Chemistry 125: Lecture 68April 14, 2010

HIO4 Cleavage; AlcoholsGrignard, Wittig Reactions

Green ChemistryMitsunobu Reaction

Acids and Acid DerivativesPreliminary

This

For copyright notice see final page of this file

TeleologyLectures 69 (4/15)

Determining Bond Strength by Prof. G. B. Ellison (Cf. Lect. 37,38)

Lecture 70-71 (4/18-20)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)

Vicinal Diol Cleavage by Periodic Acid

(e.g. J&F Sec. 16.14b p. 807)

IHIO4

H2SO4

I

“Ketal”

I

?

?C+1 C+2

I+7 I+5

Periodic Acid Cleavage of Carbohydrates as a Diagnostic Tool

CH2=O +OH

HC=OCH2=O + HCO2H

OH

OH

HOH2O

HIO4

HIO4

OH

OH 2 CH2=OHIO4

OH

OH

OH

HIO4

Formaldehyde (CH2O) arises from primary alcohols

Formic acid (HCO2H) arises from secondary alcohols

from F. E. Ziegler

OH

OH

CHOHIO4

OH

OH

OH

HIO42 CH2=O + HCO2H

CH2=O + 2 HCO2H

HIO4

OH

OH

O CH2=O + OH

CO2H HIO4CH2=O + CO2

• RCH2OH CH2=O

• R2CHOH HCO2H

• RCH=O HCO2H

CO2• R2C=O

Periodic Acid Cleavage of Carbohydrates as a Diagnostic Tool

from F. E. Ziegler

Periodic Acid Cleavage of Carbohydrates

HCO2H

HCO2HHCO2H

HCO2HHCO2H

H2COCH2OH

CHO

HOOHOH

OH

D-glucose

CH2OH

HOOHOH

CH2OH

HO

D-mannitol

H2CO

HCO2HHCO2HHCO2HHCO2H

H2CO

H2CO

HCO2HHCO2HHCO2H

H2CO

CO2

HOOHOH

CH2OH

O

OH

D-fructose

Periodic Acid Cleavage of Carbohydrates as a Diagnostic Tool

from F. E. Ziegler

Periodic Acid Cleavage of Methyl -Glucopyranoside

HOHO

HO

OHO

OCH3

OHO

OCH3

OHC

OHCHCO2H

HIO4

20°C24 hr.

H3O+

OH

OH

CHO

+ OHCCHO + CH3OH

D-glyceraldehyde

glyoxal Problem:What would other ring

sizes have given?from F. E. Ziegler

D

+

-

Alcohol (retro)Synthesis(e.g. J&F Secs. 16.13, 16.15)

Hydride Reduction(e.g. J&F Sec. 16.13 p. 802, Sec. 16.18)

H+

R-M = R-MgX , R-Li, etc.

+

- H+H H H

H

LiAlH4 NaBH4

H-M = H-AlH3 Li , H-BH3 Na, etc.- - ++

also NADH

simultaneous

Versatility of Grignard Reagents

R-OH R-Br R-MgBrPBr3 Mg

nucleophile? / electrophile?

Suggest high-yield syntheses incorporating carbon only from alcohols with no more

than three carbons and any other reagents.

(e.g. J&F problem 16.24)

H2C=O

PCC CH2Cl2

H3C-OH

n-C3H7-MgBr +

n-C2H5-MgBr +

H2C=CH2

mCPBA

NaOHD

CH3-MgBr + ?not in an activated position

Versatility of Grignard ReagentsSuggest high-yield syntheses incorporating

carbon only from alcohols with no more than three carbons and any other reagents.

(e.g. J&F problem 16.24)

nucleophile? / electrophile?

n-C3H7-MgBr +

PCC

CH 2Cl2

i-C3H7-MgBr +

n-C3H7-MgBr +

Is there a preferred order?

n-C3H7-MgBr +i-C3H7-MgBr +

“Versatility” of Grignard Reagent

1) CH3MgBrO

OH

CH3

95%

2) H+ / H2O MgBr

OH

t-Bu

0%

1) t-BuMgBr

2) H+ / H2OO

1) t-BuCH2MgBr

2) H+ / H2OO

OH

CH2-t-Bu

4%

OMgBrH

H

OH

65%

H- reduction

H-CH2-t-Bu

Ha

H-t-Bu+ ketone

35%

H+

+ enolate ketone90%

from Roberts & Caserio (1965)

Cf. 2 t-Bu t-Bu-H

+

no H

avoid steric hindrance

Ha

:-(

+

“Versatility” of Grignard Reagent

Risk of Reduction

no H

no reduction

Preferred

H

and steric

hindrance

(CH3)2C=CH2

Wittig Reaction(e.g. J&F Sec. 16.17)

Ph3P=O (100 kcal/mole)

vs.

(CH3)3N-O (70 kcal/mole)

Ph3P: CH3-BrpKa ~30

Ph3P-CH3 Br-+Ph3P-CH2

+ -Bu-Li

Ph3P=CH2

O=CR2

Ph3P-CH2

+

-O-CR2

Ph3P-CH2

O-CR2

Ph3P=O

H2C=CR2

Replaces O= directly

with H2C=+

CH3MgBrH+

minor

major

Pharmaceuticals generate < 0.2% of the chemical industry’s product mass, but some 25% of its $ value,

and >50% of its chemical waste.

Pharmaceuticals generate < 0.2% of the chemical industry’s product mass, but some 25% of its $ value,

and >50% of its chemical waste.

13 Processes That Need Improving

AstraZeneca, GSK, Lilly, Pfizer, Merck, Schering-Plough

(5 votes / company / area)

14 New Processes Desired

“Key green chemistry research areas - a perspective from pharmaceutical manufacturers”

Green Chemistry, 2007, 9, 411-420

Frequency of Use, Volume, Safety

SolventsSolvent-less reactor cleaning.

Replacements for NMP, DMAc, DMF.

“Lithium aluminum hydride, having a molecular weight of 38 and four hydrides per molecule, has the highest hydride density and is frequently used, even though it cogenerates an inorganic by-product which is difficult to separate from the product…slow filtration and product loss through occclusion or adsorption are typical problems…”

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

“…the use of stoichiometric high-valent metals (Mn, Os, Cr) have virtually been eliminated

from pharmaceutical processes…”

Votes

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

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

C

61% yield>99% inversion

great leaving group

pKa = 13

(enolate nucleophile)

HO COOH

COOH

C 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

H

O-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 + 2H2

with 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±1.0

AcOEt -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 13, 2011

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Biological Oxidation

NAD+ , NADH revisited (sec. 16.18)