Chemistry 125 Lecture 45 January 29 2010 Nucleophilic

Chemistry 125: Lecture 45 January 29, 2010 Nucleophilic Substitution and Mechanistic Tools: Rate Law, Rate Constant, Structure 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

Rate Constant Dependance on Nu: Nucleophile Nu Solvent R-L (+) Nu-R Leaving Substrate Group krel (-) L Product p. Ka (Nu. H+) H 2 O [1] -1. 7 F- 80 3. 2 Cl- 1, 000 -8 Br- 10, 000 -9 HO- 16, 000 15. 7 I- 80, 000 -10 HS- 126, 000 7 For first-row elements nucleophilicity (attack C-L ) parallels basicity (attack H+). Both require high HOMO. But as atoms get bigger, they get better at attacking C-L (compared to attacking H+) Sec. 7. 4 d, Table 7. 3

Rate Constant Dependance on Nucleophile Nu R-L Leaving Substrate Group krel p. Ka [1] -1. 7 F- 80 3. 2 Cl- 1, 000 -8 Br- 10, 000 -9 HO- 16, 000 15. 7 I- 80, 000 -10 HS- 126, 000 7 Nu-R L Polar solvents accelerate reactions that generate (or concentrate) charge, and vice versa. (Nu. H+) krel CH 3 I in H 2 O harder [1] to break 14 H-bonds to smaller ions 160 CH 3 Br in Acetone Backwards H 2 O (-) (+) Sec. 7. 4 dg 11 5 [1] Sensible Nu: Solvent

Rate Constant Dependance on Nu: Nucleophile Solvent R-L Leaving Substrate Group L (-) (+) Nu-R L p. Ka (LH+) Weak bases are good leaving groups (H like R, as expected) H 2 O good -1. 7 F- bad 3. 2 Cl- good -8 Br- good -9 R-OH v. bad HO- v. bad 15. 7 R-OH 2+ good I- v. good -10 HS- bad 7 RSO 2 O- good -3 (acid catalysis) R-OSO 2 R’ good (Kenyon/Phillips) Sec. 7. 4 e

OH Leaving-Group-Trick Lore (sec 7. 4 f) p. Ka ~16 OH 2 p. Ka -1. 7 + Ether / HBr Good Nucleophile Good Leaving Group

OH Leaving-Group-Trick Lore (sec 7. 4 f) OSO 2 R p. Ka -3 Cf. Kenyon & Phillips (1923)

OH Leaving-Group-Trick Lore (sec 7. 4 f) OSOCl gases

OH Leaving-Group-Trick Lore (sec 7. 4 f) OPXn + PClx

OH Leaving-Group-Trick Lore (sec 7. 4 f) OP+ 2 1

Maximizing Synthetic Speed to support PET scanning (from Loudon, Org. Chem. ) http: //en. wikipedia. org/wiki/Positron_emission_tomography 18 O= + 7 Me. V proton 18 F - neutron or 11 C t ~ 20 min 1/2 13 N t ~ 10 min 1/2 15 O t ~ 2 min 1/2 t 1/2 110 min Connecting coincident scintillations tells where 18 F’s were. e+- positron Need to get 18 F where cancer is and you have to do it within a couple hours.

Yale PET What to synthesize?

Mannose to 18 2 -F Glucose KF 18 S N 2 ? - ASAP 2 -Fluoroglucose F 18 H 2 O H+ and by K+cation Maybe it would suck up F tied up by H-bonding 2 -Fluoroglucose as well. HO a horrid leaving group trifluormethanesulfonate wrong C-OH could be attacked K+ K+ F 18(Triflate) CH 3 CN inversion (aprotic solvent) gives wrong configuration O Cl-SO 2 CF 3 Ac. O = CH 3 C-O- start with Rapid metabolism of. Mannose tumor sucks up glucose. Problems : well known for sugars (acetate protecting group)

Loudon, Organic Chemistry Office Hours 3 -4: 30 this afternoon 181 SCL

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

So far we’ve just been beating up on the D/A mechanism (trivalent C intermediate) though there are cases (SN 1) where it in fact applies. The tougher problem is to distinguish between concerted and A/D with a very weakly stabilized intermediate. (see supplementary reading on Course website)

Might there be Pentavalent A/D Intermediate instead of a Concerted SN 2 Transition State? Nu C L Transition State Nu C L Pentavalent Intermediate

Might there be Pentavalent A/D Intermediate instead of a Concerted SN 2 Transition State? 2. 64 Å Quantum Mechanics says Transition State for H 2 O attacking protonated t-Bu. OH. 1. 88 Å Quantum Mechanics says Transition State for OH- attacking less crowded CH 3 OH. But neither reaction is practical in the laboratory! What does experiment say? X-ray?

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

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

CH 3 + NOT elongated to reflect superposed CH -O(CH ) BF 3 2 4 OCH 3 3 O + O average of two “bell-clapper” C structures. Powerful alkylating + agent like “Meerwein’s : : . Reagent” ARE THERE BONDS HERE? - 4 Et 3 O+ BF HOYWAT F 3 BF BF 3 2. 64 Å JACS 4354 -4371 (2005)

Pentavalence seemed to BUT be a safe without central C+ etc. inference shortened by 0. 21 Å! Eclipsedbent in repulsion 125° 113° 114° 4. 75 Å Å 4. 86 4. 96 5. 02 Å shortened by 0. 16 Å Pentavalent C attraction?

CF 3 Eclipsed repulsion 125° 124° O 5. 00 Å Å 4. 86 113° 116° 5. 08 Å Å 5. 02 Central O only slightly repulsive compared to C+. Si. O 2

BF 2 does seem to suck in CH 3 O groups. Eclipsed repulsion 126° BF 2 4. 56 Å 112° 4. 92 Å

Double minimum with stronger nucleophile O(higher HOMO & lower LUMO) CF 3 1. 47 Å 127° 113° 109° 125° and. 4. 86 Å 2. 99 Å 5. 02 4. 84ÅÅ 1. 88 Å O- K+ nearby

CH 3 O + OCH 3 C Bonded O (or S) seems to “use up” the vacant AO. For F withdrawal dominates donation. Higher neighbor HOMOs favor tetravalence. Range Compared to what? CH 3 O C + OCH 3

A-X distances (Å) Short & Long X A X Distances A X Pressed in by H CH 3 repulsion C+ C+ B stability No sign of nonbond “loose” ~ equal for pentavalent reference like H symmetrical SN 2 “intermediate ” transistion state (as by q. state mech. ) calculated transistion H B “tight” Bonded? Compound very Bdifferent tetracoordinate unsymmetrical

End of Lecture 45 Jan. 29, 2010 Copyright © J. M. Mc. Bride 2010. 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-Non. Commercial-Share. Alike 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. Mc. Bride, Chem 125. License: Creative Commons BY-NC-SA 3. 0