1. 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

2. From small difference of large numbers!
The Importance of Solvent for Ionic Reactions
E±Coulomb = / 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) 
BDE HO-H 120
pKa = 15.8
H2O (g)
6.3
21.5
H2O (aq)
H+(aq) + OH-(aq)

3. Brønsted Acidity Substitution at Hydrogen
ABN
F CH2
CH 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)

4. 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.

5. 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.

6. Factors that Influence Brønsted Acidity

7. Learning from pKa Values16 12 8 4
pKa -4
HOH
(BDE 119)
(BDE 91)
(BDE 136)
H3NH +
HSH FH
H2OH +

8. (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 ~ ~
BDE
~ -3
~ -5
~ -9 88 71

9. Learning from pKa Values16 12 8 4
pKa -4
HOH
H2OH +
HSH FH
H3NH
CH3-C-CH-C-CH3 O H
CH3-COH O
ClCH2-COH O
CH3
H3NCH-COH O +

10. 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 +

11. 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! pK 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 pK
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 +

12. Approximate “pKa” Values50 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.

13. 1st of 6 pages from http://evans. harvard. edu/pdf/evans_pKa_table
1st of 6 pages from Cf.

14. 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.

15. 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
CH H
:OH
"E2 Elimination"
ABN
AON
Make Two
Break Two F
H OH
CH2

16. 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

17. 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.)

18. End of Lecture 43 Jan. 24, 2011
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