Physical Organic Chemistry

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Physical Organic Chemistry: 

Physical Organic Chemistry

Substituent Effect [Ref: Jack Hine, Physical Organic Chemistry, Edn. II, McGraw-Hill, Tokyo, p-159-162]: 

Substituent Effect [Ref: Jack Hine, Physical Organic Chemistry , Edn. II, McGraw-Hill, Tokyo, p-159-162] It has been recognized that for a given nucleophilic atom nucleophilicity is fairly well correlated with the basicity of the nucleophilic reagent . For example : Smith has pointed out that in the reaction of the chloroacetate ion with 32 ncleophilic anions whose nucleophilic atom is oxygen the variation in the logarithms of the basicity constants is very nearly proportional to the differences in the logarithms of the basicity constant. The sulphite and thiosulphate anions, which form carbon- sulphur bonds rather than carbon-oxygen bonds, were much more nucleophilic than would be expected from their basicity.

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By restricting the variation in structure to meta- and para- substituents on the aromatic ring, a still better correlation may be obtained, at least partially because of the elimination of steric effects, which can destroy the correlation, since nucleiphilc attack on carbon is usually more subjected to steric hindrance than is coordination with a proton. Reaction constant,  , have been calculated for several series of reactions involving aniline derivatives and substituted phenolate anions as nucleophilic reagents. The negative values of  show that the nucleophilicity to be increased by electron donating groups in all cases.

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Similar results are found in the nucleophilic attack of anilines on halo-nitro aromatic compounds and on acid halides. Another generalization is that nucleophilicity increases, within a given group of the periodic table, with the atomic number of the atom forming the new bond to carbon. That is , , etc. It is noted that this variation, which is the one usually but not invariably observed, is in the direction opposite to that which would expected from the basicities of the various nucleophilic reagents.

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In increased nucleophilicity is most commonly attributed to the increase in polarizability that accompanies the increase in the distance of the outer electronic shell from the nucleus. The greater ease of distortion of the outer shell permits an easier adjustment to the requirements of a stable transition state. The nucleophilicity of some of the anions, particularly is decreased considerably by their strong solvation and is markedly increased in nonhydroxylic solvents.

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It may be noted that the relative order of nucleophilicities of nucleophilic reagents be invariable in a given solvent. That is, since the iodide ion is more reactive than the hydroxide ion towards 2,3-epoxypropanol in aqueous solution, it should be more reactive than hydroxide ion in all nucleophilic displacements on carbon taking place in aqueous solution. It has been found that towards the ethylene-  -chloroethylsulphonium ion the hydroxide ion is about 12 times as reactive as the iodide ion.

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There is thus a change in the relative reactivates of the two ions of more than 100-fold. Similarly, triethylamine is 26 times as reactive as pyridine toward methyl iodide, whereas toward isopropyl iodide pyridine is 6 times as reactive as triethylamine. This 150-fold reversal in the relative reactivity of the two amines is reasonably explained on the basis of steric hindrance. Despite its greater steric requirements, the more basic triethylamine is more reactive than pyridine toward methyl iodide. Since any attack on isopropyl iodide is much more hindered, the steric effects are too large to overcome in this case and pyridine is the more reactive. However, some other explanation must be given for the increased reactivity of the hydroxide ion toward the ethylene-  -chloroethylsulphonium ion.

Linear Free Energy Relationships [Ref: Gurdeep Raj, Advanced Physical Chemistry, Goel Pbln. House,Vth Edn., 2001, p-776-777] : 

Linear Free Energy Relationships [Ref: Gurdeep Raj, Advanced Physical Chemistry , Goel Pbln. House,V th Edn., 2001, p-776-777] We know that the introduction of a group in an organic molecule alters the reaction rate to an appreciable extent. The substituent is having a definite effect on the distribution of electron density in a molecule. For instance the alkaline hydrolysis of enthyltrichloroacetate (I) takes place about 8 million times faster than the alkaline hydrolysis of trimethylacetate (II).

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Also, the rate of reaction of methyl pyridine with methyl iodide has been larger than that of pyridine without a substitute. In 1993, Hammett gave a quantitative relationship between structure and reactivity of substances and showed that for a number of reactions of methyl esters with NMe 3 . ----- (1)

The rate of reaction has been linearly related to the ionisation constants of the corresponding carboxylic acids in water. -------(2) A plot of the logarithm of rate constant (-log k) for reaction (1) vs. equilibrium constant (-log K) for ionization of acid would yield a reasonably good straight line in (Fig 1). It is possible to characterise the reactivates of substances quantitatively either by free energy change (if equilibrium is taken into consideration) or by free energy of activation (if reaction rate is considered).

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Hence the relation between equilibrium constant, K, rate constant, k r and free energy change may be put as follows: Fig 1: Linear relationship

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where, K=equilibrium constant, k r =rate constant, h =Planck’s constant and K ! =Boltzmann’s constant. Thus, Fig 2, under the title of Hammett’s relation has been equivalent to a straight line relationship between  G # , the energy of activation for the reaction (related to k r rate constant) and , the free energy change for the ionisation of acid (related to K). Thus, there exists a straight line or linear relationship between free energy terms for these two different reaction series. These type of straight line Hammett plots in Fig 1 are termed as linear free energy relationships.

Hammett equation [Ref: Gurdeep Raj, Advanced Physical Chemistry, Goel Pbln. House,Vth Edn., 2001, p-778-781] : 

Hammett equation [Ref: Gurdeep Raj, Advanced Physical Chemistry , Goel Pbln . House,V th Edn., 2001, p-778-781] It is known that the rate of a reaction at a given temperature depends on the nature of the reactants and the products formed. Scientists have been established some theoretical correlations with the help of which the reaction rates and mechanisms of reactions could be predicated from a knowledge of the structure and properties of isolated reactants and products. There are few scientists who did succeed in establishing at least empirical correlations which could be able to describe the trends in rate constants and equilibrium constants over sets of closely related reactions involving, in particular, aromatic compounds. By using these relations, it become possible to predict the rate constants or equilibrium constants of the reactions of substituted aromatic compounds provided the values for the parent compound are known.

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Rate constants and equilibrium constants are measured for a series of reactions involving hydrolysis of substituted ethyl benzoates, the substituents (X) being F, Cl, Br, I, NO 2 , -NH 2 , OH, etc ., present in meta- and para- positions. Hence: Similar measurements are made for several other sets of reactions of substituted ethyl benzoates. Rate constants and equilibrium constants are known for hundreds of reactions involving differently substituted aromatic compounds.

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The Hammett equation in organic chemistry describes a linear free-energy relationship relating reaction rates and equilibrium constants for many reactions involving benzoic acid derivatives with meta- and para- substituents to each other with just two parameters: a substituent constant and a reaction constant . The basic equation is: --------------- (3) relating the equilibrium constant , k, for a given equilibrium reaction with substituent R and the reference k 0 constant when R is a hydrogen atom to the substituent constant  which depends only on the specific substituent R and the reaction constant  which depends only on the type of reaction but not on the substituent used.

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The , the substituent constant, may be regarded as quantitative measure of the electron-releasing or electron-withdrawing power of the substituent group and may be having a positive or negative value. A positive value of  reveals stronger electron-attracting ability relative to hydrogen, while a negative value of this constant reveals that it attracts less strongly than hydrogen. The substituent may also exert a field effect. The magnitude of the reaction constant,  refers to a measure of the sensitivities of the reaction to changes in the polarity of the substituents in the adjacent benzene ring. The larger the absolute value of , the more sensitive would be the reaction in question.

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The signs of the constant, , characterise the kind of reaction transformation. The negative value of  reveals the development of positive charge at the reaction centre in the transition state for the rate-determining step of the overall reaction and whereas a positive value of  reveals the pulling back of electron density from the reaction centre in the transition state for the rate-determining step of the overall reaction.

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Fig 2: Plot log k vs log K In Fig. 2 there is a plot for a series of m - and p -substituted aromatic acids vs. log K for ionisation of corresponding acid which happens be a straight line. On applying the general equation for straight line: Log k =  log K x + c [where  slope of the straight line, c intercept x meta- or para- substituent in the benzene ring of the species concerned, k rate constant and K equilibrium constant]. P---NO 2 m---NO 2 m---Cl p---Br p---Cl p---CH 3 O p---CH 3

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Substituent para - effect meta- effect Amine -0.66 -0.161 Methoxy -0.268 +0.115 Ethoxy -0.25 +0.015 Dimethylamino -0.83 -0.211 Methyl -0.170 -0.069 None 0.000 0.000 Fluoro +0.062 +0.337 Chloro +0.227 +0.373 Bromo +0.232 +0.393 Iodo +0.276 +0.353 Nitro 0.778 +0.710 Cyano +0.66 +0.56 Table 1

Taft equation: [Ref: Wikipedia] : 

Taft equation: [Ref: Wikipedia] The Hammett equation is not applicable very well to either o -substituted benzoic acid or aliphatic compounds as steric effects play an important role in governing the rate of reaction. This gives rise to non-linear, or even to apparently rantom plots. For aliphatic compounds, R, Taft postulated that : ------------- (4)

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where log( k s /k CH3 ) is the ratio of the rate of the substituted reaction compared to the reference reaction, σ* is the polar substituent constant that describes the field and inductive effects of the substituent, E s is the steric substituent constant, ρ* is the sensitivity factor for the reaction to polar effects , and δ is the sensitivity factor for the reaction to steric effects.

[Ref: Gurdeep Raj, Advanced Physical Chemistry, Goel Pbln. House,Vth Edn., 2001, p-[ 781-782] : 

[ Ref: Gurdeep Raj, Advanced Physical Chemistry , Goel Pbln . House,V th Edn., 2001, p-[ 781-782] The Taft constant σ* refers to a measure of the electron-attracting ability of the substituent. It is purely an inductive effect because it gets transmitted through an aliphatic chain. The σ* values in equation (2) can’t be defined in terms of the dissociation constant. It was determined by Taft by separating the total effect of a substituent into a steric term and polar term on the suggestion of Ingold. The basis of the method has been as follows: It is found that σ values for the acid- catalysed hydrolysis of m - and p - substituted benzoic acid have been nearly +0.03, very nearly to be zero. The lack of effect of substitutents for some steps can be cancelled out by others.

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In the above reaction, an electron-releasing substituent will tend to favour step I but hinder step II. Due to this balancing effect, the overall  from the acid- catalysed reaction would be zero.

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σ values for the base- catalyed hydrolysis has been positive and large (+2.2 to +2.8). Experiments reveal that the rates of base- catalyed hydrolysis are very sensitive to the substituents, while in acid hydrolysis the nature of the substituents are having no effect on the rate. It is, therefore, reasonable to regard that steric effect plays an important role in the acid- catalysed hydrolysis. It is evident that close similarity exists between the transition state of two reactions and they may be represented by structures I and II. They have been both tetrahedral but differ only by the presence of two additional protons in the acidic case.

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According to Taft the steric effect has been substantially the same in both acid and base catalysed hydrolysis due to close spatial similarity of the two activated complexes. The ratio k/k0 in alkaline hydrolysis refers to a measure of the two effects (polar and steric) whereas in acid hydrolysis the relative rate has been proportional to the steric effect of the substitution. The values of the polar parameter (σ*) may be obtained from:

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---------- (5) Where A and B refer to the acid- and base- catalysed hydrolysis, k denotes the observed rate constant, k 0 , denotes the rate constant for the standard compound and the constant, is the reciprocal of the average  for several ester hydrolyses for which there exist no steric effects. The steric parameter, E s , can be obtained from the eqution : ---------- (6) where  =1.0 for the hydrolysis of esters.

Table 2: The steric parameter ( Es ) & polar parameter (σ*) found by Taft have been included: 

Table 2: The steric parameter ( E s ) & polar parameter (σ*) found by Taft have been included

Solvent Polarity and Parameters [Ref: Gurdeep Raj, Advanced Physical Chemistry, Goel Pbln. House,Vth Edn., 2001, p-[ 783-784]: 

Solvent Polarity and Parameters [Ref: Gurdeep Raj, Advanced Physical Chemistry , Goel Pbln . House,V th Edn., 2001, p-[ 783-784] It is to be noted that the value of σ for a particular reaction in a given solvent gets changed with change in solvent. Table: 3 Reaction σ 1 [by definition] 1.60 1.96 1.83 2.54

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A variation of the values of σ reveals that it gets changed on changing the solvent from water to ethanol. The change in rate of a particular reaction in a range of differing solvents can be correlated with change in dielectric constant. However, this correlation is not proved very useful. Grunwald and Winstein tried an attempt to establish reactivity/solvent correlations employing linear free energy equation of the type: ---------- (6) where k = rate constant for the solvolysis of a compound in any solvent, k 0 = rate constant for the slovolysis of the same compound in the standard solvent (80% ethanol), y = measure of the ionising power, m = 1.00 for standard halide. The application of this equation needs that y values can be determined with respect to standard.

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Grunwald and Winstein selected S N 1 solvolysis of t- butylchloride and 80% aqueous ethanol as standard reaction and standard solvent, respectively. On setting up a Hammett-like equation, we get --------------- (7) where k A rate constant for the solvolysis of tertiary halide in a solvent A, k 0 rate constant in the standard solvent (80% ethanol), y A empirical solvent parameter in solvent A and y 0 empirical solvent parameter in standard solvent.

Table 4: Typical values of yA: 

Table 4: Typical values of y A The y A value can be found out by setting the value of y 0 zero when k 0 in the different range of solvents are known. Typical values of y A are given in Table 4: Solvent A y A Water 50% ethanol 80% ethanol 69.5% methanol Formic acid 50.6% dioxane + 3.56 +1.604 +0.0000 +1.023 +2.08 +1.292

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The values of m can be done for diagnostic purpose because it provides some measure of the extent of ion-pair formation in the transition state for the rate-determining step of the solvolysis reaction. Higher values of m have been indicative of well advanced ion pair formation in the transition state for S N 1 solvolysis of halide. A lower value of m has been characteristic of the S N 2 pathway of solvolysis of halide. Grunwald-Winstein treatment is having limited applications and is its major defect.

What is special salt effect; an ion exchange in an ion-pair? [Christian Reichardt & Thomas Welton, Solvent Effects in Organic Chemistry, 2011, p 718]: 

What is special salt effect; an ion exchange in an ion-pair? [Christian Reichardt & Thomas Welton, Solvent Effects in Organic Chemistry , 2011, p 718] This effect is produced during S N reactions on addition of an ionic compound and shows the importance of return from the solvent separated ion-pair. The addition of an inert salt e.g ., NaClO 4 at a very low concentration to the solution of some substrates undergoing solvolysis leads to an initial large rate increase. This rate subsequently falls off to become a normal ionic strength effect and the effect is called special salt effect . In the absence of the added salt, the solvolysis proceeds with intimate ion-pair formation with considerable return to the starting substance.

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The perchlorate ion exchanges with the leaving group ion (nucleofuge) to prevent its return, since, attack of the solvent occurs more rapidly than external return of the leaving group ion. Consequently the net rate enhances, as a large proportion of ionization will give the product, as an additional channel for the reaction is available.

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Scheme: 4

Hammond's postulate [Ref: Wikipedia]: 

Hammond's postulate [Ref: Wikipedia] Hammond's postulate is useful for understanding the relationship between the rate of a reaction and the stability of the products. While the rate of a reaction depends just on the activation energy (often represented in organic chemistry as ΔG ‡ “delta G double dagger”), the final ratios of products in chemical equilibrium depends only on the standard free-energy change ΔG (“delta G”). The ratio of the final products at equilibrium corresponds directly with the stability of those products. Hammond's postulate connects the rate of a reaction process with the structural features of those states that form part of it, by saying that the molecular reorganizations have to be small in those steps that involve two states that are very close in energy.

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This gave birth to the structural comparison between the starting materials, products, and the possible "stable intermediates" that lead to the understanding that the most stable product is not always the one that is favoured in a reaction process. The formation of a relative stability of carbocation has significance in an S N 1 reaction. It means that the energy of activation for the slow step (scheme: 5) will be low enough for the overall reaction to occur at reasonable rate. This step is endothermic and according to postulate made by Prof.Hammond, the transition state of an endothermic step (step-II in scheme: 5) should bear a strong resemblance to the product of the step.

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As the product of this step (an intermediate) is a carbocation, factors that stabilize it will also stabilize the transition state in which the charge is developing. Stabilization of the transition state lowers its potential energy and, therefore, lower the energy of activation. Scheme: 5

Curtin-Hammett Principle [Ref: Wikipedia]: 

Curtin-Hammett Principle [Ref: Wikipedia] It states that, for a reaction that has a pair of reactive intermediates or reactants that interconvert rapidly (as is usually the case for conformers), each going irreversibly to a different product, the product ratio will depend both on the difference in energy between the two conformers and the free energy of the transition state going to each product. As a result, the product distribution will not necessarily reflect the equilibrium distribution of the two intermediates. The Curtin–Hammett principle has been invoked to explain selectivity in a variety of stereo- and regioselective reactions.

Definition: : 

Definition: The Curtin–Hammett principle applies to systems in which different products are formed from two substrates in equilibrium with one another. The rapidly interconnecting reactants can be enantiomers, diastereomers, or constitutional isomers. Product formation must be irreversible, and the different products must be unable to interconvert. For example, given species A and B that equilibrate rapidly while A turns irreversibly into C, and B turns irreversibly into D: Scheme: 6

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K is the equilibrium constant between A and B, and k 1 and k 2 are the rate constants for the formation of C and D, respectively. When the rate of interconversion between A and B is much faster than either k 1 or k 2 , then the Curtin–Hammett principle tells us that 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. If reactants A and B were at identical energies, the reaction would depend only on the energy of the transition states leading to each respective product. However, in a real-world scenario, the two reactants are likely at somewhat different energy levels, although the barrier to their interconversion must be low for the Curtin-Hammett scenario to apply. In this case, the product distribution depends both on the relative quantity of A and B and on the relative barriers to products C and D.

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Fig 3: An energy diagram illustrating the Curtin-Hammett principle. The reaction coordinate free energy profile can be represented by the scheme: 6

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The ratio of products depends on the value labeled ΔΔG ‡ in the Figure : 3 will be the major product, because the energy of TS 1 is lower than the energy of TS 2 . The commonly made assertion that the product distribution does not in any way reflect the relative free energies of substrates A and B is incorrect. As shown in the derivation below, the product ratio can be expressed as a function of K, k 1 , and k 2 .

Classes of reactions under Curtin-Hammett control: 

Classes of reactions under Curtin-Hammett control Three main classes of reactions can be explained by the Curtin–Hammett principle: either the more or less stable conformer may react more quickly, or they may both react at the same rate. Case I: More stable conformer reacts more quickly One category of reactions under Curtin-Hammett control includes transformations in which the more stable conformer reacts more quickly. This occurs when the transition state from the major intermediate to its respective product is lower in energy than the transition state from the minor intermediate to the other possible product. The major product is then derived from the major conformer, and the product distribution does not mirror the equilibrium conformer distribution.

Example: Piperidine Oxidation:: 

Example: Piperidine Oxidation: An example of a Curtin-Hammett scenario in which the more stable conformational isomer reacts more quickly is observed during the oxidation of piperidines. In the case of N-methyl piperidine, inversion at nitrogen between diasteriomeric conformers is much faster than the rate of amine oxidation. The conformation which places the methyl group in the equatorial position is 3.16 kcal/mol more stable than the axial conformation. The product ratio of 95:5 indicates that the more stable conformer leads to the major product.

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Scheme 7

Case II: Less stable conformer reacts more quickly: 

Case II: Less stable conformer reacts more quickly A second category of reactions under Curtin-Hammett control includes those in which the less stable conformer reacts more quickly. In this case, despite an energetic preference for the less reactive species, the major product is derived from the higher-energy species. An important implication is that the product of a reaction can be derived from a conformer that is at sufficiently low concentration as to be unobservable in the ground state.

Example: Tropane Alkylation: 

Example: Tropane Alkylation The alkylation of tropanes with methyl iodide is a classic example of a Curtin-Hammett scenario in which a major product can arise from a less stable conformation. Here, the less stable conformer reacts via a more stable transition state to form the major product. Therefore, the ground state conformational distribution does not reflect the product distribution. Scheme 8: A scheme of tropane alkylation using carbon 13-labeled methyl iodide.

Case III: Both conformers react at the same rate: 

Case III: Both conformers react at the same rate It is hypothetically possible that two different conformers in equilibrium could react through transition states that are equal in energy. In this case, product selectivity would depend only on the distribution of ground-state conformers. In this case, both conformers would react at the same rate.

Example: Radical Methylation: 

Example: Radical Methylation When ground state energies are different but transition state energies are similar, selectivity will be degraded in the transition state, and poor overall selectivity may be observed. For instance, high selectivity for one ground state conformer is observed in the following radical methylation reaction. Scheme 9: Radical methylation.

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The conformer in which A(1,3) strain is minimized is at an energy minimum, giving 99:1 selectivity in the ground state. However, transition state energies depend both on the presence of A(1,3) strain and on steric hindrance associated with the incoming methyl radical. In this case, these two factors are in opposition, and the difference in transition state energies is small compared to the difference in ground state energies. As a result, poor overall selectivity is observed in the reaction. Scheme 10: Selectivity in radical methylation .

The Principle of Microscopic Reversibility [Ref: Jack Hine, Physical Organic Chemistry, Edn. II, McGraw-Hill, Tokyo, p 69-72] : 

The Principle of Microscopic Reversibility [Ref: Jack Hine, Physical Organic Chemistry , Edn. II, McGraw-Hill, Tokyo, p 69-72] According to the principle of microscopic reversibility, the mechanism of a reversibility, the mechanism of a reversible reaction is the same, in microscopic detail (except for the direction of reaction), for the reaction in one direction as in the other under a given set of conditions. Thus, for example, if the transformation of ‘A’ to ‘D’ proceeds only through the intermediate ‘B’, Scheme: 11

Fig 4: Plot for the reactant ‘A’ yielding the kinetically controlled product ‘B’ and the equilibrium-controlled product ‘C’.: 

Fig 4: Plot for the reactant ‘A’ yielding the kinetically controlled product ‘B’ and the equilibrium-controlled product ‘C’. then, under the same conditions, ‘D’ must be transformed to ‘A’ only through ‘B’ and not through ‘C’.

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It is obvious that, if the path of minimum-free-energy expenditure leading from ‘A’ to ‘D’ passes through ‘B’, the minimum-free-energy path from ‘D’ to ‘A’ must also pass through ‘B’. Similarly, if the same amount of free energy of activation is required to react via intermediate ‘C’ as via ‘B’, then ‘A’ will be transformed to ‘D’ to an equal extent by the two reaction paths and ‘D’ will revert to ‘A’ just as frequently via ‘C’ as via ‘B’. This principle is of importance in the calculation of rate constants for individual steps of reactions. Such reactions are usually not really reversible since the reverse reaction is not accompanied by the emission of light (of the same wavelength as that absorbed).

Kinetic Isotope Effects: 

Kinetic Isotope Effects It has been observed that isotopic substitution can change the rates of chemical reactions by much larger factors than it changes most equilibrium constants. In most reactions that have been studied a bond is broken in the isotopically substituted molecule. When the isotopic change is made at an atom bound by the bond being broken (or formed), the rate change is called primary kinetic isotope effect.

The difference in rate between the breaking of an A-----B bond and an A------B * bond, where B and B * are isotopes, can be rationalized in terms of the loss of the A-----B stretching frequency in the transition state. At ordinary reaction temperatures most bonds in ordinary molecules are at their lowest vibration level, but even at this level they contain the zero-point vibrational energy , which is equal to ½h . The difference in the zero-point energies of the reactants may be compensated by a difference in the zero-point energies of the transition states.

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In the case of transfer of the atom ‘B’ to another atom ‘C’, via a linear transition state there is a “symmetrical” mode of vibration involving the movement of ‘B’ as well as of ‘A’ and ‘C’, if ‘B’ is attached to either one of these two atoms more strongly than to the other. It depends on the difference in the strength of attachment of ‘A’ to ‘B’ and “C’, the frequency of this vibration will depend on the mass of ‘B’. There will be a difference in the zero-point energies of the two transition states that may partly or completely balance the difference in zero-point energies of the reactions.

Secondary kinetic isotope effect: 

Secondary kinetic isotope effect However, when B is attached to A and C with equal strength in the transition state, the symmetrical vibration does not involve any movement of B. In such a case the symmetrical vibration frequency does not depend on the mass of B and no difference in zero-point energies of the transition state arise from this source. In certain cases, however, much smaller primary kinetic isotope effects have been observed. Some of these were observed for very rapid processes, in which reaction may occur at every collision. Very small kinetic isotope effects would be expected in such reactions, since isotopic substitution has little effect on the collision rates of any but very small molecules.

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There are other relatively slow reactions for which small primary kinetic isotope effects have been found. For these, the atom B is probably held much more strongly to one of the two atoms A and C than it is to the other. Since some such primary kinetic isotope effects are almost as small as certain secondary kinetic isotope effects (in which the isotopic change is made at an atom not involved in any bond breaking during the reaction), it is not possible to distinguish the two types of isotope effects by magnitude alone.

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Thus, in the case of carbon-bound deuterium a number of secondary kinetic isotope effects ranging up to a maximum of about 30 % per deuterium have been reported. Hence, k H / k D value of more than about 2.0 were found for a given reaction (near room temperature). It is confident that the hydrogen (or deuterium) atom was being transferred during the reaction. With very much smaller k H / k D values, however, it would be difficult to tell whether there was a hydrogen transfer in the rate-controlling step of the reaction or not.

Nucleophilic Catalysis – General and Specific Acid-Base Catalysis [Ref: Jack Hine, Physical Organic Chemistry, Edn. II, McGraw-Hill, Tokyo, p 104-108 ] : 

Nucleophilic Catalysis – General and Specific Acid-Base Catalysis [Ref: Jack Hine, Physical Organic Chemistry , Edn. II, McGraw-Hill, Tokyo, p 104-108 ] Bronsted and coworkers have shown that it sis possible to divide acid/base catalyzed reactions into two categories. According to these, the catalysis is kinetically attributable to all the acids /bases present in the solution or merely to the conjugate acid/base of the solvent. The first type is called general acid/base catalyzed reaction and the second, a specific acid/base catalyzed reaction.

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That is, a reaction in aqueous solution whose rate is merely proportional to the H 3 O + ion concentration and the concentration of the reactant, is said to be specific acid-catalyzed. Whereas in a general acid-catalyzed reaction there will be a term proportional to the concentration of each of the acids in solution. Example: - Hydrolysis of Ethyl Orthoacetate [general acid catalysis]

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It is possible to study the reaction under such conditions that the further hydrolysis of the ethyl acetate formed is negligible and the concentrations of the acids and bases present remain essentially constant. Under these conditions it is found the reaction is always of the first order, being pseudounimolecular.  = k [ethyl orthoacetate] The extent of acid/base catalysis may then be determined by measuring k (dilatometrically) in the presence of varying concentrations of acids/bases.

Other general and Specific Acid- and Base-catalyzed Reactions.: 

Other general and Specific Acid- and Base-catalyzed Reactions. A specific H 3 O + ion catalyzed reaction is one whose rate constant is simply proportional to the H 3 O + ion concentration. Bronsted and Wynne-Jones reported that the hydrolysis of ethyl orthopropionate and ethyl orthocarbonate was also general acid-catalyzed, but that the hydrolysis of dethylacetal was specific H 3 O + ion catalyzed.

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An example of a general base-catalyzed reaction is the decomposition of nitramide. The decomposition of nitrosotriacetonamine appears to be a specific hydroxide-ion-catalyzed reaction. k = k OH [OH - ] Many reactions are catalyzed by both acids and bases. Familiar examples are the hydrolyses of esters, amides and nitriles. The mutarotation of glucose and the enolization of acetone have been found to be general acid- and general base-catalyzed, whereas oxygen exchange between H 2 O and acetone is reported to be general acid-catalyzed but base- (OH - ion) catalyzed.

Method of determining reaction mechanism: 

Method of determining reaction mechanism A reactant may thus require both an acid and a base to assist in its transformation to the product, it does not necessarily follow that both must enter the reaction at or before the rate-controlling step. If an acid can take part in the rate-controlling step and the base enter only into a subsequent rapid step. If the reaction involves the transformation of very weakly basic reactant S to its conjugate acid as its rate-controlling step in order to reach the product P.

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then the rate equation for the reaction = k 1 [S][HA] will predict general acid catalysis regardless of the nature of the rapid second step of the reaction.