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WELCOME

MULLESH.M M.pharm -Part 1

Pharmaceutical Chemistry

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CONTENTSIntroduction

Methods of determining reaction mechanism

Reference

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INTRODUCTIONReaction mechanism is the step by step

sequence of elementary reactions in a chemical change

It describes about the reactant involved,intermediates and products

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Methods 0f Determining of Mechanism1 Identification of products

2 Determination of the presence of intermediates

2.1 Isolation of intermediates

2.2 Detection of intermediates

2.3 Trapping of intermediates

2.4 Addition of a suspected intermediate

3 Study of catalysis

3.1 General acid catalysis

3.2 Specific acid catalysis

4 Labeling study

4.1 Group labeling

4.2 Isotope labeling

.4.3 Crossover experiments5

5 Stereochemical study

6 Kinetic studies

7 Kinetic isotope effects7.1 Deuterium isotope effects

DETERMINATION OF MECHANISM

IDENTIFICATION OF PRODUCTS Mechanism must be compatible with its products including the by-product.

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CH4 + Cl Cl CH3 Clh ν

This reaction fail to account for the formation of small amount of ethane

Eg:

CH3

O

NH2 N a O B r

H 2 O

- C O 2

CH3 NH2

1

Eg:2

Determination of the presence of intermediates

Isolation of intermediatesIsolate the intermediate which can give the same products

when subjected to the same reaction conditions

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R

CH-

R1

N OTs

R

R1

H

N

Azirine

R1

R

H

O

NH2

H

H

R

N

R1

OTsB a s e

H2O

Eg: Neber rearrangement

Determination of the presence of intermediates

Detection of an intermediateIn many cases, intermediate cannot be

isolated but can be detected by IR, NMR, UV-Vis or other spectra.

Radical and triplet species can be detected by ESR and by Chemically Induced Dynamic Nuclear Polarization (CIDNP).

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H H

Cis - stilbene

R S .

C

HRS H

- R S .

H

H

trans -stilbene

Eg:-Free radical can be determined by addition of double bonded compound in the reaction mixture and it’s fate is traced

Determination of the presence of intermediates

Trapping of an intermediateIn some cases, the suspected intermediate is known

to be one that reacts in a given way with a certain compound.

Benzynes react with dienes in the Diels-Alder reaction

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F

Br

O

O

Lithium

Benzyne

(trap)

Determination of the presence of intermediatesAddition of a suspected intermediate

Perform a reaction by using a suspected intermediate obtained by other means can be used for a negative evidence.

Eg : Von Richter rearrangement

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CO2H

CO2H

von Ritchercondition

von Ritchercondition

NO2

CN

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Nitrogen Ammonia would be compatible with nitrile intermediate(hydrolysis product of nitrile)

Study of catalysis

Mechanism must be compatible with its catalysts , initiator and inhibitors.

Utilization of catalytic amount of peroxide and iodine usually suggests a radical mechanism.

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Kinetic study of acid-base catalyzed reaction can reveal the rate determination step (RDS.) if it is involved with the proton transfer process

A) General acid (or base) catalysis usually indicates that the proton transfer process is the RDS

B) Specific acid (or base) catalysis usually indicates that the proton transfer process is not the RDS

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A) General acid (or base) catalysis

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• In general acid catalysis all species capable of donating protons contribute to reaction rate acceleration.

• The strongest acids are most effective (k1 is the highest).

• Reactions in which proton transfer is rate-determining exhibit general acid catalysis, for example diazonium coupling reactions.

• When keeping the pH at a constant level but changing the buffer concentration a change in rate signals a general acid catalysis. (A constant rate is evidence for a specific acid catalysis.)

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B) Specific acid (or base) catalysis

In specific acid catalysis taking place in solvent S , the reaction rate is proportional to the concentration of the protonated solvent molecules .

The acid catalyst itself (AH) only contributes to the rate acceleration by shifting the chemical equilibrium between solvent S and AH in favor of the SH+ species. S + AH SH+ + A-

Eg: Acid catalysed aldol reaction

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Labeling study

A) Isotope labeling: Difficult to obtain the starting materials but no group alteration to affect the mechanism.

B) Crossover experiments: The experiments are closely related to either group or isotope labeling.

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D can be detected by NMR, IR and MS13C can be detected by 13C-NMR and MS14C can be traced by its radio activity15N can be detected by 15N-NMR18O can be detected by MS

e.g.

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RCOO- + BrCN RCN* *

Isotope labeling

N C Br

R C O-

O

N

C O

C Br

O-

R C

N C O

R R C

N C

OO

Oisolatedintermediate

R

C

N

O

C

O

+

+

Isotope labeling The hydrolysis of ester proceed through “alkyl” or

“acyl” cleavage

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R O

O

R' H218O R 18OH

O+ R'OH

R 18O

O

R' H2O R OH

O+ R'18OH

In these cases, the products can be easily identified by MS.

Crossover ExperimentsUse for distinguishing between intra- and intermolecular reaction

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A B AB

A' B' A'B'

+ +

A B AB

A' B' A'B'

+ +

+

+

A'B

AB'

+

crossoverproducts

• Crossover products indicate intermolecular reaction.

• The method requires identification of products in the mixture.

.

No crossover product

Crossover ExperimentsIs benzidine rearrangement an inter- or intramolecular process?

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HN

HN

H2N NH2

HN

HN

H2N NH2

OR ORRO OR

HN

HN

OR' OR'

H2N NH2

R'O OR'

No crossover product indicates an intramolecular rearrangement

R=OCH3 R`=OC2H5

Stereochemical evidencesSN2 reaction

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OTs OAc

KOAc

OTs OAc

KOAc

and

• The reaction is stereospecific with 100% inversion indicating that the reaction is concerted and the nucleophile attacks from the back side of the leaving group.

• The proposed transition state is a trigonal bipyramid.

Ph

H CH3

OTsAcOδ− δ−

Mechanistic information obtained from kinetic studies

Order of reaction can give information about which molecules take part in rate determining step and the previous steps.

Changes in rate constants upon structural and condition changes can give much information about mechanisms. (Linear free energy relationships)

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Kinetic isotopic effectExchange of an atom in the starting product of a

reaction for one of its heavier isotope leads to reduction in reaction rate

When a hydrogen in a reactant molecule is replaced by deuterium, there is a change in the rate

Such changes are known as deuterium isotope effect

It is expressed by KH/kD

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Types of kinetic isotope effects

Primary kinetic isotope effectsSecondary kinetic isotope effects

i.Normal

ii.Inverse Kinetic solvent isotope effects

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Primary kinetic isotopic effectsWhen reaction rate is decreased by the

exchange of D for a H from the X-H(X=C, N, O, S, etc..) that is cleaved during rate-determining step

Elevation of activation energy of RDS

KH/kD is up to 7Extent of bond cleavage or formation can be

inferred

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Secondary kinetic isotope effectsThe chemical bond varied by the isotopic exchange is not

cleaved during the reaction

KH/kD is 0.7 to 1.5

Normal secondary kinetic isotope effect (KH/kD > 1) reaction rate is reduced by exchanging an atom for one its heavier isotopes

Inverse secondary kinetic isotope effect(KH/kD <1)

reaction rate is increases by exchanging an atom for one its heavier isotopes

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Kinetic solvent isotope effectsReaction rate is influenced by an isotopic

exchange of the solvent, rather than that of a reactant that has been exchanged for one of its isotopes

Eg: H2O is exchanged for D2O

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RefeRenceJeRRy maRch; “advanced oRganic

chemistRy” 4th edition page no:297-

327

www.chemgapedia.com

www.wikipedia.com

Discussion

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