Embed Size (px)
Citation preview
Museum of Anatolian Civilizations, B.C. 2. centuryMuseum of Anatolian Civilizations, B.C. 2. century
Biyoteknolojik yöntemlerle kiral biyoaktif ürünlere
geçiş
YEŞİL KİMYA
AYHAN S. DEMIROrta Doğu Teknik ÜniversitesiAnkara [email protected]
KimyaOrganik kimya
Öldürür Güldürür AglatırBayıltırMutlu ederMutsuz ederHasta ederTedavi ederAşkın temelidir
Savaştırır
Barıştırır
Principles of Principles of Principles of Principles of Principles of Principles of Principles of Principles of greengreengreengreengreengreengreengreen chemistrychemistrychemistrychemistrychemistrychemistrychemistrychemistry
Green chemistry strategies target each stage of a product’s lifecycle to continually
improve its biological and ecological safety,reduce its energy consumption, and
eliminate the production of hazardous and product waste.
http://www.coeh.ucla.edu/Greenchemistry.pdf
�� � � �� � � �� �� � � � � � � � � � � � � � � � � � �
http://www.coeh.ucla.edu/Greenchemistry.pdf
� Of the 81,600 chemicals
in the TSCA inventory,
62,000 were not
subjected to review for
their potential hazards to
human health or the
environment. The U.S.
EPA found that 85% of
notices submitted by
producers for new
chemicals lacked health
effects data
http://www.coeh.ucla.edu/Greenchemistry.pdf
While the public perception is that plastics are recycled, in fact, plastic recovery
has hovered around 3 percent, while plastic waste generation grows steadily.
Source: U.S. EPA, 2005
http://www.coeh.ucla.edu/Greenchemistry.pdf
Environment
� � � � � � � �� �
Air and waterAir and waterAir and water contaminationcontaminationcontaminationcontamination
� California DTSC estimates
that 61 of 85 of the
state’s largest hazardous
waste sites are leaking
into groundwater. Of 51
sites inspected for
groundwater intrusion,
94% were found to
present, “a major threat
to human health or the
environment.
http://www.coeh.ucla.edu/Greenchemistry.pdf
� � � � � � � � � � � � � � � � �Breast milk contains many industrial chemicals, including methylene
chloride, toluene, trichloroethylene and xylene. While on balance breast
milk protects infant health, the potential effects of even minute amounts
of chemical contaminants in breast milk are of serious concern.
http://www.coeh.ucla.edu/Greenchemistry.pdf
� � � � � � � �
’ Health
The vast majority of chemicals to which children are commonly
exposed have never been examined for their long-term effects on
the developing brain.
http://www.coeh.ucla.edu/Greenchemistry.pdf
http://www.coeh.ucla.edu/Greenchemistry.pdf
The incidence of certain pediatric and reproductive health disorders is on the
rise, including hypospadias, reduced sperm count (variable by region), and the
childhood cancers that are most commonly linked to chemical exposures. Source:
Sharpe and Irvine, 2004, Surveillance Epidemiology and End Results (SEER)
Program 2004.
� � ! " # # $ % " & 'In 2004, more than 4,000 Californians died prematurely from
chronic diseases attributable to workplace chemical exposures.
http://www.coeh.ucla.edu/Greenchemistry.pdf
() * * + , - * . /0 1) 2offers many promises,
including substantial reductions in
the environmental footprint of many
chemical processes, improvements in
the health and safety of those
exposed to chemicals, and enhanced
security at facilities with hazardous
materials.
3 45 6 78 9 : ;5< 7=>Chemical designChemical designChemical design
• Formulate chemicals to
be effective while
reducing human and ecosystem toxicity
• Favor renewable
materials over fossil fuel
feedstocks where it
provides a net ecological gain
• Design chemicals to break down into
innocuous substances
after use
http://www.coeh.ucla.edu/Greenchemistry.pdf
Green chemistry can be summarized in five
points as;
less
safe
process-oriented
waste-reducing
sustainable
For a reaction to be green, it must;
• Use benign solvents or completely dispense with the solvent.
• Use alternate, more efficient and effective
reagents/catalysts.
• Optimize the reaction conditions by using cost-effective,
ecofriendly alternative processes.
Six methods exist for activating molecules
in chemical reactions;
Classical methods
thermal
photochemical
electrochemical
Nonclassical methods
sonication
mechanical
microwave
Comparison of the methodologies;
? � �� � � � @ � � A �B C � � � � � � � � � � �� � D� �� � � � �Ultrasound Vs. Thermal Assisted ReactionsUltrasound Vs. Thermal Assisted ReactionsUltrasound Vs. Thermal Assisted Reactions
ICOOMe
ULTRASOUND;
Pd(PPh3)4, NEt3, CH3CN,
C6H6, 50oC, )))), 6h
COOMeTHERMAL;
76% (stir, 80oC, 24h, 71%)
HP
O
OEtOEt
S
NH
CH3
ULTRASOUND;
PhCH3, )))), 80oC, 90min, >90%
THERMAL;Thermal reaction exhibits an induction period of ca. 1 h, then proceeds to give 50% of the adduct after 2 h.
P
O
OEtOEt
NH
HS
H3C
� � � � � � E� A �B C � � � � � � � � � � �� � D� �� � � � �Microwave Vs. Thermal Assisted ReactionsMicrowave Vs. Thermal Assisted ReactionsMicrowave Vs. Thermal Assisted Reactions
COOH H2SO4
(MW, 1min) (thermal, 80min)
CO2CH3
OMe HBr (MW, 1min)
(thermal, 72 hours)
OH
F 45 8 4 9 : :5> = 5< GH I ;5< 7=> 7> = 9< J> K 45 K 78 I H L K5 8 9>therefore be listed as;
• Minimize overall number of steps.
• Maximize yield per step.
• Maximize atom-economy per step.
• Use stoichiometric conditions.
• In multistep syntheses, perform the following:
Maximize frequency of condensations, MCRs, rearrangements, C-C
and non-C-C bond-forming reactions. Minimize frequency of substitutions (protecting group strategies) and redox reactions.
• If forced to use oxidations, opt for hydrogen peroxide as oxidant.
• If forced to use reductions, opt for hydrogen as reductant.
• Devise electrochemical transformations.
• Devise catalytic methods where catalysts are recycled and reused.
• Devise regio-/stereoselective synthetic strategies.
• Opt for solventless reactions, recycle solvents, or use benign solvents
(ionic liquids).
• Minimize energy demands: heating, cooling, reactions under pressure.
� � � � � � � � �
Green Chemistry
• Catalytic reagents reduce the energy of the
transition state, thereby reducing the energy
input required for a process.
• Catalysts are required in small quantities. In the
case of biocatalysts, the number of catalysts
(generally enzymes)needed compared to the
quantity of reactants is very low.
• The regeneration and reversibility of catalysts
are good for green processes.
CH3
OH
3 CrO3 H2SO4CH3
O
3 Cr2(SO4)3 6H2O
Jones oxidation of secondary alcohol
CH3
OH
1/2O2catalyst CH3
O
H2O
Atom-economical oxidation of secondary alcohol
• The use of zeolites in the manufacture of cumene is of immense
importance. About 7 million metric tons of cumene are produced
annually worldwide.
• The earlier-used process involved alkylation of benzene over a solid
phosphoric acid or an aluminum chloride catalyst.
• The Mobil/Badger cumene process (Mobil Technology Co., 1997)uses the less toxic carozine zeolite catalyst (see Fig. 3.7). In addition, it also generates less waste and requires less energy than
the earlier catalysts, thus simultaneously satisfying various
conditions of green chemistry.
Zeolite Catalyst
Mobil/Badger cumene process.
Synthesis of the anti-inflammatory drug naproxen
H3CO
CH3
O
1.CO2, electrolysis
2.H3O+
H3CO
CH3
OHCOOH
H2O
acid catalysis
chiral catalyst H3CO
CH2
COOHH2O
H3CO
CH3
COOH
BINAP [2,21-bis(diaryl phospheno)-
1,11-binaphthyl] is used
M � � � � C � � N � � � � �
GREEN CHEMISTRY
o The use of enzymes and microorganisms, which nature has developed,is undoubtedly an ideal choice toward "greening" chemical reactions.
o The industrial use of enzymes and microorganisms in food processing and in the production of fine chemicals, drugs, and detergents has been undergoing a drastic development in the last decades (Stinson, 1999; Thayer, 2001).
o Stereospecific synthesis - the main stay of biotransforma-
tions - is of immense importance in the drug industry, with an estimated market of about US$100 billion worldwide (Stinson, 1999; Krishna, 2002).
o Moreover, the homochiral drug market is expected to grow even bigger, increasing from having 25% to accounting for 70% of the total fine chemical market during the 21st century (Schulze and Wubbolts, 1999).
M �� � � � � � � � D� �� � � � E �B � � � � � � � D� �� � � �
M � � C D � � � O � D � � C � � � �Enzymes can carry out exquisitely selective chemistry that
is very difficult to achieve by conventional means; thus, they may offer many valuable advantages across a range
of industry sectors.
Which industry sectors benefit from biotransformations?Which industry sectors benefit from biotransformations?Which industry sectors benefit from biotransformations?Which industry sectors benefit from biotransformations?
• Pharmaceuticals
• Fine & Bulk Chemicals
• Food
• Cosmetics
P � � � �� � � � � � �� � � � � �� � � � � � What are the potential benefits of What are the potential benefits of What are the potential benefits of
biotransformations?biotransformations?biotransformations?biotransformations?
o Reduced cost of goods
o Environmentally friendly ('green' technology)
o Reduced by-products
o Cleaner effluent streams
o Shorter manufacturing routes
o Control/selection of required enantiomers by assymetric route development
o Chiral intermediates
o Resolution of racemic mixtures
o Eliminate need for heavy metals, high temperatures & pressures
o Neutral reaction conditions
o Natural processing
CHIRALITY
Chiral molecules are
chemically identical to each
other but possess unique
three-dimensional shapes,
making them mirror-images
that are not superimposable
on each other. Although
chemically identical, chiral
molecules may possess very
different biological properties
Enantiomers can be separated - or one of the two can be preferentially
produced - through the use of biotransformations
http://www.novactabio.com/biotrans.php
BIOCATALYTIC REACTIONSBIOCATALYTIC REACTIONSBIOCATALYTIC REACTIONSBIOCATALYTIC REACTIONSBIOCATALYTIC REACTIONSBIOCATALYTIC REACTIONSBIOCATALYTIC REACTIONSBIOCATALYTIC REACTIONS
ENZYMATICWHOLE
CELL
Patents:EU : 1297159, 2000WO: 02002753, 2002.
J. Chem. Soc., Perkin Trans. I, 2001, 633
Adv. Synth. Catal. 2002, 344, 96
Org. Lett. 2003, 5, 2047
Clean 2007
Benzaldehyde lyase from Benzaldehyde lyase from Pseudomonas fluorescensPseudomonas fluorescens Biovar I Biovar I (BAL (BAL
EC 4.1.2.38)EC 4.1.2.38)
Catalyzed EnantioselectiveCatalyzed Enantioselective
Synthesis of Hydroxy Ketones Synthesis of Hydroxy Ketones viavia Cleavage anCleavage and d FormationFormation ofof
AcyloiAcyloin n LinkageLinkage
91-99%eeGonzales, B; Vicuna, R. J. Bacteriol, 1989, 171, 2401
O
O
OCH3
OCH3
O
OH
OCH3
OCH3*
NH2
OH
O
OH*
P h eny lisoserin e(Ta xol sid e chain )
BAL BAL APPLICATIONSAPPLICATIONS
TAXOL
O
O
OHOO
O
OH O
O
OH H
O
NH
OH
O
OH
O
+
Baccatin III
Taxol Side Chain
NH
OH
O
O
O
O
O
OHOO
O
OH O
O
H
OTaxol
O
OH
Cl
O
OH
F
O
OHFF
SO2CH3FF F
N
Cl
O
HO
N
N
N O
H
HO
F
F
NH
F
F
N
N
N
N
S
CN
OH
Bupropion Sch 42427/ Sm9164 ER-303465
Ro 09-3355
1555U88
O
H
BAL
buffer/DMSO
acetaldehyde
O
OH
ee 97% - > 99%
cy: 80-98%
R R
Adv. Synthesis and Catalysis, 2002, 344, 96
Tetrahedron Asymmetry, 2001, 12, 1953
HN
O N
S
COOH
HH
O
Me2SiCl2
PhNMe2CH2Cl2
HN
O N
S
COOSiMe2
HH
OCl
CH2Cl2 -40oC
PCl5
N
Cl N
S
COOSiMe2
HH
OCl
1. ROH
2. H2O
+H3N
N
S
COO-
HH
O
6-APA
Synthesis of PenicillinSynthesis of PenicillinSynthesis of PenicillinSynthesis of Penicillin----GGGG
Classical Method
Bio-catalytic Method (Enzymatic)
HN
O N
S
COOH
HH
O
Penicillin
acylase
+H3N
N
S
COO-
HH
O
COOR
6-APA
� � � � � � � � � � � �� � � � �H3PO4
400-600 pSi
200-260oC
O2/ 80-130oC
SO2/ 60-100oC
OH O
70% H2O2
EDTAFe2+ or Co2+
70-80oC
OH
OH
OH
OH
Classical Method
O
OH
OH
OH
HOOH
E.coli AB2834/pKD136/pKD9.069 A
OH
OH
Bio-catalytic Method (Whole cell)
www.cbc.ca/consumers/market/files/cars/biodiesel/
Biodiesel Production
Biodiesel is biodegradable which means when it spills it
breaks down much faster than petroleum diesel
Biodiesel Pros
- It's renewable, because it's produced from natural sources
- Can help stop our dependence on foreign oil
- Can help stop global warming
- Biodiesel is safer to
store and transport than petroleum diesel
