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

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

3. Solvent Leaving Group Substrate Rate Constant Dependance on Nu: R-L Nu-R L (+) (-)(-) Nucleophile 80 1,000 10,000 16,000 126,000 [1] k rel Br - F-F- H2OH2O HO - Cl - Nu HS - e.g. J&F Sec. 7.4dg I-I- 80,000 -8 -9 7 -10 3.2 15.7 -1.7 pK a (NuH + ) Polar solvents accelerate reactions that generate (or concentrate) charge, and vice versa. k rel CH 3 I in H 2 O [1] 14 160 k rel CH 3 Br in Acetone 11 5 [1] harder to break H-bonds to smaller ions Sensible Backwards

4. Nucleophile Solvent Rate Constant Dependance on Nu: R-L Nu-R L (+) (-)(-) e.g. J&F Sec. 7.4e Substrate Leaving Group goodRSO 2 O - -3 bad good v. bad bad good Br - F-F- H2OH2O HO - Cl - HS - I-I- v. good -8 -9 7 -10 3.2 15.7 -1.7 LpK a (LH + ) Weak bases are good leaving groups (Stable anions form easily. Those that don’t hold tightly to H + don’t hold tightly to Nu  - C in the Nu  - C L  - S N 2 transition state, as expected)

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

6. N HO + NH 2 Bartlett and Knox (J.Am.Chem.Soc. - 1939) (J.Am.Chem.Soc. - 1939) Molecule specifically designed and prepared to test these mechanistic questions * Cl N O N O N + + H + + H + H H2OH2O N2N2 Need a Fabulous Leaving Group! Can generate even bridgehead cation! How? now an “allylic” rearrangement shifts H from N to O Near the end of the semester we’ll discuss R-COOH R-CNH 2 R-NH 2 pK a H-NH 2 = 34 H-N + H 3 = 9

7. Nucleophile Solvent Rate Constant Dependance on Nu: R-L Nu-R L (+) (-)(-) e.g. J&F Sec. 7.4e Substrate goodRSO 2 O - -3 Leaving Group bad good v. bad bad good Br - F-F- H2OH2O HO - Cl - HS - I-I- v. good -8 -9 7 -10 3.2 15.7 -1.7 LpK a (LH + ) Weak bases are good leaving groups (H like R, as expected) R-OH v. bad R-OH 2 + good R-OSO 2 R’ good (Kenyon/Phillips) (acid catalysis)

8. OH Leaving-Group-Trick Lore (e.g. J&F sec 7.4f) OH 2 + Good Leaving Group Good Nucleophile H-O + H 2 pK a -1.7 Good leaving group H-OH pK a 16 Bad leaving group H-Br pK a -5 Br - CH 3 -CH 2 -OH CH 3 -CH 2 + OH - Br CH 3 -CH 2 + OH 2 Br Br - CH 3 -CH 2 -O + H 2 Ether Cleavage by HBr O excess 47% HBr 8 hr Br OHBr H Br - O +

9. Kenyon & Phillips (1923) OSO 2 R OH Leaving-Group-Trick Lore (e.g. J&F sec 7.4f) H PhCH 2 CH 3 CH O ClSO 2 CH 3 PhCH 2 CH 3 CH O SO 2 CH 3 toluenesulfonic acid pK a -3 H OSO 2 CH 3 CO O PhCH 2 CH 3 CH OCH 3 C O “tosylate”

10. OSOCl gases OH Leaving-Group-Trick Lore (e.g. J&F sec 7.4f) b.p. 75°C 61°C

11. OPX n + OH Leaving-Group-Trick Lore (e.g. J&F sec 7.4f) OH PCl x Inaccessible for S N 2 (CH 3 ) 2 CHCH 2 OH PBr 3 -10°C, 4 hr (CH 3 ) 2 CHCH 2 Br (58%) + P(OH) 3 (“100%”) Cl CaCO 3 ether 0°C, 3 min PCl 5 Substitution of RO - for Cl - at P (probably A/D mechanism) generates good leaving group. Larger rings allow flattening of bridgehead cation.

12. OP + Ph 3 OH Leaving-Group-Trick Lore (e.g. J&F sec 7.4f) Substitution of P for CCl 3 at Cl pK a ~17 pK a 24 A/D substitution at P (vacant d-orbitals) e.g. CCl 4 25°C, 24 hr 3P3P OH D D H D D Cl H (~85%) Appel Reaction (Wikipedia)

13.  Using S N 2 Mechanistic Knowledge to Maximize Synthetic Speed for PET scanning (from Loudon, Org. Chem.) e-e-  e+e+ 18 O = + 7 MeV proton - neutron 18 F - t 1/2 110 min http://en.wikipedia.org/wiki/Positron_emission_tomography Need to get 18 F where tumor is or 11 C t 1/2 ~ 20 min 13 N t 1/2 ~ 10 min 15 O t 1/2 ~ 2 min positron Connecting simultaneous scintillations shows where 18 F’s were. and you have to do so within a few hours of preparing the element. + 18 O = proton neutron

14. Yale PET What to synthesize?

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

16. K+K+ CH 3 CN (aprotic solvent) 18 F - 18 F tied up by H-bonding and by K + cation Glucose2-Fluoroglucose KF 18 S N 2 Cl-SO 2 CF 3 “deprotection” H 2 O H + Protected Triflate to 2-Fluoroglucose - ASAP K+K+

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

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

19. So far we’ve just been beating up on the D/A mechanism (trivalent C intermediate) though there are cases (S N 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)

20. Might there be Pentavalent A/D Intermediate instead of a Concerted S N 2 Transition State? Pentavalent Intermediate Nu L C L C Transition State

21. Quantum Mechanics says Transition State for OH - attacking less crowded CH 3 OH. 1.88 Å Quantum Mechanics says Transition State for H 2 O attacking protonated t-BuOH. 2.64 Å But neither reaction is practical in the laboratory! What does experiment say?X-ray? Might there be Pentavalent A/D Intermediate instead of a Concerted S N 2 Transition State?

22. End of Lecture 45 Jan. 28, 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).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