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C-C Single Bond Forming Reactions

The document discusses C-C single bond forming reactions through enolate chemistry. It focuses on pKa values, which indicate acidity and affect regioselectivity and stereoselectivity of enolate formations. Common bases used for enolate generation are also described, and factors that influence kinetic vs thermodynamic control and E/Z selectivity are examined, such as temperature, substrate structure, counterion, base nature, and co-solvents.

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asif Mehmood
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45 views16 pages

C-C Single Bond Forming Reactions

The document discusses C-C single bond forming reactions through enolate chemistry. It focuses on pKa values, which indicate acidity and affect regioselectivity and stereoselectivity of enolate formations. Common bases used for enolate generation are also described, and factors that influence kinetic vs thermodynamic control and E/Z selectivity are examined, such as temperature, substrate structure, counterion, base nature, and co-solvents.

Uploaded by

asif Mehmood
Copyright
© © All Rights Reserved
We take content rights seriously. If you suspect this is your content, claim it here.
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Download as PDF, TXT or read online on Scribd
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22/03/2017_L- 2

C-C single bond forming reactions :

•pKa
•Enolate Chemistry
• Regioselectivity
• E/Z Stereoselectivity
• α,β-unsaturated ketone enolate

22/03/2017 CHEM 706 FZB 1


pKa????
pKa
The negative logarithm of the ionization constant
of an acid, a measure of the strength of an acid.
The lower the pKa, the stronger the acid.

pKa tells us how acidic (or not) a given


hydrogen atom is in a molecule.

22/03/2017 CHEM 706 FZB 2


Structural Effects of pKa
View the complete course:
https://www.youtube.com/watch?v=q1GStqFwrl8&list=PLqOZ6FD_RQ7mjll_2I34
SguRYiCOILUxD&index=9
(2:25-12:31 min)
22/03/2017 CHEM 706 FZB 3
Table showing pKa values of different carbonyl compounds
CH3SO3H -2.6
CF3SO3H -14.7

There is a fundamental relationship between the stabilizing functional group and the
acidity of the C−H groups
Lower the pKa value, Higher the acidity (Easier to pull the proton).
22/03/2017 CHEM 706 FZB 14
pKa values of common carbonyl compounds

pKa ~20 pKa ~25

pKa ~9 pKa ~11

22/03/2017 CHEM 706 FZB 5


Commonly used bases for enolate generation
Amide base : LDA (since 1968) : for less acidic proton

LDA, pKa ~36 LTMP/LiTMP ~ 36 LiHMDS, pKa ~26


Stable under 0oC Non-nucleophilic Stable at r.t.No reducing ability

LiHMDS, pKa of ~26 making it is less basic that other lithium bases, such
as LDA (pKa ~36), but it is more sterically hindered and hence less nucleophilic It
can be used to form various organolithium compounds including acetylides, or
lithium enolates

DBU DBN

Et3N, NaOH, NaH, NaNH2, NaOEt, tBuOK : for more acidic proton
pKa ???

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Calculating Keq and predicting concentration of Enolate at
Equilibrium

7
22/03/2017 CHEM 706 FZB
Regioselectivity & Stereoselectivity in Enolate Formation

Are these enolates


same??

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Regioselectivity

•Formation of kinetic enolate is met experimentally by using a very


strong base such as LDA or LiHMDS in an aprotic solvent in the absence
of excess ketone.
•Fast Deprotonation
•Aprotic solvent
•Complete consumption of ketone
•Formation of Thermodynamic enolate requires weak base, protic
solvent and excess ketone.
•Slow Deprotonation
•Protic solvent
•Excess ketone

22/03/2017 CHEM 706 FZB 9


Examples:
Regioselective (Kinetic and Thermodynamic) Control in Enolate
depends on:

Different Temperature:

58% mixture of Z and E

22/03/2017 CHEM 706 FZB 10


Examples:
Regioselective (Kinetic and Thermodynamic) Control in Enolate
depends on:
Nature of Substrate:
Kinetic Thermodynamic
E Z

E,Z- combined

In the case of 1-phenyl-2-propanone, Thermodynamic


enolate is favored in both Kinetic and Thermodynamic
conditions.

22/03/2017 CHEM 706 FZB 11


Examples:
Regioselective (Kinetic and Thermodynamic) Control in Enolate
depends on:
Effect of counterion:

Li+ is a better counterion than Na+ or K+ for regioselective generation of


the Kinetic enolate, as it maintains a tighter coordination at oxygen and
reduces the rate of proton exchange.

22/03/2017 CHEM 706 FZB 12


Examples:
Regioselective (Kinetic and Thermodynamic) and Stereochemistry (E
and Z) Control in Enolate depends on:

Nature of Bases:
Kinetic Thermodynamic
E Z

22/03/2017 CHEM 706 FZB 13


Irreland Model favors E-selectivity in enolate reaction:

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Examples:
Regioselective (Kinetic and Thermodynamic) Control in
Enolateformation of α,β-unsaturated ketones depends on:
Nature of Base:

R. A. Lee, C. McAndrews, K. M. Patel, and W. Reusch, Tetrahedron Lett. 1973:965.

22/03/2017 CHEM 706 FZB 15


Stereochemistry (E and Z) in Enolate depends on:
Effect of Co-solvent:
Deprotonation of 2-pentanone with LDA in THF, with or without HMPA.

Ratio Z:E for C(3)


deprotonation

0 oC, THF-HMPA 1.0


HMPA
-60 oC, THF-HMPA 3.1

1. Z:E ratio for C(3) deprotonation is sensitive to the presence of HMPA.


2. Addition of HMPA can distrupt cyclic transition state in Irreland Model and gives
more Z-enolate is formed

22/03/2017 CHEM 706 FZB 16

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