Chemistry 125: Lecture 70April 18, 2011

Green ChemistryMitsunobu Reaction

Acids and Acid Derivatives This

For copyright notice see final page of this file

Rest of the YearLecture 71 (4/20)

Acid Derivatives and Condensations (e.g. F&J Ch. 18-19)

Lecture 72-73 (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)

New Processes Desired

Aromatic cross-coupling (avoiding haloaromatics) 6

Aldehyde or ketone + NH3 & reduction to chiral amine 4

Asymmetric hydrogenation of olefins/enamines/imines 4

Greener fluorination methods 4

Nitrogen chemistry avoiding azides (N3), H2NNH2, etc. 3

Asymmetric hydramination 2

Greener electrophilic nitrogen (not ArSO2N3, NO+) 2

Votes

Asymmetric addition of HCN 2

+ NH3 + NADH

H

H+ glutamic acid

Like Nature

Current Processes That Need Improving

Amide formation avoiding poor atom-economy reagents 6

OH activation for nucleophilic substitution 5

Reduction of amides without hydride reagents 4

Oxidation/Epoxidation (without chlorinated solvents) 4

Safer and more environmental Mitsunobu reactions 3

Friedel-Crafts reaction on unactivated systems 2

Nitrations 2

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 Nugreat leaving group

Oyo Mitsunobu(1934-2003)

O. Mitsunobu Synthesis (1981)

H

MitsunobuReaction

61% yield>99% inversion

pKa = 13

“active methylene” compound

Oyo Mitsunobu(1934-2003)

O. Mitsunobu Synthesis (1981)

HO C epimers?

mild

painful

HO COOH

COOH

2

CO2

C

29

PhP:1

“DEAD”2

MitsunobuReaction Oyo Mitsunobu

(1934-2003)

HAcO

(R)

HHO

(R)-OH

OHH

(S)

Allows correcting a synthetic “mistake”!

O. Mitsunobu Synthesis (1981)

MitsunobuInversion

Ph3PDEAD

AcOH

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)

(reduced DEAD)

Eliminating H2O (18 mol.wt.)

generates 450 mol.wt.of by-products.

“atom inefficient”

but complete separation requires chromatography!unless hooked to polymer beads

Three Nucleophiles“tuned” just right

OR2

H+H+HOR2

pKa < 15

if X- attacks P+, it comes off again

irreversible

Green Oxidation of Aldehydes and

Alcohols

Oil of Bitter

Almonds

BenzoicAcid

O2

Air Oxidation of Benzaldehyde

Cf. sec. 18.12a

but Ru-H won’tquite reach.

+

Reminiscent of closely balancedNAD+ NADH

GREEN

H

Milstein et al., J.A.C.S. 127, 10840 (2005)

H

H

HO-C-R

H

Catalytic Formation of Ester + H2

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!

H

H

H

H

H

+

H O-C-RH

H

H H

H H

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±1.0

AcOEt -114.8±0.2

H2 0

Hrxn 17.4endothermic!

but forming 3 molecules from 2 is favored

by entropyespecially at low pH2

Also Amines

Milstein et al., Angew. Chem. IEE. 17, 8661 (2008)

Imines, Amides, etc.

Acids and Acid Derivatives

This

Acidity of RCO2H (e.g. J&F p. 836)

pKa

4.8

4.5

4.1

2.8

4.8

2.9

1.3

0.7

-0.3

1.9

1.6

0.6

“Inductive Effect”

Additivity

Acidity of RCO2H (Rablen, JACS 2000)

Resonance

Resonance

Oind × 2

Oind

+ 34.1 = 3 Oind

Oind = 11.4Resonance = 4.8

Resonance Oind × 3

+39 (calc)

Resonance Oind × 2× 2

-13.2 (calc)

Resonance / InductiveNumerology

From this viewpoint only ~20% of the special acidity of the carboxylic acid

is due to resonance!

DpKa = 16 – 5 = 11

DHH2O = 4/3 * 11 = 15

localized chargemeans better solvation

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

R-Li & LiAlH4 (e.g. J&F Sec. 17.7f)

stop at C=O?

End of Lecture 70April 18, 2011

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