1. Mitsunobu Reaction Acids and Acid Derivatives
Chemistry 125: Lecture 70 April 18, Green Chemistry
Mitsunobu Reaction Acids and Acid Derivatives
This
For copyright notice see final page of this file

2. Rest of the Year Lecture 71 (4/20) Lecture 72-73 (4/22,25)
Acid Derivatives and Condensations (e.g. F&J Ch )
Lecture (4/22,25)
Carbohydrates - Fischer's Glucose Proof (e.g. F&J Ch. 22)
Lecture 74 (4/27)
Synthesis of an Unnatural Product (Review)
(Anti-Aromatic Cyclobutadiene in a Clamshell)
Lecture 75 (4/29)
Synthesis of a Natural Product (Review)
(Woodward's Synthesis of Cortisone)

3. Like Nature New Processes Desired Votes
Aromatic cross-coupling (avoiding haloaromatics)
Aldehyde or ketone + NH3 & reduction to chiral amine
Asymmetric hydrogenation of olefins/enamines/imines
+ NH3 + NADH H H+
glutamic acid
Greener fluorination methods
Like Nature
Nitrogen chemistry avoiding azides (N3), H2NNH2, etc
Asymmetric hydramination
Greener electrophilic nitrogen (not ArSO2N3, NO+)
Asymmetric addition of HCN

4. Current Processes That Need Improving
Votes
Amide formation avoiding poor atom-economy reagents
OH activation for nucleophilic substitution
Reduction of amides without hydride reagents
Oxidation/Epoxidation (without chlorinated solvents)
Safer and more environmental Mitsunobu reactions
Friedel-Crafts reaction on unactivated systems
Nitrations

5. Mitsunobu Reaction Oyo Mitsunobu Ph3P O R Nu- Very general for
( )
Mitsunobu Reaction
Ph3P O R
Nu-
Very general for
acidic Nu-H (pKa < 15)
e.g.
R-CO2-
(RO)2PO2-
(RCO)2N-
N3-
“active methylene compounds”
Ph3P O
R Nu
great leaving group
O. Mitsunobu Synthesis (1981)

6. Mitsunobu Reaction Oyo Mitsunobu mild painful C epimers? (1934-2003)
PhP: 1
“DEAD” 2
mild
COOH
pKa = 13 2
CO2
painful HO C
C epimers? H HO
COOH
“active methylene” compound
61% yield
>99% inversion 29
O. Mitsunobu Synthesis (1981)

7. O. Mitsunobu Synthesis (1981)
Oyo Mitsunobu
( )
Mitsunobu Reaction OH H
(S) H
AcO
(R) H HO
(R)
Mitsunobu Inversion
Ph3P
DEAD
AcOH
-OH
Allows correcting
a synthetic “mistake”!
O. Mitsunobu Synthesis (1981)

8. Mitsunobu Mechanism HOR2 Ph3P H OR Ph3P O R Nu- Ph3P O R Nu
Three Nucleophiles
“tuned” just right
O. Mitsunobu Synthesis (1981)
Mitsunobu Mechanism
Diethylazodicarboxylate
(DEAD) -3
Ph3P
H OR
need an oxidizing agent
pKa < 15
Nu-
Ph3P O R
Ph3P O
R Nu
great leaving group -1
OR2
if X- attacks P+,
it comes off again
HOR2
but complete separation requires chromatography! H H+ +
unless hooked to polymer beads
Eliminating H2O (18 mol.wt.)
generates 450 mol.wt.
of by-products.
“atom inefficient”
(reduced DEAD)
irreversible

9. Green Oxidation of Aldehydes and Alcohols

10. Benzoic Acid O2
Oil of Bitter Almonds

11. Air Oxidation of Benzaldehyde
Cf. sec a

12. Catalytic Formation of Ester + H2
O-C-R H
O-C-R H H H H H +
Reminiscent of
closely balanced
NAD NADH
Another oxidation involving analogous removal of H2 from RCH(OH)2 plus
some kind of C-O coupling, completes
2 R-CH2-OH  R-CO2-CH2R + 2 H2 +
with no other activation!
but Ru-H won’t
quite reach.
GREEN
Milstein et al.,
J.A.C.S. 127, (2005)

13. Catalytic Formation of Ester + H2
Thermochemistry of 2 EtOH  AcOEt + 2 H2
Hf
HOEt ±0.5
x ±1.0
AcOEt ±0.2 H
Hrxn
endothermic!
but forming 3 molecules from 2 is favored
by entropy
especially at low pH2
Milstein et al.,
J.A.C.S. 127, (2005)

14. Also Amines Imines, Amides, etc. Milstein et al., Angew IEE 2008, 8661
Angew. Chem. IEE. 17, 8661 (2008)

15. Acids and
Acid Derivatives
This

16. Acidity of RCO2H (e.g. J&F p. 836)
Additivity
pKa
4.8
4.5
4.1
2.8
4.8
2.9
1.3
0.7
1.9
1.6
0.6
“Inductive Effect”
-0.3

17. Acidity of RCO2H (Rablen, JACS 2000)
Resonance / Inductive
Numerology
From this viewpoint only ~20% of
the special acidity of the carboxylic acid is due to resonance!
Resonance
Oind
× 2
DpKa = 16 – 5 = 11
localized charge
means better solvation
Resonance
Oind
DHH2O = 4/3 * 11 = 15
= Oind
Resonance = 4.8
Oind = 11.4
Resonance
Oind
× 3
+39 (calc)
Resonance
× 2
Oind
× 2
-13.2 (calc)

18. Making RCO2H by Oxidation and Reduction (e.g. J&F Sec. 17.6)

19. R-Li & LiAlH4 (e.g. J&F Sec. 17.7f) stop at C=O?

20. End of Lecture 70 April 18, 2011
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