Solvation & Water Dissocation Brønsted Acidity Chemistry 125: Lecture 43 January 24, 2011 Solvation & Water Dissocation Brønsted Acidity Nucleophilic Substitution and its Components This For copyright notice see final page of this file

From small difference of large numbers! The Importance of Solvent for Ionic Reactions E±Coulomb = -332.2 / dist (Å) [long-range attraction; contrast radical bonding] kcal/mol 400 300 200 100 392 H+ + OH- (g) Sum = 370 164 ! 106 H+ :OH2 bonding + - etc, etc plus close proximity of + to eight electrons (polarizability shifts e-cloud) similar OH- (aq) + - e transfer + - 28 H3O+ (g) 18 100 From small difference of large numbers! H3O+ (aq) K  10-(3/4  386)  10-290 BDE HO-H 120 pKa = 15.8 H2O (g) 6.3 21.5 H2O (aq) H+(aq) + OH-(aq)

Brønsted Acidity Substitution at Hydrogen ABN F CH2 CH2 H :OH "E2 Elimination" ABN AON Make Two Break Two F H OH CH2 In a Solvent! F H :OH2 F H OH2 + Make & Break (Cf. Lecture 16)

Fortunately solvation energies of analogous compounds are similar enough that we can often make reasonably accurate predictions (or confident rationalizations) of relative acidities in terms of molecular structure.

When pH = pKa [H+] [B-] Ka = [HB] [B-] Why should organic chemists bother about pH and pKa, which seem like topics for general chemistry? a) Because whether a molecule is ionized or not is important for predicting reactivity (HOMO/LUMO availability), conformation, color, proximity to other species, mobility (particularly in an electric field), etc. b) Because the ease with which a species reacts with a proton might predict how readily it reacts with other LUMOs (e.g. *C-X or *C=O). Ka = [H+] [B-] [HB] [HB] [B-] pH = pKa + log = pKa, when HB is half ionized With known pKa, measure pH by measuring [B-] / [HB]. Single indicators work best over ~2.5 pH units (95:5 - 5:95). Bootstrap with overlapping indicators for wide coverage.

Factors that Influence Brønsted Acidity

Learning from pKa Values 16 12 8 4 pKa -4 HOH 15.7 (BDE 119) (BDE 91) (BDE 136) H3NH 9.2 + HSH 7.0 FH 3.2 H2OH -1.7 +

(e-negativity difference) E-Mismatch (e-negativity difference) Decrease of Overlap Ease of Heterolysis, Ka Ease of Homolysis H CH3 H NH2 H OH H F H SH H Cl H Br H I pKa ~55 ~35 16 3 BDE 105 108 119 136 7 ~ -3 ~ -5 ~ -9 91 103 88 71

Learning from pKa Values 16 12 8 4 pKa -4 HOH 15.7 H2OH -1.7 + HSH 7.0 FH 3.2 H3NH 9.2 9 CH3-C-CH-C-CH3 O H 4.8 CH3-COH O 2.9 ClCH2-COH O CH3 H3NCH-COH O +

Titration of Alanine pH Equivalents of OH- added slow (buffered) slow CH3 H2NCH-CO- O pH 12 10 8 6 4 2 Equivalents of OH- added 0.5 1.0 1.5 2.0 slow (buffered) CH3 H3NCH-CO- O + HH2 It requires 0.50 equivalents to change the ratio 9-fold (from 75/25 to 25/75) And only 0.03 equivalents to change the ratio 9-fold (from 3/100 to 1/300) slow (buffered) But only 0.22 equivalents to change the ratio 9-fold (from 25/75 to 3/97) CH3 H3NCH-COH O +

But it is 400 times harder than the corresponding ester. Titration of Alanine CH3 H2NCH-CO- O pH 12 10 8 6 4 2 Equivalents of OH- added 0.5 1.0 1.5 2.0 Then proximity of negative charge should make it ~300 times harder to remove H+ from alanine “zwitterion” than from H3N+-CH2CH3 (pKa 10.6). Actually it is 5 times easier! pK2 9.87 Ar H3NCH-COCH3 O + (pKa 7.3) But it is 400 times harder than the corresponding ester. CH3 H3NCH-CO- O + Apparently the CO2 group without charge is sufficiently electron withdrawing to destabilize the cation more than the negative charge stabilizes it. HH2 pK1 2.35 Reasonable that proximity of positive charge makes it ~300 times easier to remove H+ from alanine cation than from acetic acid (pKa 4.5) CH3 H3NCH-COH O +

Approximate “pKa” Values 50 40 30 20 10 pKa * CH3-CH2CH2CH2H ~ 52 sp3 C_ (best E-match C-H) CH3-CH2CH=CHH ~ 44 sp2 C_ (no  overlap) : (allylic) CH3-CH=C=CHH CH3-C C-CH2H ~ 38 C_ HOMO -  overlap (better E-match N-H) ~ 34 H2NH : sp C_ (no  overlap) CH3-CH2C CH ~ 25 (bad E-match O-H) 16 HOH * Values are approximate because HA1 + A2- = A1- + HA2 equilibria for bases stronger that HO- cannot be measured in water. One must “bootstrap” by comparing acid-base pairs in other solvents.

1st of 6 pages from http://evans. harvard. edu/pdf/evans_pKa_table 1st of 6 pages from http://evans.harvard.edu/pdf/evans_pKa_table.pdf Cf. http://research.chem.psu.edu/brpgroup/pKa_compilation.pdf

Problems for Wednesday: List factors that help determine pKa for an acid. Choose a set of several related acids from one of the pKa Tables or from your text (inside back cover of J&F), and explain what they teach about the relative importance of these factors. Explain your conclusions to at least one other class member and decide together how unambiguous your lesson is. Feel free to consult a text book and its problems or the references at the end of the Tables. Hint: this could provide a good exam question.

Nucleophilic Substitution and -Elimination Chapter 7 (Cf. Lecture 16) F H :OH F H OH "Acid-Base" F CH3 CH3 OH  "SN2 Substitution" ABN Make & Break Same F CH2 CH2 H :OH "E2 Elimination" ABN AON Make Two Break Two F H OH CH2

All are Nucleophilic Substitution Generalization All are Nucleophilic Substitution Williamson Ether Synthesis (1852) O- Na+ EtBr + OEt Br- * LUMO HOMO Exchange Ions (Double Decomposition) Finkelstein Reaction (1910) Na+ Cl- I- + RCl RI () acetone also RBr Na+ Br- Menschutkin Reaction (1890) Et3N + RI Et3N-R + I- + Create Ions Meerwein Reagent (1940s) RO- Na+ (CH3)3O BF4 + ROCH3 + Na+ BF4 + (CH3)3O - Destroy Ions Solvolysis (CH3)3C-Br EtOH HBr + (CH3)3C-OEt Breaking apart by solvent

Generality of Nucleophilic Substitution Solvent Nu: R-L Nu-R L (+) (-) Leaving Group Nucleophile Substrate Product But there are different mechanisms! + - Substitute SR2 for “OH” at C METHIONINE Substitute NHR2 for SR2 at C + OH : : CH3 ADENINE + H : OH ARGININE ARGININE Substitute NR2 for “OH” at C ADENOSINE H RIBOSE Biological Methylation Substitute Base for NR3 at H S-Adenosylmethionine (Protein Modification by Methyl Transferase, etc.)

End of Lecture 43 Jan. 24, 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