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Chemistry 125: Lecture 68
April 13, 2010
HIO4 Cleavage; Alcohols
Grignard, Wittig Reactions
Green Chemistry
This
For copyright
notice see final
page of this file
Rest of the Year
Lectures 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)
I
“Ketal”
I+7
I
I
I+5
HIO4
H2SO4
C+1
?
pinacol
Wittig
?
O
?3
C+2
Periodic Acid Cleavage of Carbohydrates as a Diagnostic Tool
OH
HIO4
OH
OH
OH
OH
HIO4
2 CH2=O
HC=O
HIO4
CH2=O +
CH2=O +
OH
H2O
HO
OH
HIO4
HCO2H
OH
Formaldehyde (CH2O) arises from primary alcohols
Formic acid (HCO2H) arises from secondary alcohols
from F. E. Ziegler
Periodic Acid Cleavage of Carbohydrates as a Diagnostic Tool
OH
OH
OH
HIO4
2 CH2=O +
HCO2H
CHO
OH
HIO4
CH2=O +
2 HCO2H
• RCH2OH
CH2=O
• R2CHOH
HCO2H
• RCH=O
HCO2H
• R2C=O
CO2
OH
OH
O
OH
from F. E. Ziegler
HIO4
CO2H HIO
4
CH2=O +
CH2=O +
OH
CO2
Periodic Acid
Periodic
Cleavage
Acid of
Cleavage
Carbohydrates
of Carbohydrates
as a Diagnostic Tool
CHO
OH
HO
OH
OH
CH2OH
HCO2H
HCO2H
HCO2H
HCO2H
HCO2H
O
D-glucose
CH2OH
HO
HO
OH
OH
CH2OH
D-mannitol
from F. E. Ziegler
OH
H2CO
HO
H2CO
HCO2H
HCO2H
HCO2H
HCO2H
H2CO
OH
OH
CH2OH
D-fructose
H2CO
CO2
HCO2H
HCO2H
HCO2H
H2CO
Periodic Acid Cleavage of Methyl -Glucopyranoside
OH
OH
HIO4
O
HO
HO
O
OHC
20°C
24 hr.
HCO2H OHC
HO
OCH3
H3
O+
OCH3
D
CHO
OH
+
OH
D-glyceraldehyde
from F. E. Ziegler
OHCCHO
glyoxal
+
CH3OH
Problem:
What would other ring
sizes have given?
Alcohol (retro)Synthesis
(e.g. J&F Secs. 16.13, 16.15)
R-M = R-MgX , R-Li, etc.
+
H+
simultaneous
Hydride Reduction
LiAlH4
NaBH4
(e.g. J&F Sec. 16.13 p. 802, Sec. 16.18)
+
+
H-M = H-AlH3 Li , H-BH3 Na, etc.
H
also NADH
+
H
-
H
H+
H
Versatility of Grignard Reagents
Suggest high-yield syntheses incorporating
carbon only from alcohols with no more
than three carbons and any other reagents.
nucleophile? / electrophile?
n-C3H7-MgBr
n-C2H5-MgBr
CH3-MgBr
R-OH
PBr3
(e.g. J&F problem 16.24)
+
+
?+
H2C=O
PCC CH2Cl2
H3C-OH
mCPBA
not in an
NaOH H2C=CH2
activated position
D
Mg
R-Br
R-MgBr
Versatility of Grignard Reagents
Suggest high-yield
syntheses
incorporating
nucleophile?
/ electrophile?
carbon only from alcohols with no more
than three carbons and any other reagents.
n-C3H7-MgBr +
i-C3H7-MgBr
n-C3H7-MgBr
+
+
n-C33HH77-MgBr
i-C
-MgBr ++
Is there a preferred order?
(e.g. J&F problem 16.24)
“Versatility” of Grignard Reagent
1) CH3MgBr
O
2) H+ / H2O
Cf. 2 t-Bu  t-Bu-H
avoid steric +
hindrance
CH3
O
+
H MgBr
MgBr
OH
95%
H- reduction
1) t-BuMgBr
t-Bu
OH
2) H+ / H2O
OH
H
H
O
0%
H
O
no H
1) t-BuCH2MgBr
2) H+ / H2O
65%
CH2-t-Bu
OH
35%
H-CH2-t-Bu
H+
+ enolate  ketone
:-(
4%
H-t-Bu
+ ketone
90%
from Roberts & Caserio (1965)
“Versatility” of Grignard Reagent
(CH3)2C=CH2
Risk of
Reduction
H
and steric
hindrance
Preferred
no H
no reduction
Wittig Reaction
Ph3P=CH2
(e.g. J&F Sec. 16.17)
Ph3P:
CH3-Br
+
Ph3P-CH3
pKa ~30
Br-
Bu-Li
+
Ph3P-CH2
Ph3P=O (100 kcal/mole)
vs.
O=CR2
(CH3)3N-O (70 kcal/mole)
Ph3P=O
H2C=CR2
Replaces O=
directly
with H2C=
-
Ph3P-CH2
O-CR2
CH3MgBr
+
Ph3P-CH2
-O-CR
2
H+
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.
“Key green chemistry research areas a perspective from pharmaceutical manufacturers”
Green Chemistry, 2007, 9, 411-420
AstraZeneca, GSK, Lilly, Pfizer, Merck, Schering-Plough
Frequency of Use, Volume, Safety
Solvents
Solvent-less reactor cleaning.
Replacements for NMP, DMAc, DMF.
13 Processes That Need Improving
14 New Processes Desired
(5 votes / company / area)
Current Processes That Need Improving
Votes
Amide formation avoiding poor atom-economy reagents
6
OH activation for nucleophilic substitution
5
Reduction of amides without hydride reagents
4
“Lithium aluminum hydride, having a molecular weight of 38 and four
Oxidation/Epoxidation
chlorinated
solvents)
4
hydrides
per molecule, has(without
the highest
hydride density
and is frequently
used, even though it cogenerates an inorganic by-product which is
difficult
to separate
the product…slow
filtration metals
and product loss
“…the
use offrom
stoichiometric
high-valent
Safer and
more environmental
Mitsunobu
reactions
3
through
occclusion
or
adsorption
are
typical
problems…”
(Mn, Os, Cr) have virtually been eliminated
from pharmaceutical processes…”
Friedel-Crafts reaction on unactivated systems
2
Nitrations
2
End of Lecture 68
April 13, 2011
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J. M. McBride, Chem 125. License: Creative Commons BY-NC-SA 3.0