way

(intramolecular “SN2”) Synthesis Games (e.g. J&F sec. 7.10) Epoxide or Oxirane OH Cl O + Cl- 73% yield NaOH / H2O 25°C 1 hr O- Cl OH- Backside Attack (intramolecular “SN2”) Nu: Note: Epoxides are ethers with strain & thus a built-in RO- leaving group for adding C-C-O to a nucleophile. Nu O- O

N C and RC C are particularly interesting, as are anions like Synthesis Games (e.g. J&F sec. 7.10) pKa 25 pKa 9 N C and RC C are particularly interesting, as are anions like CH3-C-CH-C-CH3 O because they are nucleophiles that form C-C bonds by attacking C R-C C-H R-C C- Na+ + NH3 Na+ NH2- NH3 pKa 34

SN1 NaOH + R-Br HO-R + NaBr -1 1 -2 -3 -4 EtOH/H2O (4:1) 55°C (0.01 M) NaOH + R-Br HO-R + NaBr -1 1 -2 -3 -4 log (fraction of R-Br converted to HOR/min) Rate extrapolated from lower temperature. plus ~19% E2 k2 (M-1min-1) concerted displacement slowed by crowding (CH3)3C [OH-] SN1 k1 (min-1) D/A accelerated by crowding, (CH3)3C+ cation stabilization, polar solvent Depends on [OH-] CH3 CH3CH2 Hughes Ingold (1933-1940) (CH3)2CH

SN1 and E1 Product Determined After Rate (e.g. J&F sec. 7.6-7.8) SN1 and E1 Product Determined After Rate by Competition for Short-Lived Cation (CH3)3C-Br (CH3)3C-CN K+CN- H2O + (CH3)3C-OH rate determining step Product ratio depends on [K+CN-] but the rate does NOT! HOH CN- (CH3)3C+ (CH3)3C-Br (CH3)3C-OH (CH3)3C-CN

SN1 and E1 Rearrangement Demonstrates Cation Intermediate CH3 C CH2 I (e.g. J&F sec. 7.6-7.8) SN1 and E1 Rearrangement Demonstrates Cation Intermediate CH3 C CH2 I CH3 C CH2 OH AgNO3 Ag+ H2O

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