physical chemistry

1. CH 3029: Organic
Chemistry
Dr. Dinesh Aluthge
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2. Syllabus
Reaction Mechanisms: Review of reaction mechanisms, use of curved arrows to describe
mechanisms; substitution reactions - SN1, SN2, and SNi mechanisms, neighboring group
participation; the non-classical carbocation; elimination reactions - E1, E2, and E1cb
mechanisms; review of electrophilic and other addition reactions of alkenes, electrophilic
and nucleophilic aromatic substitutions, and nucleophilic addition reactions of aldehydes
and ketones.
Physical Organic Chemistry: The Hammett equation: applications, free energy diagrams;
failures and modifications Hammett equation; Yukawa – Tsuno equation and its applications.
Taft equation. steric effects in organic reactions, solvent effects, conformational effects,
Curtin-Hammett principle; isotope effects, stereo-electronic effects.
Organic Synthesis: Retrosynthetic analysis of organic molecules - disconnections and
synthons; methods for forming C–C single and C=C double bonds; use of enolates,
enamines, organolithium, -magnesium, and -copper compounds; stereoselectivity and
regioselectivity; umpolung; 1,2-, 1,3-, 1,4-, and 1,5-dioxygenated systems, aldol and Claisen
condensations, and the Michael addition; techniques of forming 3-, 4-, 5-, and 6-membered
rings; coupling reactions; synthesis of C-N and C-O bonds; protecting groups; oxidations and
reductions; examples of syntheses of somewhat complex molecules.
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3. Organic synthesis
● Synthesis is the intentional construction of molecules usually in a
laboratory or industrial setting.
● Organic synthesis is a branch of synthesis where molecules primarily
composed of carbon are made.
● An important area of organic synthesis is the total synthesis of molecules
which refers to the complete synthesis of complex molecules, often
natural products from simple, commercially available starting material.
● Organic synthesis also involves the development of new reactions to carry
out various transformations. This is referred to as methodology in organic
synthesis.
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4. Total synthesis and methodology
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Total synthesis
● Total synthesis often necessitates the development new methodologies while
advances in methodology allows for more challenging total syntheses to be
possible
Methodology

5. History of organic synthesis
● Before the early 1800s a widely held belief was that chemicals that are
found in living organisms could not be synthesized in a lab as it required a
“vital force” that could be found in living beings.
● Synthesis of urea by Friedrich Wöhler in 1828 was the first widely
reported example of a laboratory synthesis of a natural product.
● This and the 1845 synthesis of acetic acid by Hermann Kolbe ended the
mainstream acceptance of the theory of vitality.
● After this by the early 20th century many natural products including
camphor and acetylsalicylic acid (Aspirin)
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6. History of organic synthesis
● In subsequent year improvements in synthetic methodology allowed for
the synthesis of more complex molecules including synthetic dyes and
pharmaceuticals such as quinine.
● Some important milestones in synthetic methodology are discovery
Friedel-Crafts alkylation/acylation and development of Grignard reagents
(1912 Nobel Prize in Chemistry for Victor Grignard).
● By 1950 many important C-C bond forming reactions including the Diels-
Alder reaction had been reported.
● In the 1950/1960s R.B. Woodward (1965 Nobel Prize) from Harvard
University led a movement that targeted the total synthesis of highly
complex molecules including vitamin B12.
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8. History of organic synthesis
● Since then, significant improvements in methodology has allowed for
facile synthesis of complex molecules.
● Many complex natural products have been synthesized in a
stereoselective manner with precise setting of stereocenters.
● With time the synthetic strategy became more systematic with detailed
planning at the onset.
● The widely used method of retrosynthetic analysis, pioneered by E.J.
Corey uses a disconnection method to work backwards from the target
molecule to identify the best synthetic route.
● At present machine learning based software tools exist to aid with
retrosynthetic analysis and to identify optimal pathways.
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9. Organic synthesis
● Construction of complex organic molecules from simple, commercially
available starting material.
● Retrosynthetic analysis focuses main only the design of the synthesis and
is agnostic about aspects such as reagent costs and yields
● Your synthetic strategy would factor in many different things including;
cost of starting material, available synthetic methods, number of steps,
selectivity and yields for each step etc.
● Hence this is an inherently complicated process. For this course we will
only focus on synthetic design with retrosynthetic analysis
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10. What you must achieve in organic synthesis
● When synthesizing a complex molecule, one must do the
following often in parallel:
-Build the carbon skeleton
-Functionalize the skeleton
-Set stereocenters with the correct absolute configuration
● In this course we will mainly focus on the first two aspects.
However, it should be noted that stereoselective synthesis is
critical in the synthesis of molecules, particularly
pharmaceutical and other bioactive compounds.
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Strychnine

11. Linear vs. convergent synthesis
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12. Linear vs. convergent synthesis
● Convergent syntheses are preferred over linear ones due to higher yields,
flexibility.
● Individually building subunits and combining them is much easier to
execute than trying to build up complexity in a linear manner.
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