Chemistry 125 Lecture 45 January 28 2011 This

Chemistry 125: Lecture 45 January 28, 2011 This Nucleophilic Substitution and Mechanistic Tools: Solvent, Leaving Group PET Scanning Pentavalent Carbon? For copyright notice see final page of this file

SN 2 Nucleophilic Substitution Solvent Nu: R-L Nucleophile Substrate (+) (-) Nu-R L Product Leaving Group the Pragmatic Logic of Proving a Mechanism with Experiment & Theory (mostly by disproving all alternative mechanisms)

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 krel CH 3 Br in Acetone Backwards H 2 O (-) (+) 11 5 Sensible Nu: Solvent [1] e. g. J&F Sec. 7. 4 dg

Rate Constant Dependance on Nu: Nucleophile Solvent R-L Leaving Substrate Group L (+) Nu-R (-) L p. Ka (LH+) HO- v. bad 15. 7 HS- bad 7 F- bad 3. 2 H 2 O good -1. 7 RSO 2 O- good -3 Cl- good -8 Br- good -9 I- v. good -10 Weak bases are good leaving groups (Stable anions form easily. Those that don’t hold tightly to H+ don’t hold tightly to Nud- C in the Nud- C Ld. SN 2 transition state, as expected) e. g. J&F Sec. 7. 4 e

How? With permission of the Edmund S. Muskie Archives and Special Collections Library – Bates College Molecule specifically designed and prepared to test these mechanistic questions Cl Lawrence H. Knox Paul D. Bartlett (1908 -1964) (1907 -1997) Bartlett and Knox * (J. Am. Chem. Soc. - 1939)

Need a Fabulous Leaving Group! O Cl now an “allylic” N H + Nrearrangement shifts H 2 O HO H O 2 H from N to O p. Ka N + Cl H H-NH 2 = 34 + Can generate even + NH 2 H-N+H 3 = 9 bridgehead cation! + Near the end of the semester we’ll discuss R-COOH R-CNH 2 R-NH 2 How? Molecule specifically designed and prepared to test these mechanistic questions Cl Bartlett and Knox * (J. Am. Chem. Soc. - 1939)

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

OH Leaving-Group-Trick Lore (e. g. J&F sec 7. 4 f) OH 2+ Br. CH 3 -CH 2 -OH H-Br p. Ka -5 Br. CH 3 -CH 2 -O+H 2 Br CH 3 -CH 2 + OH- Bad leaving group Br CH 3 -CH 2 + OH 2 H-O+H 2 p. Ka -1. 7 Good leaving group H-OH p. Ka 16 Ether Cleavage by HBr Br- excess 47% HBr O Br 8 hr Br + Good Leaving Group OH O H Br Good Nucleophile

OH Leaving-Group-Trick Lore (e. g. J&F sec 7. 4 f) OSO 2 R O H Ph. CH 2 CH CH 3 Cl SO 2 H OSO 2 CH 3 toluenesulfonic acid p. Ka -3 Kenyon & Phillips (1923) O SO 2 Ph. CH 2 CH CH 3 “tosylate” O O C CH 3 Ph. CH 2 CH CH 3

OH Leaving-Group-Trick Lore (e. g. J&F sec 7. 4 f) OSOCl b. p. 75°C 61°C gases

OH Leaving-Group-Trick Lore (e. g. J&F sec 7. 4 f) OPXn (CH 3)2 CHCH 2 OH PBr 3 (CH 3)2 CHCH 2 Br + P(OH)3 (58%) -10°C, 4 hr Larger rings allow flattening Inaccessible for S N 2 of bridgehead cation. PCl 5 + OH PClx Ca. CO 3 ether 0°C, 3 min Substitution of RO- for Cl- at P (probably A/D mechanism) generates good leaving group. Cl (“ 100%”)

OH Leaving-Group-Trick Lore (e. g. J&F sec 7. 4 f) OP+Ph 3 Appel Reaction (Wikipedia) p. Ka ~17 Substitution of P for CCl 3 at Cl p. Ka 24 A/D substitution at P (vacant d-orbitals) H e. g. D D OH Cl f 3 P CCl 4 25°C, 24 hr H D D (~85%)

Using SN 2 Mechanistic Knowledge to Maximize Synthetic Speed for PET scanning (from Loudon, Org. Chem. ) http: //en. wikipedia. org/wiki/Positron_emission_tomography Connecting simultaneous scintillations shows where 18 F’s were. 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 e +- positron +18 O= proton neutron Need to get 18 F where tumor is and you have to do so within a few hours of preparing the element.

Yale PET What to synthesize?

Protected Triflate to 2 -Fluoroglucose - ASAP Glucose KF 18 S N 2 ? 2 -Fluoroglucose F 18 and by K+cation would suck up 18 F Maybe tied upitby H-bonding 2 -Fluoroglucose as well. HO a horrid leaving group trifluormethanesulfonate wrong C-OH could be attacked (Triflate) “protection” is Now to introduce 18 F sugar chemistry. SN 2 inversion gives wrong configuration start with Rapid metabolism of. Mannose tumor sucks up glucose. SN 2 Problems : This kind of well known in p. Ka ~ -14 Cl-SO 2 CF 3 O Ac. O = CH 3 C-O- (acetate protecting group)

Protected Triflate to 2 -Fluoroglucose - ASAP Glucose 2 -Fluoroglucose KF 18 S N 2 “deprotection” H 2 O H+ and by K+cation 18 F tied up by H-bonding K+ K+ 18 FCH 3 CN (aprotic solvent) Cl-SO 2 CF 3

Vertical Section viewed from front PET Scan Image measured 1 hour after administering fludeoxyglucose (18 F) shows high glucose metabolism in brain and in a cancerous lymph node. Horizontal Section viewed from beneath Linus Pauling 1901 -1994 Akira Kouchiyama

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?

End of Lecture 45 Jan. 28, 2011 Copyright © J. M. Mc. Bride 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-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