Chemistry 125: Lecture 68April 14, 2010
Mitsunobu ReactionAcids and Acid Derivatives This
For copyright notice see final page of this file
TeleologyLectures 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)
Table 1 Reactions companies use now but would strongly prefer better reagents
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
Friedel-Crafts reaction on unactivated systems 2 votes
Nitrations 2 votes
“Key green chemistry research areas - a perspective from pharmaceutical manufacturers” Green Chemistry, 2007, 9, 411-420
Research AreaNumber of roundtable companies voting for this research area as a priority area
Safer and more environmentally friendly Mitsunobu reactions 3 votes
Very general for acidic Nu-H
(pKa < 15)
e.g.
R-CO2-
(RO)2PO2-
(RCO)2N-
N3-
“active methylene compounds”
MitsunobuReaction
Nu-Ph3P O R
Ph3P O R Nu
C61% yield
>99% inversion
great leaving group
pKa = 13
(enolate nucleophile)
HO COOH
COOHC epimers?
-CO2
C
C
Oyo Mitsunobu(1934-2003)
HAcO
(R)
HHO
(R)-OH
OHH
(S)
MitsunobuInversion
Allows correcting a synthetic “mistake”!
O. Mitsunobu Synthesis (1981)
MitsunobuMechanism
O. Mitsunobu Synthesis (1981)
Nu-Ph3P O R
Ph3P O R Nugreat leaving group
Ph3P H OR-3
-1
need an oxidizing agent
Diethylazodicarboxylate(DEAD)
H+
(reduced DEAD)
Eliminating H2O (18 m.wt.)
generates 450 m.wt. of by-products.
“atom inefficient”
but separable only by chromatography!unless hooked to polymer beads
Three Nucleophiles“tuned” just right
HOR2
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
GREEN
H
Milstein et al., J.A.C.S. 127, 10840 (2005)
H O-CH2-RH
H
HO-C-R
H
Catalytic Formation of Ester + H2
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 + 2H2with no other activation!
H
H
H
H
H
3
Milstein et al., J.A.C.S. 127, 10840 (2005)
Catalytic Formation of Ester + H2
Thermochemistry of2 EtOH AcOEt + 2 H2
Hf
HOEt -66.1±0.5 x 2 -132.2±1.0AcOEt -114.8±0.2
H2 0
Hrxn 17.4endothermic!
K3/2 RmT 10-1/2 17.4
10-9
need pH2 > 10-9 atm
Also Amines
Milstein et al., Angew. Chem. IEE. 17, 8661 (2008)
Imines, Amides, etc.
Oil of Bitter
Almonds
BenzoicAcid
O2
Air Oxidation of Benzaldehyde
Cf. sec. 18.12a
R-Li & LiAlH4 (sec. 17.7f)stop at C=O?
End of Lecture 68April 14, 2010
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