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Chemist important notes part 1 2 3 for students in university. These doc are very valuable for letchures and professional studies
Typology: Schemes and Mind Maps
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**1. Learning Outcomes
rings linked through trans ring junctions and does not undergo ring inversion are rigid towards reactivity.
(ii) Conformationally mobile diastreomers: Those molecules which exist in erythreo and threo isomeric forms come under this category. In this case, the relative specific reaction rates of the two diastreomers depend on the corresponding rates and their populations in the equilibrium mixture of each diastereomer. For example , 2,3,4-triphenylbutyric acid exists in two diastreomers, threo and erythreo respectively. Threo is the preferred conformation having the - COOH group very close to the - CH 2 Ph group at C-4 carbon atom. It cyclizes with anhydrous HF mainly to tetralone (I), while erythro having the - COOH group very close to the - Ph group at C-3 carbon atom cyclizes with anhydrous HF mainly to indanone (II).
(iii) Single substrate with two or more conformers: The overall specific reaction rate (k) of a substrate in mobile equilibrium depends both on the ground state population of conformer and on their specific reaction rate as given in the equation: K = ni ki where, ni = mole fraction of ith^ conformer ki = Specific reaction rate K = Overall specific reaction rate Quantitative correlation between conformation and reactivity has been explained by two principles, these are: (1) Curtin-Hammett principle and (2) Winstein-Eliel rate equation. At one time, these equations were extensively used to determine the conformational free energies.
Here, K is the equilibrium constant between conformers A and B , and k C and k D are the rate constants for the formation of products C and D respectively. When K is larger than either k C or k D, then according to the Curtin-Hammett principle, the C:D product ratio is not equal to the A:B reactant ratio, but is instead determined by the relative energy of the transition states. K is larger than either k C or k D means the rate of inter-conversion between the reactants A and B is much faster than the rate of formation of products C or D. If both the reactants A and B are at identical energy, then the reaction will depend only on the energy of the transition states leading to products C and D. However, if the two reactants A and B are at different energy levels (having low energy barrier for their inter-conversion) then the product distribution depends both on the relative quantity of A and B and on the relative barriers to products C and D. The reaction coordinate free energy profile can be represented by the following scheme:
The ratio of products depends on the free energy (Δ G ‡). Here C will be the major product, having lower (Δ G ‡) for TS C , while product D has higher (Δ G ‡) for TS D , so formed in less amount. Form this we conclude that the product distribution depends on the relative free energies of substrates A and B.
Case I Less stable conformer leads to the major product or less stable conformer reacts more quickly than the more stable conformer: Less stable conformer is at high energy and thus it is present in less concentration at room temperature. On the other hand, more stable conformer is at low energy and thus it is present in high concentration at room temperature. Here, the less stable conformer reacts faster and form the product due to the low free energy (Δ G ‡) of the transition state.
low free energy (Δ G ‡) transition state. Here also the product distribution does not reflect the equilibrium conformer distribution. For example: Diastereomeric conformer of 4 - tert - butyl- 1 - methyl-piperidine in which both the methyl and tert - butyl substituents are at the equatorial position is 3.16 kcal/mol more stable than the conformer in which methyl is at the axial position and tert - butyl substituent is at the equatorial position. Here, more stable conformer of 4 - tert - butyl- 1 - methyl-piperidine leads to the major product with the product ratio of 95:5. Case III
Both conformers react at the same rate: Two different conformers in equilibrium react at the same rate through transition states having same energies. In this case, the selectivity of product formation depends only on the distribution of ground-state conformers. For example : Cyclohexyl iodide reacts with radiolabeled iodide (I*) and forms both axial substituted and equatorial substituted product through the same transition state. Hypothetically both the products should form in 1:1 ratio, but this is not the case.
(i) Application to dynamic kinetic resolution: Kinetic resolution is used to differentiate between two enantiomers in a racemic mixture. For example, if two enantiomers (S R and S S ) are allowed to react with a chiral catalyst or reagent in a chemical reaction, then they reacts at a different reaction rate and results in the formation of an enantio-enriched sample of the less reactive enantiomer. The less reactive enantiomer is further separated from the products. It is shown below:
DKR is applied in Noyori’s asymmetric hydrogenation. It is a chemical reaction in which ketones, aldehydes and imines are hydrogenated enantioselectively using chiral BINAP-Ru catalyst. The ( R )-BINAP-Ru catalyze the synthesis the ( R )-product, and the ( S )-BINAP Ru catalyze the synthesis the ( S )-product with high ee. Rapid equilibration between the enantiomeric conformers and irreversible hydrogenation place the reaction under Curtin-Hammett control. The use of a chiral catalyst results in a higher-energy and a lower-energy transition state for hydrogenation of the two enantiomers. The transformation occurs via the lower-energy transition state to form the product as a single enantiomer. Consistent with the Curtin-Hammett principle, the ratio of products depends on the absolute energetic barrier of the irreversible step of the reaction, and does not reflect the equilibrium distribution of substrate conformers. The relative free energy profile of one example of the Noyori asymmetric hydrogenation is shown below:
In the above example, -keto-ester (3) exists in two conformers (2 and 4), which are in equilibrium with each other. The chiral catalyst ( R )-BINAP-Ru lowers the energy of the (2) conformer in comparison to the (3) conformer. Thus, conformer (2) reacts faster and exclusively forms the 100% product (1) rather than (5). (2) Application to regioselective acylation: Curtin-Hammett principle is used to explain regioselectivity in the acylation of 1,2-diols. Usually, the least-hindered site of an asymmetric 1,2-diol undergo esterification faster due to least steric hindrance between the diol and the acylating reagent. But Curtin-Hammett principle is used to explain selective esterification of the most substituted hydroxyl group in the synthesis of carbohydrates and other polyhdyroxylated compounds using stannylene acetals as shown below:
and (3) having 1.43 kcal/mol difference in transition state energies between the two conformers. The observed product ratio was 91:9.
It correlates the overall specific reaction rate (K) of a substrate with Specific reaction rate (k) of individual conformer irrespective of whether the products are equilibrating or non-equilibrating. For example, trans - 4 - t - butylcyclohexyl tosylate does not undergo E 2 elimination, since the equatorial conformer cannot have the tosyl group antiperiplanar with an adjacent hydrogen atom. On the other hand, cis - 4 - t - butylcyclohexyl tosylate undergoes E 2 elimination with a specific rate 7.1 10 -^3 Lmol-^1 sec-^1.
The conformation-reactivity relationship is very important in understating the stereochemical aspects of product formation. Curtin-Hammett principle applies to systems in which different products are formed from a substrate which exists in two different forms which are in equilibrium with one another. The rapidly interconverting reactants can be enantiomers, diastereomers, or constitutional isomers. Curtin-Hammett principle is used in the dynamic kinetic resolution. Kinetic resolution is used to differentiate between two enantiomers in a racemic mixture. Curtin-Hammett principle is also applied in the asymmetric epoxidation. Curtin-Hammett principle is used to explain regioselectivity in the acylation. Noyori’s asymmetric hydrogenation is also dependent upon the Curtin-Hammett principle. Winstein-Eliel rate equation correlates the overall specific reaction rate (K) of a substrate with Specific reaction rate (k) of individual conformer irrespective of whether the products are equilibrating or non-equilibrating.
