Chemistry 125: Lecture 68 April 14, 2010 HIO 4 Cleavage; Alcohols Grignard, Wittig Reactions Green Chemistry Mitsunobu Reaction Acids and Acid Derivatives Preliminary This For copyright notice see final page of this file
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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)
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