III

Outline

HOMOLUMO)






() Lewis

(+) Lewis


HCl + NaOH H-OH + NaCl

+ C N
N +

O
O

F
+
F B O +
F

F
F B

F F
F F
B

N+
N


(1s


(AO)(MO)
(LCAO)AO

AOMO


MO
MOAO



Nu E Nu E

 HOMOLUMO

HOMO LUMO
HOMOLUMO
O O
Nu
Nu



From nucleophile To electrophile
(Nu, or Nu) (E, or E+)

O, N, P, S

O N P S
H H H H Me Me Me Me
H Me

H O Me S Br

C N
Li

H H

H H

H+

Lewis
F Cl
F B Cl Al
F Cl

O Nu O
Nu

+
O + O H+ O
H

+
O Nu O
Nu
H H
 2
* SN2 H + H
H Br Nu H
Nu
+ H H
Cl H Nu
H H
+
Cl H Nu Nu Br Nu
H H
H H

* C-Br

*

HOMOLUMO

HOMOLUMO

**
 HSAB (Hard & SoL Acids & Bases)
Hard Nucleophile (low-energy HOMO, negaOve charge)
SoL Nucleophile (high-energy HOMO, not necessary negaOve charge)

Hard F, OH, RO, SO42
Cl, H2O, ROH, ROR, RCOR
Hard F, 3OH
NH , RO, RLi
, RMgBr, SO42
Borderline Cl3, H
N CN2O, ROH,2,ROR,
, RNH RNHRRCOR
NH
Br 3, RMgBr, RLi

Borderline
Soft IN,3RS
, CN , RNH
, RSe
2, RNHR
, S

Br RSR, R3P
RSH,
Soft I, RSaromatic
C=C, , RSe, Ssp2
2

RSH, RSR, R P
Hard Electrophile (high-energy LUMO, posiOve c3harge)
C=C, aromatic sp2
SoL Electrophile (low-energy LUMO, not n+ecessary p+ osiOve charge)
Hard + H , Li , K , Mg , Al , Ti4
+ + +

BF3, AlCl3
Hard H+, (Li+, K+, Mg+, Al+, Ti4+
HX )
Borderline BF2+
Cu 3,,AlCl
Zn2+3, Sn2+,
HX
R 3C (
+ )
Borderline
Soft Cu+2+, ,Ag
Zn+,2+Au
, Sn
+,2+
Hg, 2+,
R3 C
RS +,+RSe+,

Soft ICu +, Ag+, Au+, Hg2+,

2, Br 2

RS+, RSe+,
I2, Br2
HOMOLUMO
H
H H H Br
Br
+
Br
H H H Br
H

H
H H
N

+
H H
B
H


HOMO




* or *)


H H H H
+
SM O H N H +
TM

O + H N H
H
H H H

SM TM
O HO O
HO

H H
H Br + Br
+
Br

MeS
O Nu O Br
Nu
SMe

+ Br

B, C, N, O
H
+ +
Ph3P H3C I X Ph3P C I Ph3P H3C I Ph3P CH3 + I
H H

H
H H H H
E+ X H B E E+ H H
B B + H E
B
H H H H H H H

H
H H H
Nu
+N X Nu N H Nu H H N + Nu H
+N
H H H H H H
H H

Williamson ether synthesis

HO R

H+ + H +
R OH R O R O R H+ R O R
H H2O
H


(Push)

O HO O
HO

(Pull)

H
H Br
+

+ N
N + OH
H2O
N2


SMTM




TM







TM



O H3O+ O

Ph OH EtOH Ph OEt

H H
+ H H H
O O O
+
H H O O
O H + H H H
O
OH2 Ph OH Ph O
Ph OH Ph + OH +
Ph OH O O O H
HO Et Et Et
Et H

H OH2 O
+
O
Et Ph OEt
Ph O


O O
NaOEt
Ph OEt EtOH Ph OH

O OH O OH
O O HCl O
Ph OEt Ph OEt Ph OEt Ph O Ph OH
O O
H

 pKa
O
O O
+ OH + H H
H

pKa = 20 pKaH = 16

O
Bu H + OH Bu + H H

pKa = 25 pKaH = 16

pKapKaH
pKaH (base) > PKa (Acid)

H H H
H+ H O O
O + O
O R2 R2 H+ R2
R2 R2 R1 +N R1 N R1 N+
R1 H+ H
N R1 N OH OH O H
H H O H H H
H
H H

+
H O
O
H+ R1 OH
R1 OH
+
H+ H3N+R2
H2NR2

H+ + H H
O O O O O
H+
R2 R2 + R2 R2 + R2
R1 N R1 N R1 N R1 N R1 N H
H H H
H H


O 10% NaOH aq O

R1 NH2 100 C, 3 h R1 O

O O O O
H
R1 NH2 NH R1 O R1 O
R1 NH2 2
OH OH OH

OH (pKaH 15)NH2 (pKaH 35)NH2

O KOt-Bu (6 equiv) O Ot-Bu (pK 19)

aH
Ph NMe2 DMSO-H2O, rt Ph OH

then, HCl aq

Ot-Bu

O O
O O
O H O
Ph NMe2 Ph NMe2 NMe 2
Ph NMe2 Ph O
OH

NaOH H2SO4
Ph CO2H Ph CN Ph CO2H
H2O, 100 C H2O, 100 C, 3 h

H+ H H+ O +
Ph Ph + + Ph H O
N N O +
Ph H
H Ph H H+ N
NH2
O N H H
H H H
O
Ph Ph CO2H
H+
NH2

O H+
Ph H O O
Ph Ph Ph
N N H+ NH NH2
OH
H H
O

Mandelic Acid Extract of almond

O NaCN, HCl OH H2SO4 OH

Ph H H2O Ph CN H2O Ph CO2H