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Determination of reaction mechanisms
- 1. 1 WELCOME
- 2. MULLESH.M M.pharm -Part 1 Pharmaceutical Chemistry 2
- 3. CONTENTS Introduction Methods of determining reaction mechanism Reference 3
- 4. INTRODUCTION Reaction mechanism is the step by step sequence of elementary reactions in a chemical change It describes about the reactant involved,intermediates and products 4
- 5. Methods 0f Determining of Mechanism 1 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 experiments 5 5 Stereochemical study 6 Kinetic studies 7 Kinetic isotope effects 7.1 Deuterium isotope effects
- 6. DETERMINATION OF MECHANISM IDENTIFICATION OF PRODUCTS Mechanism must be compatible with its products including the by-product. 6
- 7. 7 CH4 + Cl Cl CH3 Cl h 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
- 8. Determination of the presence of intermediates Isolation of intermediates Isolate the intermediate which can give the same products when subjected to the same reaction conditions 8
- 9. 9 R CH - R 1 N OTs R R 1 H N Azirine R 1 R H O NH2 H H R N R 1 OTs B a s e H2O Eg: Neber rearrangement
- 10. Determination of the presence of intermediates Detection of an intermediate In 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). 10
- 11. 11 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
- 12. Determination of the presence of intermediates Trapping of an intermediate In 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 12 F Br O O Lithium Benzyne (trap)
- 13. Determination of the presence of intermediates Addition 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 13 CO2H CO2H von Ritcher condition von Ritcher condition NO2 CN
- 14. 14 Nitrogen Ammonia would be compatible with nitrile intermediate(hydrolysis product of nitrile)
- 15. 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. 15
- 16. 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 16
- 17. A) General acid (or base) catalysis 17 • 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).
- 18. • Reactions in which proton transfer is rate- determining exhibit general acid catalysis, f or example diazonium coupling reactions. • When keeping the pH at a constant level but changing the buffer concentration a ch ange in rate signals a general acid catalysi s. (A constant rate is evidence for a specifi c acid catalysis.) 18
- 19. 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 19
- 20. 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. 20
- 21. D can be detected by NMR, IR and MS 13 C can be detected by 13 C-NMR and MS 14 C can be traced by its radio activity 15 N can be detected by 15 N-NMR 18 O can be detected by MS e.g. 21 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 Oisolated intermediate R C N O C O + +
- 22. Isotope labeling The hydrolysis of ester proceed through “alkyl” or “acyl” cleavage 22 R O O R' H2 18 O R 18 OH O + R'OH R 18 O O R' H2O R OH O + R'18 OH In these cases, the products can be easily identified by MS.
- 23. Crossover Experiments Use for distinguishing between intra- and intermolecular reaction 23 A B AB A' B' A'B' + + A B AB A' B' A'B' + + + + A'B AB' + crossover products • Crossover products indicate intermolecular reaction. • The method requires identification of products in the mixture. . No crossover product
- 24. Crossover Experiments Is benzidine rearrangement an inter- or intramolecular process? 24 H N H N H2N NH2 H N H N H2N NH2 OR OR RO OR H N H N OR' OR' H2N NH2 R'O OR' No crossover product indicates an intramolecular rearrangement R=OCH3 R`=OC2H5
- 25. Stereochemical evidences SN2 reaction 25 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 OTsAcO δ− δ−
- 26. 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) 26
- 27. Kinetic isotopic effect Exchange 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 27
- 28. Types of kinetic isotope effects Primary kinetic isotope effects Secondary kinetic isotope effects i.Normal ii.Inverse Kinetic solvent isotope effects 28
- 29. Primary kinetic isotopic effects When 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 7 Extent of bond cleavage or formation can be inferred 29
- 30. Secondary kinetic isotope effects The 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 30
- 31. Kinetic solvent isotope effects Reaction 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 31
- 32. RefeRence JeRRy maRch; “advanced oRganic chemistRy” 4th edition page no:297- 327 www.chemgapedia.com www.wikipedia.com
- 34. Discussion 34