CSO201A: Organic Chemistry:
Fundamentals and Applications
Instructors
Prof. Manas K. Ghorai and Dr. Ramkrishna Sarkar
Department of Chemistry, IIT Kanpur
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First Course Handout (FCH); Course-CSO201A: Organic Chemistry: Fundamentals and Applications,
Department of Chemistry, IIT Kanpur
Instructors: Prof. Manas K. Ghorai and Dr. Ramkrishna Sarkar
1. Course Content:
Olefin Metathesis: Catalysts and Catalysis (8 L): Introduction, Olefin metathesis, Catalysts types (Schrock, Grubbs-I, Grubbs-II),
Ring closing metathesis (RCM), Ring opening metathesis (ROMP), ene-yne metathesis, Industrial and Organic Synthesis
applications
Transition metal catalysed cross coupling reactions (8 L): Palladium based reactions such as Heck, Stille, Suzuki, Sonogashira,
Buchwald-Hartwig couplings; Tsuji-Trost C-C bond formations; Mechanism and stereochemistry of various coupling reactions.
Industrial and Organic Synthesis applications
Organocatalysis (8 L): Introduction, historical perspective, HOMO-Raising Organocatalysis (a-functionalisation of carbonyl
compounds; enamine organocatalytic activation mode; bifunctional vs. steric control; catalyst synthesis and reactivity.) LUMO-
Lowering Organocatalysis (β -functionalization of a-β unsaturated carbonyl compounds; iminium organocatalytic activation
mode)., Applications to synthesis of natural products
Visible Light Photocatalysis (8L): Introduction, An Overview of the Physical and Photophysical Properties of catalysts, Visible-
Light-Mediated Free Radical Synthesis, Atom Transfer Radical Addition using Photoredox Catalysis, Metal-Free Photo (redox)
Catalysis, Application of Visible-Light Photocatalysis in the Synthesis of Natural Products
Click chemistry (8L): Introduction, Mechanistic and synthetic perspectives, Various types of click chemistry, Applications of click
chemistry in the area of peptide, and nucleic acids, drug discovery, and development, Azide–alkyne click reaction in polymer
science 2
First Course Handout (FCH); Course-CSO201A
2a. Credits: L-T-P-A [C] – 3-1-0-0 [11], C=Credits (3L+1T+0P+0A)
L-Lectures p/w (per Week), T-Tutorial p/w, P-Practical p/w, A-Additional Classes p/w.
2b. Prerequisite: As per SPGC/SUGC
3. References:
1. Organic chemistry: Jonathan Clayden Nick Greeves and Stuart Warren.
2. Name reactions and reagents in organic chemistry: Bradford P. Mundy, Michael G. Ellerd and Frank G. Favaloro Jr.
3. Visible-Light Photocatalysis: Does It Make a Difference in Organic Synthesis? by Dr. Leyre Marzo, Dr. Santosh K. Pagire,
Prof. Dr. Oliver Reiser, Prof. Dr. Burkhard König https://doi.org/10.1002/anie.201709766
4. Transition Metal Catalyzed Cross-Coupling Reactions edited by Ioannis D. Kostas,
https://www.mdpi.com/books/pdfdownload/book/4714
5. Olefin Metathesis: Theory and Practice, Editor(s):Karol Grela, First published:2 May 2014 Print ISBN:9781118207949,
Online ISBN:9781118711613, DOI:10.1002/9781118711613
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First Course Handout (FCH); Course-CSO201A
4. Contact details of instructors:
Prof. Manas K. Ghorai,
Professor, Department of chemistry, IIT Kanpur, Email: mkghorai@iitk.ac.in
Address: Southern Lab SL-208C, Department of Chemistry, IIT Kanpur, Kanpur-208016 Phone: 91-512-2597518.
Dr. Ramkrishna Sarkar,
Assistant professor, Department of chemistry, IIT Kanpur, Email: ramkrishna@iitk.ac.in
Address: Room no: F B 435, Faculty Building, IIT Kanpur, Phone: 0512-259-2304.
5) Schedule and Venue:
Lectures are scheduled on Monday (M) and Wednesday (W) and Thursday (Th) at L18, from 12 P.M
Tutorials are scheduled on Friday (F) at L1, L2, L3, L4, L14 and L15 from 17.10
6) Evaluation:
Final Exam: 50%
Mid Semester: 35%
One quiz (surprise/announced) /assignment: 15%
7) Attendance policy: Minimum of 80% attendance is compulsory
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First Course Handout (FCH); Course-CSO201A
8) Grading Policy:
Marks 95 and above – A* Grade (Outstanding)
•Marks lie in [85, 94] – A Grade (Excellent)
•Marks lie in [75, 84]– B+ Grade (Very Good)
•Marks lie in [65, 74]– B Grade (Good)
•Marks lie in [55, 64] – C+ Grade (Fair)
•Marks lie in [45, 54] – C Grade (Satisfactory)
•Marks lie in [35, 44] – D+ Grade (Marginal)
•Marks lie in [30,34] – D Grade (Pass)
•Marks lie in [25,29] – E Grade (Exposure but Fail)
•Less than 24 marks – F Grade (Fail)
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Olefin Metathesis
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Metathesis
q A chemical reaction between two compounds in which parts are interchanged and form two new
compounds. It is also called a double displacement reaction
NaCl + AgNO3 → NaNO3 + AgCl
Olefin (alkene) metathesis
Ethylene
q Alkenes are also called olefins (oil-forming) as alkenes (smaller) form oily products when they are reacted with
chlorine or bromine
q In olefin metathesis the redistribution of alkenes substituents takes place
q Olefin metathesis is a reversible reaction.
q Olefin metathesis has several industrial applications
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2005 Nobel in chemistry; Olefin metathesis
q Robert H. Grubbs, Richard R. Schrock, and Yves Chauvin were awarded the 2005 Nobel Prize in Chemistry for
their contribution to olefin metathesis
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https://www.nobelprize.org/prizes/chemistry/2005/summary/
Classifications of metathesis reactions
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9.1.2023
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Olefin Metathesis: The Beginning
q In 1964, R. L. Banks and G. C. Bailey at Phillips Petroleum Company described olefin disproportionation converting propylene
to an equal mixture of ethylene and 2-butene.
2
Propylene Ethylene 2-butene
Catalysts: Molybdenum hexacarbonyl, tungsten hexacarbonyl, and molybdenum oxide
q In 1967, Nissim Calderon examined the disproportionation reaction of 2-pentene and coined the term “olefin metathesis”.
2-pentene 3-hexene 2-butene
Catalyst: Tungsten hexachloride (WCl6)and the organoaluminum compound (EtAlMe2)
Ind. Eng. Chem. Prod. Res. Dev. 1964, 3, 3, 170–173 11
Mechanism of Olefin Metathesis
q Calderon proposed two mechanisms: trans-alkylation and trans-alkylidenation.
Trans-alkylation: Exchange of the alkyl segment
Trans-alkylidenation: Exchange of the alkylidene segment
q The alcohol part in the ester group exchanges
with another alcohol
q Metathesis of 2-butene with its all-deuterated isotopologue confirmed a transalkylidenation mechanism.
Observed
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J. Am. Chem. Soc. 1968, 90, 15, 4133–4140
Chauvin’s mechanism
cyclopentene 2-pentene
q Chauvin (in 1971) examined the reaction of cyclopentene and 2-pentene with catalyst tungsten(VI) oxytetrachloride and
tetrabutyltin
q The three principal products C9, C10 and C11 were found in a 1:2:1 regardless of conversion.
Metallacycle
intermediate
q Chauvin proposed a four-membered metallacycle intermediate that explains the statistical distribution of products.
Die Makromolekulare Chemie. 141 (1): 161–176. doi:10.1002/macp.1971.021410112 13
Chauvin’s mechanism
Initiation R1
Same starting (Catalyst)
materials +
R2
2+ 2 cyclo addition Metallacycle New metal
of alkene and intermediate alkylidene
metal alkylidene
Propagation
2+ 2 cyclo addition Metallacycle Metathesis product
of alkene and intermediate
metal alkylidene
Overall mechanism
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Statistical distribution
Cross-metathesis-1 Cross-metathesis-2
2+ 2 addition of alkene Metallacycle Metathesis product
and metal alkylidene intermediate
Self-metathesis-1 Self-metathesis-2
Overall reaction
Product ratio
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Chemical reaction and Activation energy
A B ΔG=ΔH−TΔS ΔG = change in Gibbs free energy of
the reaction; ΔH = change in enthalpy
(Reactant) (Product) ΔG < 0 spontaneous reaction ΔS = change in entropy
ΔG> 0 nonspontaneous.
Activation energy (Ea): The minimum amount of extra energy required by a
reacting molecule to get converted into a product.
A
k=Ae−Ea/RT Arrhenius equation
K=rate constant, Ea = activation energy, R =gas constant, T =temp. (in K)
B
q The higher activation energy makes reaction slower
k=Ae−Ea/RT lnk=lnA−Ea/RT Arrhenius plot
q Ea can be determined from the Arrhenius plot
https://www.khanacademy.org/science/ap-biology/cellular-energetics/enzyme-structure-and-catalysis/a/activation-energy 16
Catalyst lowers the Activation energy
A B Catalyst ü Enhance the reaction
A B
(Reactant) (Product) feasibility
(Reactant) (Product)
ü Faster reaction
No reaction or too slow reaction
q Approximately 35% of the world's GDP is influenced by catalysis.
q The production of 90% of chemicals (by volume) is assisted by catalysts
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Catalyst in Olefin metathesis
q Olefin metathesis requires metal catalysts.
(Catalyst)
Catalyst
Heterogeneous catalysts Homogeneous catalysts
(Catalysts and reactants are in different phases) (Catalyst is in the same phase as the reactants)
q Often prepared by in-situ activation of a metal
halides (MClx) using organoaluminium or organotin
ü Schrock catalyst,
compounds,
ü Grubbs catalyst
(Nissim Calderon)
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11.1.2023
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Chauvin’s mechanism
(Catalyst)
Initiation
Dance of the “catalyst pair” and the “alkene pair”
2+ 2 cyclo addition Metallacycle New metal
of alkene and intermediate alkylidene
metal alkylidene
Propagation
The “catalyst pair” and the A united ring dance with one of leave their old partners and
“alkene pair” dance their hand holding onto the dance on with their new ones
previous partner
https://www.nobelprize.org/uploads/2018/06/popular-chemistryprize2005.pdf
2+ 2 cyclo addition of Metallacycle Metathesis product
alkene and metal intermediate
alkylidene 20
Chauvin’s mechanism in details
Initiation
1, 2 3, 4
Metallacycle New metal
intermediate alkylidene
Catalyst
1 2 3 4
2 3 4
1. The coordination of the olefin onto the metal atom
2. The shift of the coordinated olefin,
3. shifts of the to a new coordinated olefin
4. liberation
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Chauvin’s mechanism in details
Propagation
1, 2 Metallacycle
3, 4
Product
intermediate
1 2 3 4
2 3 4
1. The coordination of the olefin onto the metal atom
2. The shift of the coordinated olefin
3. shifts of the new coordinated olefin
4. liberation
Similar propagation for
will results in other metathesis product 22
Catalyst requirements
Challenges in metathesis: Most catalysts were undefined, sensitive to air and moisture, and also relatively short-
lived
Tunable
reactivity Stable
Catalyst
requirements
Metathesis in the presence of other functional
Tolerance of groups. The compound is important for anti-
Well-defined functional groups cancer activities.
These conditions are fulfilled by
ü Schrock catalyst,
ü Grubbs catalyst
Molybdenum-based Schrock catalysts Grubbs Catalyst® 1st Generation 23
Schrock catalyst
q In 1990, Schrock and co-workers reported the construction of a group of very active, well-defined molybdenum,
tungsten, and tantalum catalysts
Synthesis of tantalum-based Schrock catalyst
q Schrock catalysts are more active but sensitive to oxygen and moisture
q Reactivity and selectivity of metathesis reaction can be tuned by varying the ligands
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Metathesis using Schrock catalyst
Molybdenum-based Schrock catalysts Metathesis with Schrock catalysts
Advantages of Schrock’s catalyst
1.It has high activity
2.It is applicable to both terminal
and internal alkene.
Disadvantages of Schrock’s
catalyst
1.Poor functional group tolerance
2.This catalyst is very sensitive to
With a Schrock catalyst modified with a BINOL ligand, in a O2 and moisture.
norbornadiene ROMP leading to highly
, stereoregular cis,
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isotactic polymer.
E and Z selectivity
Z, from German zusammen = together
E from German entgegen = opposite
q A metathesis reaction results in six alkenes
q E alkane is more stable than Z, so E forms predominantly
q The inherent reversibility of olefin metathesis (products can re-enter the catalytic cycle) and the higher reactivity of Z alkenes
(versus E isomers) causes E forms predominantly 26
Z selectivity in cross metathesis using Schrock catalyst
q The free rotation of large monodentate aryloxide causes the incoming alkene to be oriented such that its substituent (R2) is
situated syn to that of the alkylidene (R1).
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Anti-tumor agent KRN7000
Anti-tumor and anti-cancer agent
a. Z selective Metathesis reaction
b. Diastereoselective dihydroxylation
q Z-Selective CM thus provides access to shorted route (9 steps than 14 otherwise) is the shortest synthesis of route KRN7000
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Nature, 2011, vol-471, 461-466 doi:10.1038/nature09957
12.01.2023
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Grubbs catalyst
(Catalyst)
q Grubbs catalysts are a series of ruthenium-based transition metal carbene complexes, less reactive than Schrock catalyst
But more selective
q Grubbs catalysts tolerate many functional groups, are air-tolerant and are compatible with a wide range of solvents
The first well defined ruthenium catalyst developed by Grubbs. It was prepared from
RuCl2(PPh3)4 and diphenylcyclopropene.
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SonBinh T. Nguyen, Lynda K. Johnson, and Robert H. Grubbs* J. Am. Chem. Soc. 1992, 114, 10, 3974–3975
Grubbs catalyst
First-generation Grubbs catalyst Preparation of first-generation Grubbs catalyst
q Grubbs’ catalysts are used in a daily basis as (standard) catalysts for metathesis
q The first-generation Grubbs catalyst was the first well-defined Ru-based catalyst. It is also important as a
precursor to all other Grubbs-type catalysts
Metathesis in the presence of other functional groups. The compound
is important for anti-cancer activities.
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Schwab, P.; France, M. B.; Ziller, J. W.; Grubbs, R. H. Angew. Chem. Int. Ed. 34 (18), 1995, 2039–2041. doi:10.1002/anie.199520391
Grubbs catalyst
Bewboubhf t pgHsvccỤt gjst uhf of sbujpo dbubm
zt u
1.It is easy to handle because it is stable to air and moisture.
2.It shows good functional group tolerance to
aldehyde, alcohol, and acids.
3. More selective
Disadvantages of Grubb’s first-generation catalyst
1. less reactivity as compared to the Schrock catalyst
2. The catalyst cannot be recycled and catalysts
contamination
3. Challenges with Ring-opening polymerization reaction First-generation Grubbs catalyst
4.This catalyst is not suitable for the preparation of tri,
tetrasubstituted olefins.
5.This is not useful for deactivated olefins.
6.Catalyst does not work well in presence of primary amines.
.
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Grubbs 2nd and 3rd generation catalyst
Grubb’s second-generation, one of the
Pcy3 groups are replaced with an N-
heterocyclic carbene ligand.
q Grubbs 2nd Gen catalyst has i jhi f s!bdujwjuz!
q Ring-closing metathesis of t uf sjdbm m
z!cvml z!
ejf of !boe!ef bdujwbuf e!pm
f gjot !is possible
by using this catalyst
Grubbs Catalyst®
1st Generation (M102) 2nd Generation (M204)
Grubbs Catalyst (third generation) M300
https://www.sigmaaldrich.com 33
Catalyst modifications are endless
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Polymer and block copolymer
Monomer
Dimer
A
Trimer
Tetramer Polyethylene (PE)
Polymer (homopolymer)
Polymerization B
Polymer Polyethylene (PE) Propylene (PP)
https://www.pslc.ws/macrog/kidsmac/basics.htm
(homopolymer)
Block copolymer of Polyethylene
Catalyst and Polypropylene (PE-b-PP)
≡ q The loss of ring strain is the driving force
Norbornene ROMP Polynorbornene (PNB)
(NB) q The Grubbs catalyst utilized for the copolymerization of norbornene
(homopolymer)
and 2,3-Dideuterio-norbornene
2,3-Dideuterio-norbornene (DDNB)
Catalyst
Polynorbornene (PNB) ROMP
(homopolymer) PNB-b-PDDNB
Grubbs Catalyst
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SonBinh T. Nguyen, Lynda K. Johnson, and Robert H. Grubbs* J. Am. Chem. Soc. 1992, 114, 10, 3974–3975
Cross metathesis (CM) and reactivity of olefins
The desired product will be a maximum yield of 50%, (homometathesis), 25% yield (each)
q The reactivity of one of the partners can be controlled by either electronic or steric factors in favor of CM
q Electron-rich olefins exhibit higher reactivity in metathesis
q One olefin can be added in excess
Grubbs catalyst
only One double
bond reacts
q Sterically hindered olefins are less reactive. 36
Application of self-metathesis (s-CM) to cross metathesis (CM)
q The Self-metathesis products are present in the reaction mixture and can be also converted into the expected CM
For the production of 9, alternative to using
olefins 10 or 11, “dimers” 12 or 13 can be
used.
Allylic alcohol
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Isomerization of olefin in metathesis
q C–C double bond could undergo isomerization (migration)
q Participation of the isomerized products in the metathesis can results in a large number of by-products
Isomerization problem in metathesis
q Grubbs ruthenium complexes results minimum isomerization
q Isomerization can be suppressed by using a variety of additives such as benzoquinones, phenols, or tin halides .
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