Chemistry 125: Lecture 68
April 14, 2010
Mitsunobu Reaction
Acids and Acid Derivatives
This
For copyright
notice see final
page of this file
Teleology
Lectures 69-70 (4/16,19)
Topics from Chapters 18-19 - Acid Derivatives and Condensations
Lecture 71 (4/21)
Topics from Ch. 22 - Carbohydrates
Lecture 72 (4/23,26?)
guest lecture(s) by Prof. Ziegler
Carbohydrates - Fischer's Proof of the Configuration of Glucose
Lecture 73 (4/28)
Synthesis of an Unnatural Product (Review)
(Anti-Aromatic Cyclobutadiene in a Clamshell)
Lecture 74 (4/30)
Synthesis of a Natural Product (Review)
(Woodward's Synthesis of Cortisone)
“Key green chemistry research areas - a perspective from pharmaceutical manufacturers”
Green Chemistry, 2007, 9, 411-420
Table 1 Reactions companies use now but would strongly prefer better reagents
Research Area
Number of roundtable companies voting
for this research area as a priority area
Amide formation avoiding poor atom economy reagents
6 votes
OH activation for nucleophilic substitution
5 votes
Reduction of amides without hydride reagents
4 votes
Oxidation/Epoxidation methods without the use of chlorinated solvents
4 votes
Safer and more environmentally friendly Mitsunobu reactions
3 votes
Friedel-Crafts reaction on unactivated systems
2 votes
Nitrations
2 votes
Mitsunobu
Reaction
Oyo Mitsunobu
(1934-2003)
Ph3P O R
Nu-
Allows correcting a synthetic “mistake”!
Very general
for
AcO
H
OH
acidic Nu-H
H
(S)
Ph3P O
R Nu
great leaving group
pKa = 13
C
(enolate nucleophile)
-CO2
HO
61% yield
C
epimers? >99% inversion
COOH
C C
COOH
(pKa <(R)15)
HO
-OH
H
(R)
e.g.
R-CO2(RO)2PO2-
Mitsunobu
N
“active methylene
compounds”
Inversion
(RCO)2N3
-
O. Mitsunobu
Synthesis (1981)
Mitsunobu
Mechanism
Three Nucleophiles
“tuned” just right
Diethylazodicarboxylate
(DEAD)
-3
Ph3P
H OR
need an oxidizing agent
Ph3P O R
-1
NuH+
Ph3P O
R Nu
great leaving group
but separable only by chromatography!
unless hooked to polymer beads
Eliminating H2O (18 m.wt.)
generates 450 m.wt.
of by-products.
“atom inefficient”
2
HOR
(reduced DEAD)
O. Mitsunobu
Synthesis (1981)
Acidity of RCO2H
(p. 836)
Making RCO2H by
Oxidation and Reduction (sec. 17.6)
RCOO-H to RCOO-R’ (p. 848)
Activating RCO2H (sec. 17.7b,d,e)
making OH a leaving group
Catalytic Formation of Ester + H2
H
H
O-C-R
H
H
H O-CH2-R
H
H
3
H
Another oxidation involving removal of
an H from RCHO and one from another
RCH2OH, plus C-O coupling, completes
2 R-CH2-OH  R-CO2-CH2R + 2H2
with no other activation!
GREEN
H
H
Milstein et al.,
J.A.C.S. 127, 10840 (2005)
Catalytic Formation of Ester + H2
Thermochemistry of
2 EtOH  AcOEt + 2 H2
Hf
HOEt
x2
-66.1±0.5
-132.2±1.0
AcOEt -114.8±0.2
H2
0
Hrxn
17.4
endothermic!
K3/2 RmT  10-1/2 17.4
 10-9
need pH2 > 10-9 atm
Milstein et al.,
J.A.C.S. 127, 10840 (2005)
Also Amines
Imines, Amides, etc.
Milstein et al.,
Angew. Chem. IEE. 17, 8661 (2008)
Benzoic
Acid
O2
Oil of
Bitter
Almonds
Air Oxidation of Benzaldehyde
Cf. sec. 18.12a
R-Li & LiAlH4 (sec. 17.7f)
stop at C=O?
End of Lecture 68
April 14, 2010
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