Entropy intramolecular reactions

Fig. 23 Entropy effects on intramolecular reactions of polymethylene chains. Plot of 9AS (e.u.) against number of single bonds for (O) nucleophilic substitutions at saturated carbon ( ) electron-exchange reactions (A) quenching of benzophenone phosphorescence. The straight line has intercept +30 e.u. and slope —4.0 e.u. per rotor. The right-hand ordinate reports the purely entropic EM s calculated as exp(0AS /J )...

The same models as for intermolccular processes are applied for intramolecular diastereoface differentiating double-bond additions. However, there are some advantages in the intramolecular version. Firstly, the entropy factor lowers the barrier of activation and allows reactions to proceed at lower temperatures, which increases the selectivity. Secondly, the cyclic transition states introduce the elements of ring strain and transannular interactions, which lead to enhanced differences between two diastereomorphous geometries. Both of these factors cooperate to increase the selectivity of the intramolecular reaction. For example, halolactonization, by definition, is an intramolecular process. 

It can be argued that an important factor favoring intramolecular reaction is the more favorable entropy of activation. Any bimolecular reaction must involve loss of translational entropy since two molecules are gathered into one transition state. The intramolecular reaction of a flexible molecule must involve loss of entropy because of restriction of free rotation. This negative AS will not be involved or will be less extensive, in the rigid systems. ... 

The catalytic advantage of an intramolecular reaction over its intermolecular counterpart is due to entropy. The intermolecular reaction involves two or more molecules associating to form one. This leads to an increase in order and a consequent loss of entropy. An effective concentration may be calculated from... 

The lower effective concentrations found in intramolecular base catalysis are due to the loose transition states of these reactions. In nucleophilic reactions, the nucleophile and the electrophile are fairly rigidly aligned so that there is a large entropy loss. In general-base or -acid catalysis, there is considerable spatial freedom in the transition state. The position of the catalyst is not as closely defined as in nucleophilic catalysis. There is consequently a smaller loss in entropy in general-base catalysis, so that the intramolecular reactions are not favored as much as their nucleophilic counterparts. 

Generally intramolecular reactions are easier than intermolecular reactions entropy being a major factor. If you want to make an acetal from a ketone (chapter 6) it is better to use a diol 47 rather than, say methanol. The equilibrium is in favour of the cyclic acetal 48 but not in favour of the methyl acetal 46. Two molecules—one of each—go into 48 but three—two alcohols and one ketone—go into 46. Entropy is a thermodynamic factor. 

The high rate of the lactonizations in Figure 6.27 is a consequence of the less negative than usual activation entropies, from which intramolecular reactions that proceed via three, five-,... 

Intramolecular reactions are favored by entropy. Recall that entropy is a measure of the disorder of a system. It costs energy to put order into a system—to decrease the entropy of that system. In the case of an intermolecular reaction, the nucleophile and the electrophile must first come together from their initial random positions. This requires an increase in the order of the system, an entropically unfavorable process. In the case of an intramolecular reaction, the nucleophile is held in proximity to the electrophile by the connecting carbon chain. It takes a much smaller increase in the order of the system to position the nucleophile for reaction. In other words, the nucleophile is much closer to the electrophile at all times, and attaining the proper orientation required for the reaction is much more probable. 

In this example the oxygen of the hydroxy group acts as an intramolecular nucleophile. Recall from Section 8.13 that intramolecular reactions are favored by entropy. Therefore, the formation of a cyclic hemiacetal has a larger equilibrium constant than a comparable intermolecular reaction. This reaction is especially important in the area of carbohydrates (sugars) because sugars contain both carbonyl and hydroxy functional... 

Up to this point, the structure of glucose has been shown as an aldehyde with hydroxy groups on the other carbons. However, as described in Section 18.9, aldehydes and ketones react with alcohols to form hemiacetals. When this reaction is intemiolecular— that is, when the aldehyde group and the alcohol group are in different molecules—the equilibrium is unfavorable and the amount of hemiacetal that is present is very small. However, when the aldehyde group and the alcohol group are contained in the same molecule, as is the case in the second equation that follows, the intramolecular reaction is much more favorable (because of entropy effects see Sections 8.13 and 18.9) and the hemiacetal is the predominant species present at equilibrium. 

The high rate of the lactonizations in Figure 6.22 is a consequence of the less negative than usual activation entropies, from which intramolecular reactions that proceed via three, five-, or six-membered transition states always profit. The high lactonization tendency stems from an increase in entropy, from which intermolecular esterifications do not profit Only during lactonization does the number of molecules double (two... 

Entropy dominates equilibrium constants in the difference between inter- and intramolecular reactions. In Chapter 6 we explained that hcmiacetal formation is unfavourable because the C=0 double bond is more stable than two C-0 single bonds. This is clearly an enthalpy factor depending simply on bond strength. That entropy also plays a part can be clearly seen in favourable intramolecular hemiacetal formation of hydroxyaldehydes. The total number of carbon atoms in the two systems is the same, the bond strengths are the same and yet the equilibria favour the reagents (MeCHO + EtOH) in the inter- and the product (the cyclic hemiacetal) in the intramolecular case. 

Cyclizations to form larger rings require the formation of a cyclic transition state from long-chain acyclic precursors which can adopt numerous conformations. This requirement implies a significant loss of entropy due to the coiling of the extended acyclic precursor. The increased entropy demands affect the rate of the intramolecular reaction substantially, as can be seen from the comparison of rate data for the formation of homologous lactones in the reaction of 305 306 (Scheme 2.113) ... 

As we have already mentioned, intramolecular reactions generally proceed faster compared to their intermolecular versions because of the substantial reduction in the entropy barrier. Therefore it is not surprising that intra-... 

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