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Greener way to go .
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BITS Pilani, K K Birla Goa Campus
Background
Society
is suffering from E3
________________________________
Economic crises
Energy crises
Environment crises
>97% of all manufactured products
involve one or more chemical
processes
of the resources removed from the
Earth, only 10% are retained in the
product and 90% are waste
how do we reconcile these facts with
maintaining a healthy Environment?
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BITS Pilani, K K Birla Goa Campus
Selectively,
Economically, Safely
YES (ES)
GREEN CHEMISTRY
Traditional Reactions
Nucleophilic Substitution
Nucleophilic Addition
Friedel-Crafts Reaction
Grignard Reaction
Modern Reactions
Pericyclic Reaction
Diels Alder Reaction
Organometallic Reaction
Recent Development
C-H Activation Methodologies
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BITS Pilani, K K Birla Goa Campus
Cross-coupling:
Catalytic C-C bond formation
A coupling reaction in organic chemistry is a catch-all term
for a variety of reactions where two hydrocarbon fragments
are coupled with the aid of a metal catalyst with formation of
a new carbon-carbon bond in the product.
Cross-couplings involve reactions between two different
partners and homo- couplings couple two identical partners.
Heck reaction
Kumada coupling
Fukuyama Reaction
Buchwald-Hartwig reaction
Negishi coupling
Hiyama coupling
Ullmann reaction
BITS Pilani, K K Birla Goa Campus
Over the past four decades, organometallic coupling has been brought
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to a level of practical importance.
BITS Pilani, K K Birla Goa Campus
The Heck reaction is a substitution in which one H atom of the alkene starting
material is replaced by the R' group of the vinyl or aryl halide.
MX salts
M = B(OR)2, Suzuki
= ZnX, Negishi
= SnR3, Stille
= SiR3, Hiyama
= MgX, Kumada
Most popular and reliable Aromatic C-C bond formation reaction is Suzuki-
coupling reaction.
HX salts
[O]
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BITS Pilani, K K Birla Goa Campus
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O2N
B(OH)2
Cl
O2N
Pd cat.
Cl
Cl
N
Cl
O
HN
Cl
Suzuki coupling on a massive scale takes place in this BASF plant in So Paulo,
Brazil, where the fungicide Boscalid is manufactured.
BITS Pilani, K K Birla Goa Campus
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GREEN APPROACHES
Transition-Metal-Catalyzed Cross-Coupling Reactions
---Micellar Systems
--- Mechanochemical
Synthesis of TPGS-750-M
a family of
vitamin E
Lipshutz, B. H.; Chung, D. W.; Rich, B. Org. Lett. 2008, 10, 3793.
Gelman, D.; Buchwald, S. L. Angew. Chem., Int. Ed. 2003, 42, 5993.
Microwave Synthesis:
Heck Reaction
Microwave Synthesis:
Suzuki Reaction
Microwave Synthesis:
Negishi & Kumada Reaction
Organic mechanochemistry
Types of grinding apparatus
Advantages:
Hand-Grinding
Greener method;
Minimal to no use of solvents;
Use of ambient conditions;
Facile ways of product separation;
Ball-Milling
BITS Pilani, K K Birla Goa Campus
Mechanochemical Synthesis:
Heck Reaction
catalyst loading just 0.5 mol%
Simple thermal heating performs
poorly
Su and coworkers, Appl. Organomet. Chem., 2012, 26, 145
Mechanochemical Synthesis:
Suzuki Reaction
First Report
Mechanochemical Synthesis:
Sonogashira Reaction
First Report
Glaser reaction
CuI is good as catalyst for
alkyne homocoupling product
KFAl2O3 as the milling auxiliary
Glycerol as a Solvent
MizorokiHeck reaction:
Palladium nanoparticles catalyzed diarylation
of acrylate derivatives
Liu, C.; Ni, Q.; Bao, F.; Qiu, J. Green Chem. 2011, 13, 1260.
X
X = Cl, Br
Liu, W. -J.; Xie, Y. -X.; Liang, Y.; Li, J. -H. Synthesis 2006, 860.
Br
Kitamura, Y.; Sako, S.; Udzu, T.; Tsutsui, A.; Maegawa, T. Chem. Commun. 2007, 5069.
BITS Pilani, K K Birla Goa Campus
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FG
FG
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CH Bond Functionalization
What is CH Bond Functionalization/Activation?
(C)H bond is not a traditionally reactive bond (i.e. pka > 30-35);
Selectivity is a large issue due to the ubiquitous presence of C
H bonds in all organic molecules
BITS Pilani, K K Birla Goa Campus
CH Bond Functionalization
The number of publications on the topic of C-H functionalization (blue bars) and on
the synthesis of natural products and pharmaceuticals by CH functionalization
(red dots and line) between 1980 and 2011 (taken from Angew. Chem. Int. Ed. 2012,
51, 8960 9009)
BITS Pilani, K K Birla Goa Campus
Pioneering Work
H
C-H bond activation
Pd(0)
R1
[PdII]
H2[O]
Oxidation
[O]
PdII
R2
Reductive elimination
H
R1
PdII
R2
Shi, Z.; Li, B.; Wan, X.; Cheng, J.; Fang, Z.; Cao, B.; Qin, C.; Wang, Y. Angew. Chem. Int. Ed. 2007, 46, 5554.
BITS Pilani, K K Birla Goa Campus
yield up to 92%
65-100 equiv
cosolvent
Li, B.-J.; Tian, S.-L.; Fang, Z.; Shi, Z.-J. Angew. Chem. Int. Ed. 2008, 47, 1115.
BITS Pilani, K K Birla Goa Campus
18 examples
11-93% yield
Wang, D.-H.; Engle, K. M.; Shi, B.-F.; Yu, J.-Q. Science 2010, 327, 315.
BITS Pilani, K K Birla Goa Campus
Zhang, Y.-H.; Shi, B.-F.; Yu, J.-Q. J. Am. Chem. Soc. 2009, 131, 5072.
BITS Pilani, K K Birla Goa Campus
Enantioselective CH Bond
Activation: Recent Developments
Jin-Quan Yu has published two recent examples of desymmetrizing
aryl functionalization
Shi, B.-F.; Maugel, N.; Zhang, Y.-H.; Yu, J.-Q. Angew. Chem. Int. Ed. 2008, 47, 4882.
BITS Pilani, K K Birla Goa Campus
Enantioselective CH Bond
Activation: Recent Developments
Stereochemical model for desymmetrizing alkylation reaction
Shi, B.-F.; Maugel, N.; Zhang, Y.-H.; Yu, J.-Q. Angew. Chem. Int. Ed. 2008, 47, 4882.
BITS Pilani, K K Birla Goa Campus
Enantioselective CH Bond
Activation: Recent Developments
Another example published by Jin-Quan Yu
Shi, B.-F.; Zhang, Y.-H.; Lam, J. K.; Wang, D.-H.; Yu, J.-Q. J. Am. Chem. Soc. 2010, 132, 460.
BITS Pilani, K K Birla Goa Campus
Enantioselective CH Bond
Activation: Recent Developments
Bergman and Ellman have published a few examples of enantioselective
intramolecular cyclizations
Thalji, R. K.; Ellman, J. A.; Bergman, R. G. J. Am. Chem. Soc. 2004, 126, 7192.
Harada, J.; Thalji, R. K.; Bergman, R. G.; Ellman, J. A. J. Org. Chem. 2008, 73, 6772.
BITS Pilani, K K Birla Goa Campus
Enantioselective intramolecular
cyclizations
Bergman and Ellman proposition on mechanistic aspect
Harada, J.; Thalji, R. K.; Bergman, R. G.; Ellman, J. A. J. Org. Chem. 2008, 73, 6772.
BITS Pilani, K K Birla Goa Campus
Enantioselective intramolecular
cyclizations: a similar example
Bergman and Ellman proposition on mechanistic aspect
Tsai, A. S.; Wilson, R. M.; Harada, H.; Bergman, R. G.; Ellman, J. A. Chem. Commun. 2009, 3910.
BITS Pilani, K K Birla Goa Campus
H
metal free
Sun, C.-L.; Li, H.; Yu, D.-G.; Yu M.; Shi, Z.-J. Nature Chemistry 2010, 2, 1044.
1,10-phenanthroline
KOt-Bu
R
X
TC
Examples
NC
74%
36%
Ph
78%
89%
OMe
MeO
MeO
MeOC
83%
81%
73%
68%
BITS Pilani, K K Birla Goa Campus
MeO
H
MeO
N
MeO
MeO
H
I2 (10 mol%)
LiAlH4
MeO
N
dioxane
48%
MeO
MeO
N
THF
95%
MeO
( )-cryptophenrine
Iida, H.; Watanabe, Y.; Yanaka, M.; Kibayashi, C. J. Org. Chem. 1984, 49, 2412.
Mechanism is unknown
Natural product ()-cryptopleurine synthesis
Unactivated CH Bond
Oxidation
Oxidation of Arenes Using Molecular Oxygen
Zhang, Y.-H.; Yu, J.-Q. J. Am. Chem. Soc. 2009, 131, 14654.
BITS Pilani, K K Birla Goa Campus
Unactivated CH Bond
Oxidation
Directed Functionalization of Arenes with CF3 Groups
Nitrogen heterocycles act as directing groups
Wang, X.; Truesdale, L; Yu, J.-Q. J. Am. Chem. Soc. 2010, 132 (11), pp 36483649
BITS Pilani, K K Birla Goa Campus
R1
DDQ
R3
R3
R2
R2
Examples
78%
OMe
Br
68%
65%
Me
O
O
53%
30%
OH
40%
CH3
O
BITS Pilani, K K Birla Goa Campus
R1
O
Cl
CN
Cl
SET
CN
CN
Cl
CN
O
Cl
HO
R1
CN
CN
Cl
O
H
Cl
O
H
R1
R3
O
R2
R3
R2
O
R2
O
H
R3
OH
Cl
CN
Cl
CN
OH
BITS Pilani, K K Birla Goa15
Campus
sp -sp
Org. Lett.
2004, 6, 4997.
R1
R2 N
CH
R3
R4
R1
NH
R3
R1
R2 N
CH
R3
R2 N
CH
R4
N
H
R2 N
CH
R4
R1
R3
H
R6
R4
R5
R1
R2 N
CH H
R3
R1
R2 N
CH
Eur. J. Org. Chem.
R3
2006, 103, 8928.
sp3-sp2
R1
NO2
R4
NO2
H
EWG
H
R4
EWG
sp3-sp3
R4
R6
R5
R4
R2 N
CH
EWG
R3
EWG
sp -sp
R6
H C R
5
R4
1/2 O2
HOH
R1
R6
R2 C C
R5
R3
R4
HOH
Oxygen as a oxidant
[cat.] = [Fe], [Cu], or no catalyst
R1
R2
N
NO2
R1
R2
N
O2 (1 atm.)
H2O
R3
H2O
NO2
R3
CuBr (cat.)
R4
R1
CO2R5
R2
N
CO2R5
H2O
CO2R5
R3
CO2R5
Examples
N
Ph
NO2
90%
Me
90%
Ph
NO2
Me
NO2
95%
Ph
MeO
O
O
82%
Ph
OMe
N
EtO
O
Ph
OEt
O
80%
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BITS Pilani, K K Birla Goa Campus
Synthesis.
- C. -J. Li