Nucleophilic Substitution and Mechanistic Tools: Chemistry 125: Lecture 44 January 26, 2011 Nucleophilic Substitution and Mechanistic Tools: Stereochemistry, Rate Law, Substrate, Nucleophile This For copyright notice see final page of this file

SN2 Nucleophilic Substitution Generality of Nucleophilic Substitution Solvent Nu: R-L Nu-R L (+) (-) Leaving Group Nucleophile Substrate Product But there are different mechanisms! the Pragmatic Logic of Proving a Mechanism with Experiment & Theory (mostly by disproving all alternative mechanisms)

"It is an old maxim of mine that when you have excluded the impossible, whatever remains, however improbable, must be the truth." From “Adventure of the Beryl Coronet”. Similar lines in other Holmes adventures. The Adventure of the Beryl Coronet

SN2 Nucleophilic Substitution Nu: R-L Nu-R L (+) (-) Break bond (Dissociation) Make bond (Association) the Pragmatic Logic of Proving a Mechanism with Experiment & Theory Simultaneous “Concerted” (make-as-you-break) D then A A then D (mostly by disproving all alternative mechanisms)

Concerted A/D D/A Nu L C Transition State Pentavalent Intermediate Nu Trivalent Intermediate C

Concerted A/D D/A chiral chiral achiral Unlikely for enantiomers a b c Nu L C Transition State Pentavalent Intermediate Nu L C Trivalent Intermediate C Nu Nu chiral chiral achiral Unlikely for very exothermic process ( (Hammond implausibility) Which is it normally? Stereochemical Implications!

Tools for Testing (i.e. Excluding) Mechanisms: Stereochemistry (J&F sec 7.4b) Rate Law (J&F sec 7.4a) Rate Constant (J&F sec 7.4cdefg) Structure X-Ray and Quantum Mechanics

Nucleophilic Substitution Walden Inversion (1898) - “the most astounding discovery in stereochemistry since the groundbreaking work of van’t Hoff.” E. Fischer N + RL L + RN Displacement Replacement

STEREOCHEMISTRY Kenyon and Phillips (1923) PhCH CH3 CH nucleophilic substitution at S (A/D, A favored by vacant d orbital of S) -OH H PhCH2 CH3 CH O PhCH2 CH3 CH O SO2 Cl SO2 CH3 H +31° Why not avoid acetate steps by using -OH? Backside Attack in +33° nucleophilic substitution at C=O (A/D, A favored by *) nucleophilic substitution at saturated C. CH3 C O Because it attacks H C (the only step involving chiral C) Same as starting material? J. Chem. Soc 1923 p. 44 ff. By H Phillips (advised by J. Kenyon) from Battersea Polytech. H PhCH2 CH3 CH O C OH PhCH2 CH3 CH O C H CH3 O C O PhCH2 CH3 CH OH Inversion! (R)  (S) -7° -32° Proves nothing

Concerted A/D D/A Pentavalent Intermediate Nu L C Trivalent Transition State Trivalent intermediate could be attacked from either face  racemization, not inversion.

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

NaOEt + EtBr EtOEt + NaBr [NaOEt] ( fixed [EtBr] ) rate Second Order (SN2) d[EtO-] dt = k2 [EtO-] [EtBr]

Concerted A/D D/A Pentavalent Intermediate Nu L C Trivalent Transition State Nu enters Nu enters Initial rate-limiting dissociation in D/A would give a rate independent of [Nu], not SN2.  Not D/A

NaOEt + EtBr EtOEt + NaBr EtOH Analogy pKa Ratio should be much less drastic at early SN2 transition state. EtO- + H+  EtOH EtO: + H+  EtOH H + EtO- + EtBr  EtOEt EtO: + EtBr  EtOEt H + 15.7 [NaOEt] d[EtO-] dt rate = k2 [EtO-] [EtBr] Second Order (SN2) 1017.4 at equilibrium -1.7 + k1 [EtBr] + k [EtOH] [EtBr] ~ const Pseudo First Order First Order (D/A?) k2 = 20,000  k Is it reasonable to be so different?

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

Rate Constant Dependance on Nu: R-L Nu-R L (+) (-) Solvent Leaving Group Nucleophile Substrate Product [1] krel (CH3)2CH CH3CH2 CH3 (CH3)3CCH2 CH3CH2CH2 R (CH3)3C e.g. J&F Table 7.1 p. 275 RBr + I- acetone / 25°C (CH3)2CHCH2 LUMO 145 C-L antibonding node 145x   1.2x 128x 0.82 ~same H 23x 0.0078 Surface Potential +26 to -25 kcal/mole >15x 0.036 3000x ~ 0.0005 ? Something else happens 0.000012

-Methylation Steric Hindrance Total Density (vdW) Methyl Ethyl iso-Propyl t-Butyl Steric Hindrance Total Density (vdW) -Methylation

-Methylation LUMO at 0.06 LUMO at 0.04 Total Density (vdW) Methyl iso-Propyl t-Butyl LUMO at 0.06 LUMO at 0.04 Total Density (vdW) -Methylation

-Methylation Surface Potential +26 to -25 kcal/mole Methyl Ethyl iso-Propyl t-Butyl Surface Potential +26 to -25 kcal/mole -Methylation

-Methylation Neopentyl Ethyl [1] n-Propyl 0.82 iso-Butyl 0.036 0.000012 (Cl is illustrated in this and previous frames) By mol mech gauche nPrBr is 1.6 kJ/mole above anti, gauche-gauche I-BuBr is 2.4 kJ/mole above gauche-anti -Methylation No way to avoid the third -CH3

Might it be possible to have frontside attack? Nu L C Transition State Backside Attack Planar Trivalent Intermediate C Might it be possible to have frontside attack? Nu L C Transition State Frontside Attack or formation of a non-planar cation? Nonplanar Trivalent Intermediate + C (remember planar BH3)

Bartlett and Knox (J.Am.Chem.Soc. - 1939) “In 1939 Bartlett and Knox published the account of their work on the bridge-head chloride, apocamphyl chloride. I believed then, and I believe now, that this was a fantastically influential paper. For thirty years afterwards, no one really accepted any mechanism unless it had been tested out on a bridgehead case. Molecule specifically designed and prepared to test these mechanistic questions Indeed, the Bartlett-Knox paper shaped the interests and viewpoint of many chemists about the kind of physical organic they wanted to do.” John D. Roberts Caltech 1975 Bartlett and Knox (J.Am.Chem.Soc. - 1939) *

Bartlett and Knox (J.Am.Chem.Soc. - 1939) Cl “bridgehead” chloride boat c-hexane with a bridge bicyclo[2.2.1]heptane Flattening would generate highly strained angles (estimated >23 kcal/mole). Cation would not be planar. Backside of s*C-Cl is inaccessible, and inversion would be impossible. Bartlett and Knox (J.Am.Chem.Soc. - 1939) * Attack would have to be frontside.

Bartlett and Knox (J.Am.Chem.Soc. - 1939) Although there are b-H atoms, they are not in the anti position necessary to allow sCH - s*C-X overlap during elimination of H-X to form C=C. “C=C bonds cannot originate from such a bridgehead.” (Bredt’s Rule) Horrid Overlap! gauche H Would competition from loss of HCl make it impossible to measure the expected really slow rate of substitution? Bartlett and Knox (J.Am.Chem.Soc. - 1939) * NO

Bartlett and Knox (J.Am.Chem.Soc. - 1939) Nu L C >>106 slower than typical backside attack + C >109 slower than from Et(CH3)2C-Cl 60°cooler and without Ag+ pull on Cl instead of pushing at C R-Cl: + Ag+ R+ + AgCl ( ) Bartlett and Knox (J.Am.Chem.Soc. - 1939) *

Cycloalkyl Halides (e.g. J&F Table 7.2) krelative C H Br I [1] ~109° 120° sp2 60° 90° 109° <0.0001 strain in starting material ??? increased strain in transition state 0.008 bent OK 1.6 0.01

Rate Constant Dependance on Nu: R-L Nu-R L (+) (-) Solvent Leaving Group Nucleophile Substrate Product [1] krel Br- F- H2O HO- Cl- Nu HS- e.g. J&F Sec. 7.4d, Table 7.3 I- 3.2 15.7 -1.7 pKa (NuH+) For first-row elements nucleophilicity (attack C-L ) parallels basicity (attack H+). Both require high HOMO. 80 1,000 -8 10,000 -9 But as atoms get bigger, they get better at attacking C-L (compared to attacking H+) 16,000 80,000 -10 126,000 7

Rate Constant Dependance on Nu: R-L Nu-R L (+) (-) Solvent Leaving Group Polar solvents accelerate reactions that generate (or concentrate) charge, and vice versa. Nucleophile Substrate 80 1,000 10,000 16,000 126,000 [1] krel Br- F- H2O HO- Cl- Nu HS- e.g. J&F Sec. 7.4dg I- 80,000 -8 -9 7 -10 3.2 15.7 -1.7 pKa (NuH+) krel CH3I in H2O [1] 14 160 krel CH3Br in Acetone 11 5 [1] harder to break H-bonds to smaller ions Backwards Sensible

End of Lecture 44 Jan. 26, 2011 Copyright © J. M. McBride 2011. Some rights reserved. Except for cited third-party materials, and those used by visiting speakers, all content is licensed under a Creative Commons License (Attribution-NonCommercial-ShareAlike 3.0). Use of this content constitutes your acceptance of the noted license and the terms and conditions of use. Materials from Wikimedia Commons are denoted by the symbol . Third party materials may be subject to additional intellectual property notices, information, or restrictions.   The following attribution may be used when reusing material that is not identified as third-party content: J. M. McBride, Chem 125. License: Creative Commons BY-NC-SA 3.0