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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