The Acidity of Alcohols and Phenols

Like water, alcohols and phenols are weak acids. The hydroxyl group can act as a proton donor, and dissociation occurs in a manner similar to that for water  

The conjugate base of an alcohol is an alkoxide ion (for example, methoxide ion from methanol, ethoxide ion from ethanol, and so on). 

Phenol is a much stronger acid than ethanol. How can we explain this acidity difference between alcohols and phenols, since in both types of compounds, the proton donor is a hydroxyl group  

Because phenoxide ions are stabilized in this way, the equilibrium for their formation is more favorable than that for alkoxide ions. Thus, phenols are stronger acids than alcohols. 

Polar bonds that place a partial positive charge near the negative charge on an alkoxide ion stabilize the ion by an inductive effect. 

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To compare the acidity of alcohols and phenols with that of other organic compounds, see Table C in the Appendix. 

The addition of alcohols and phenols to double bonds is catalyzed by acids or bases. When the reactions are acid catalyzed, the mechanism is electrophilic, with H as the attacking species. The resulting carbocation combines with a molecule of alcohol ... 

Several organohypervalent iodine reagents have been used for the oxidation of alcohols and phenols such as iodoxybenzene, o-iodoxybenzoic acid (IBX), bis(trifluoroa-cetoxy)iodobenzene (BTI), and Dess-Martin periodinane etc. But the use of inexpensive iodobenzene diacetate (IBD) as an oxidant, however, has not been fully exploited. Most of these reactions are conducted in high boiling DMSO or toxic acetonitrile media that results in increased burden on the environment. 

Several authors reported the use of ionic liquids containing protonic acid in catalysis (118-120). For example, strong Bronsted acidity in ionic liquids has been reported to successfully catalyze tetrahydropyranylation of alcohols (120). Tetra-hydropyranylation is one of the most widely used processes for the protection of alcohols and phenols in multi-step syntheses. Although the control experiments with the ionic liquids showed negligible activity in the absence of the added acids, high yields of product were obtained with the ionic liquid catalysts TPPTS or TPP.HBr-[BMIM]PF6. By rapid extraction of the product from the acidic ionic liquid phase by diethyl ether, the reaction medium was successfully reused for 22 cycles without an appreciable activity loss. A gradual loss of the catalyst and a reduced volume of the ionic liquid were noted, however, as a consequence of transfer to the extraction solvent. 

Three different sets of experimental aqueous-phase pKa s allow us to judge to what extent solvent effects can be ignored and, where they cannot be ignored, assess the performance of the SMS. 4 model in accounting for solvation. The first involves a diverse set of carboxylic acids and the second a diverse series of alcohols and phenols. Calculated acidities (relative to acetic acid in the case of carboxylic acids and relative to ethanol in the case of alcohols and phenols) have been obtained from the Hartree-Fock 6-311+G model. Previous comparisons with gas-phase acidities suggest that this should be as satisfactory as any other model for this purpose (see, for example. Tables 6-18 and A6-50). 6-3IG geometries have been used in place of 6-311+G geometries in order to save computation time. (See... 

Several points become apparent from a study of Table 7-VI. Equilibrium constants have not been determined with great accuracy— three- to four-fold variation between determinations is common. Solvent disturbances of the acid dimerization is clearly detected in the equilibrium constants. In benzene and CHCI3, K may be only 1/10 its value in CCI4. The two values available for ethanthiol and thiophenol show the weaker interactions of S—groups iTaBsn is about 1/25 that of comparable O—H compounds. The acid dimer is a more favorable arrangement than the dimers of alcohols and phenol. 

Parameters such as solvent, basic medium and reaction time, affecting the derivatization of alcohols and phenols with benzoyl chloride, were investigated. End analysis was by GC with UVD . a sensitive method proposed for trace determination of phenols in water consists of preconcentration by SPE with a commercial styrene-divinylbenzene copolymer, acylation with pentafluorobenzoyl chloride in the presence of tetrabutylammonium bromide and end analysis by GC with either ECD or ITD-MS. LOD was 3 to 20 ngL for ECD and 10 to 60 ngL for ITD-MS, with 500 mL samples . Acylation with the fluorinated glutaric acid derivative 43 was proposed for determination of urinary phenols, as indicative of exposure to benzene and other aromatic hydrocarbons. End analysis by GC-MS shows strong molecular ions of the derivatives by electron ionization. The proto-nated ions are the base peaks obtained by chemical ionization. LOD was 0.5 mgL and the linearity range 0-100 mg L for phenol . 

Reactions Involving the O-H Bond of Alcohols and Phenols A. Relative Acidities of Alcohols and Phenols... 

Organohypervalent iodine reagents such as iodoxybenzene, o-iodoxybenzoic acid (IBX), bis(trifluoroacetoxy)iodobenzene (BTI), and Dess-Marhn periodinane have been used for the oxidation of alcohols and phenols. Most of these reactions are conducted in high-boiling DMSO or relahvely toxic acetonitrile, which increase the burden on the environment. Further, the use of inexpensive iodobenzene diacetate (IBD) as an oxidant has not been fully exploited. Varma et al. have reported the first use of supported iodobenzene diacetate as an oxidant. In this novel oxidative protocol, alumina-supported IBD under solvent-free conditions rapidly converts alcohols to the corresponding carbonyl compounds in almost quantitative yields. The use of alumina as a support improved the yields markedly as compared to neat IBD (Scheme 2.2-40). 1,2-Benzenedimethanol, however, undergoes cyclization to afford l(3H)-isobenzofuranone [116]... 

Compound 468 readily replaced 1-0-acetyl group for a number of alkoxy, aryloxy, and thioalkoxy groups in reactions with alcohols, phenols, or thiols in the presence of p-toluenesulfonic acid. In the case of alcohols and phenols, the reaction was stereospecific and 3-anomers (472) were formed. With thiols, both anomeric thioglycosides (473) were obtained in about equal proportions. 

One of the earliest systematic efforts to find correlates between the acidities of alcohols and direct structural properties was the observation by Goulden of a linear relation between the aqueous pK s of phenols and their OH vibrational frequencies measured in carbon tetrachloride solution [276]. For carboxylic acids Goulden found three separate lines for the pK -v(OH) plots, depending on the nature of the residues connected to the COOH group. 

Another new reagent for the protection of alcohols and phenols is 2-trimethyl-silylethoxymethyl chloride (67), said to be readily available. The derived SEM ethers (Scheme 30) are stable to acidic conditions that remove 2-tetrahy-dropyranyl, 2-tetrahydrofurfuryl, and trialkylsilyl groups, but can be cleaved by fluoride ion. Phenylthiomethyl ethers may be used in the protection of phenols. They have been reported as more resistant to hydrolysis than aliphatic or aromatic methylthiomethyl ethers, and are removed with mercuric chloride. 

We have discussed the effect of structure on the acidity of alcohols and on the basicity of amines. The acid-base properties of their aromatic cousins, phenols and anilines, are affected by the aromatic ring. Both the pif values of phenols and the values of anilines illustrate this effect. 

The reagent will selectively protect the amino group in the presence of alcohols and phenols as well as carboxylic acids. Examples include the Boc protection of a kanamycin A derivative (eq 4) and of the glycopeptide antibiotic A41030A (eq 5). ... 

C2H4N2O3, NH2CONHCOOH. Unknown in the free state as it breaks down immediately to urea and COi- The NH4, Ba, Ca, K and Na salts are known and are prepared by treating ethyl allophanate with the appropriate hydroxide. The esters with alcohols and phenols are crystalline solids, sparingly soluble in water and alcohol. They are formed by passing cyanic acid into alcohols or a solution of an alcohol or phenol in benzene. The amide of allophanic acid is biuret. Alcohols are sometimes isolated and identified by means of their allophanates. 

Although the acetylation of alcohols and amines by acetic anhydride is almost invariably carried out under anhydrous conditions owing to the ready hydrolysis of the anhydride, it has been shown by Chattaway (1931) that phenols, when dissolved in aqueous sodium hydroxide solution and shaken with acetic anhydride, undergo rapid and almost quantitative acetylation if ice is present to keep the temperature low throughout the reaction. The success of this method is due primarily to the acidic nature of the phenols, which enables them to form soluble sodium derivatives, capable of reacting with the acetic... 

The reaction of alcohols and acid chlorides in the presence of magnesium has been described (68). With primary and secondary alcohols the reaction is very smooth, and affords high and sometimes quantitative yields. Difficulty esteritiable hydroxy compounds such as tertiary alcohols and phenols can be esteritied by this method. The reaction carried out in ether or benzene is usually very vigorous with evolution of hydrogen. 

Isopropenyloxytrimethylsilane. In the presence of an acid catalyst the reagent silylates alcohols and phenols. It also silylates carboxylic acids without added catalyst. 

Although much weaker than mineral acids, carboxylic acids are nevertheless much stronger acids than alcohols and phenols. The Ka of ethanol, for example, is approximately 10 l6, making ethanol a weaker acid than acetic acid... 

Further examples of the reaction ROH -> RC02R are included in Section 107 (Esters from Acid Derivatives) and in Section 45 A (Protection of Alcohols and Phenols). 

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