Esters vs. Anhydrides

Anhydrides and esters are routinely used as aeylating agents. Anhydrides, however, are the reagents of ehoice for aeylating alcohols. For example, aeetylation of cholesterol is carried out using acetic anhydride (Z = 0C(=0)CH3), and not ethyl acetate (Z = OCH2CH3). 

Anhydrides and esters may differ in two ways. One may undergo nucleophilic addition more rapidly (kinetics), but the other may create a more favorable equilibrium constant for ester formation (thermodynamics). 

Kinetic reactivity can be assessed by examining the lowest-unoccupied molecular orbital (LUMO). This is the orbital into which the nucleophile s pair of electrons will go. Compare the LUMO for acetic anhydride and ethyl acetate. For each, determine on which atom(s) the orbital has the largest lobes Do both reagents appear to be susceptible to nucleophilic attack at the carbonyl carbon  

A molecule with a lower energy LUMO will generally react more rapidly. The LUMO energies of acetic anhydride and ethyl acetate are 0.143 and 0.193 au, respectively. Which reagent is a better aeylating agent in the kinetic sense  

Calculate the thermodynamics of acetylation of cholesterol (to cholesterol acetate) using both acetic anhydride and ethyl acetate. Data for acetic acid and ethanol are available. Which reaction is more favorable  

---

Figure 2.4 Log of the relative rate constants of anhydride formation kret from mono-p-bromophenyl esters vs. the log of the probability (P) of NAC formation of each monophenyl ester of the various dicarboxylic acids (Bruice, 2000).

In 1981 Tseng et al. reported for the first time that the ester derived from the acetylation of HPC (Mw = 100,000 g/mol), the acetoxypropylcellulose (APC), in the presence of anhydride acetic using pyridine as a catalyst, readily forms cholesteric liquid crystalline solutions with organic solvents and also formed a thermotropic cholesteric phase below 180 °C. The authors additionally presented an alternative (less hazardous) synthetic route where no pyridine was used. This later method requires the use of acetic acid as an initiator of the esterification reaction. Nevertheless a longer time was needed, 1 week vs. 1 day, to achieve a similar degree of esterification DE), see Scheme 14.4. The properties of the... 

The influence of structural and electronic parameters on the acylation and deacylation rate were separately studied (catalyst-on half cycle vs. catalyst-off half cycle cf. scheme 7.10). Through kinetic H-NMR-studies it was proven that the acylation rate of the dialkyl amino alcohol catalysts and an acyl donor (butyric anhydride) depends on the number of (carbon) spacer atoms between hydroxyl and tertiary amine, the flexibility of the molecule and the presence and position of further heteroatoms. Besides, it could be detected that the methanolysis (off-half cycle) of the formed ]3-amino ester intermediate follows a similar trend as the acylation reaction, but appeared to be rate limiting in this studies setup. The information was used for the selective auto-catalytic acylation and deacylation of complex natural antibiotics. 

---