1. 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

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

3. Leaving Group Substrate Rate Constant Dependance on Solvent Nu: R-L Nu-R L (+) (-)(-) Product 80 1,000 10,000 16,000 126,000 Nucleophile [1] k rel Br - F-F- H2OH2O HO - Cl - Nu HS - Sec. 7.4d, Table 7.3 I-I- 80,000 -8 -9 7 -10 3.2 15.7 -1.7 pK a (NuH + ) 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 + )

4. 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 - Sec. 7.4dg I-I- 80,000 -8 -9 7 -10 3.2 15.7 -1.7 pK a (NuH + ) 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 Polar solvents accelerate reactions that generate (or concentrate) charge, and vice versa. Sensible Backwards

5. Nucleophile Solvent Rate Constant Dependance on Nu: R-L Nu-R L (+) (-)(-) 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)

6. OH Leaving-Group-Trick Lore (sec 7.4f) pK a ~16pK a -1.7 OH 2 + Ether / HBr Good Leaving Group Good Nucleophile

7. OH Leaving-Group-Trick Lore (sec 7.4f) Cf. Kenyon & Phillips (1923) OSO 2 R pK a -3

8. OH Leaving-Group-Trick Lore (sec 7.4f) OSOCl gases

9. OH Leaving-Group-Trick Lore (sec 7.4f) OPX n PCl x +

10. OH Leaving-Group-Trick Lore (sec 7.4f) OP + 1 2

11. Maximizing Synthetic Speed to support 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 cancer 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 coincident scintillations tells where 18 F’s were. and you have to do it within a couple hours.

12. Yale PET What to synthesize?

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

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

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

16. 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)

17. 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

18. 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?

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

20. HOYWAT JACS 4354-4371 (2005) Nu LC Held in place by molecular framework +

21. HOYWAT + JACS 4354-4371 (2005) CH 3 O O C + CH 3 -O(CH 3 ) 2 BF 4 - : : ARE THERE BONDS HERE? OCH 3 + NOT elongated to reflect superposed average of two “bell-clapper” structures. F 3 BF - BF 3 2.64 Å Powerful alkylating agent like “Meerwein’s. Reagent” Et 3 O + BF 4 -

22. 5.02 Å 4.86 Å shortened by 0.16 Å BUT without central C + etc. shortened by 0.21 Å! 4.96 Å 4.75 Å 125° 114° 125° 113° Pentavalent C attraction? Eclipsed repulsion bent in etc. Pentavalence seemed to be a safe inference

23. 5.02 Å 4.86 Å 5.08 Å 5.00 Å O SiO 2 CF 3 124° 116° 125° 113° Central O only slightly repulsive compared to C +. Eclipsed repulsion

24. 126° 112° 4.92 Å 4.56 Å BF 2 BF 2 does seem to suck in CH 3 O groups. Eclipsed repulsion

25. 125° 113° 5.02 Å 4.86 Å Double minimum with stronger nucleophile O - (higher HOMO & lower LUMO) 127° 109° 4.84 Å 1.47 Å 2.99 Å CF 3 - O K+K+ and. nearby 1.88 Å

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

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

28. End of Lecture 45 Jan. 29, 2010 Copyright © J. M. McBride 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-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