Replacement of the hydroxyl group

It is only in some special, but nevertheless not unimportant, cases that direct replacement of hydroxyl by hydrogen is of preparative importance for primary and secondary hydroxyl groups, in particular, detours are often more convenient. For primary groups the route is usually via halides, but for secondary groups also via the unsaturated compounds which are readily formed from secondary alcohols. Tertiary hydroxyl groups can usually be replaced directly by hydrogen with less difficulty, for which purpose a non-noble metal in alcohol or an acid ( e.g., sodium and alcohol or zinc and hydrochloric acid) or catalytic hydrogenation may be used. 

In the route via the halides, the latter need not be obtained in the pure state when the substituting reagent has also reducing action, as in the case of hydrogen iodide. For that reason, reactions of alcohols with hydrogen iodide will here be considered as involving direct exchange of OH for H. 

For economic reasons it is not usual to work with stoichiometric amounts of hydrogen iodide instead, red phosphorus is added, which in the presence of water continuously regenerates hydrogen iodide from the elemental iodine formed. It often suffices to use a mixture of phosphorus and iodine to which 

Hydroxy carboxylic acids are also reduced similarly to carboxylic acids. For instance, diphenylacetic acid is obtained in more than 90% yield from benzilic acid.464 

A tertiary hydroxyl group is replaced appreciably more easily than a secondary or primary one. For instance, linalool (CH3)2C=CHCH2CH2C(CH3) (OH)—CH=CH2, whose tertiary hydroxyl group lies next to a double bond, is converted into the hydrocarbon diene even by zinc dust in a bomb tube.468 In fact, it is often possible to decide from the occurrence or non-occurrence of this reaction whether a hydroxyl group is tertiary as opposed to secondary or primary.469 

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Halogenation. Normally, 2-halopropane derivatives are prepared from isopropyl alcohol most economically by reaction with the corresponding acid haUde. However, under appropriate conditions, other reagents, eg, phosphoms haUdes and elemental halogen, also react by replacement of the hydroxyl group to give the haUde (46). 

NH form e.g. 505). Most 4- and 5-hydroxy compounds of types (500) and (502) exist largely in these non-aromatic azolinone forms, although the hydroxyl form can be stabilized by chelation e.g. 506). The derived ambident anions react with electrophiles at O or C. Replacement of the hydroxyl group is sometimes possible provided electron-withdrawing groups are present as, for example, in 5-substituted 4-hydroxypyrazoles. 

Highly fluorinated tertiary alcohols usually give olefins on iluormation with sulfur tetrafluoride [759/, but in certain cases, replacement of the hydroxyl group with fluorine occurs under mild conditions Hexafluoro-2-arylpropan-2-ols react with sulfur tetrafluoride at low temperatures to give high yields of heptafluoro-isopropylarenes [766] (equation 77), and similarly, 3,8 dihydroxy 9,9,9,10,10,10-hexafluoro-p-menthane affords 3,8,9,9,9,10,10,10-octafluoromenthane [766] (equation 78)... 

Perfluoropmacol reacts with sulfur tetrafluonde in an unconventional way instead of replacement of the hydroxyl groups by fluorine, the substitution of four fluonne atoms in the sulfur tetrafluonde molecule with oxygen occurs to give the corresponding spirosulfurane [J6J] (equation 79)... 

Thus, reduction of the Mannich reaction product (65) from acetophenone leads to alcohol 66. Replacement of the hydroxyl group by chlorine (67) followed by displacement of halogen with the anion from o-cresol affords the ether 68. Removal of one of the methyl groups on nitrogen by means of the von Braun reaction or its modem equivalent (reaction with alkyl chloroformate followed by saponification) leads to racemic 69 which is then resolved with L-(+)-mandelic acid to give the levorotary antidepressant tomoxetine (69) [16]. 

In a similar way, 5-O-acetylthymidine was converted into the 3-deoxy-3-iodo derivative 72 in 55% yield. In this case, the replacement of the hydroxyl group by iodine was presumed to have taken place by retention of the configuration at C-3. The first intermediate in the reaction was proposed to be the phosphonate (70) which rapidly collapses to an O-3-cyclonucleoside (71) and the latter is subsequently attacked by iodide ion to give the product 72. It was also observed (106) that treatment of nucleosides containing a cis vicinal diol grouping such as 5-0-acetyluridine with triphenylphosphite methiodide failed to provide iodinated products but gave phosphonate derivatives instead. 

Treatment of 8 with phosphorus oxychloride leads to replacement of the hydroxyl group by chlorine... 

Replacement of the hydroxyl group on the phenyl ring with a carboxyl group forms a molecule of benzoic acid. Addition of a hydroxyl at the 2-position on a benzoic acid molecule forms 2-hydroxybenzoic acid or salicylic acid. The slightly more complex phenylpropanoid skeleton contains a linear three-carbon chain (the propanoic group) added to the benzene ring (the phenyl group). Addition of ammonia to carbon 2 of this three-carbon side chain yields the amino acid phenylalanine (Fig. 3.3). Phenylalanine... 

Synthesis of Compound I. As shown in Scheme II, 3-(thiophene-3-yl)propyl bromide can be prepared by a two-carbon homologation(2 ) of 3-thenyl bromide via reaction with diethyl malonate to form diethyl 3-thenylmalonate. This is followed by saponification, decarboxylation, reduction of acid to alcohol, (2 ) and replacement of the hydroxyl group with bromide by reacting with PBr3.(22) Compound 2 is synthesized by mono-quaternization of an excess of 4,4 -bipyridine with 3-(thiophene-3-yl)propyl bromide followed by N-methylation with CH3I. All the intermediates in Scheme II have been identified by NMR spectroscopy. 2 has been characterized by NMR and high resolution mass spectroscopy and by electrochemistry. 

D,L-Cycloserine 26 and its 3-methyl analog, derivatives of isoxazolinone, were prepared from D,L-Ser or o.L-Thr. The transformation involved replacement of the hydroxyl group by chlorine and subsequent treatment with hydroxylamine (57HCA1531). After being transformed into its 3-chloro derivative, l-G1u was transformed in a multistep conversion into 27, an intermediate in the synthesis of an antitumoric isoxazole-5-acetic acid (81JA7357). 

Several condensation routes to 2,3 -bipyridinones have been reported. Thus 3-acetylpyridine and nicotinaldehyde were condensed to the a,/ -unsat-urated ketone 45, which reacted in a Michael condensation with l-(car-bamoylmethyl)pyridinium chloride (46) to give 2,4-di(3-pyridyl)-6-pyridone (47). Compound 47 was converted to the alkaloid nicotelline 10 by replacement of the hydroxyl group of 47 by chlorine, followed by reductive dehalogenation. Related condensations have been described, including the synthesis of 4,6-diphenyl-2,3 -bipyridine. Similarly, aldehyde 48 was condensed with cyanoacetamide (49) to afford 2-(3-pyridyl)-5-cyano-6-pyridone (50), the cyano group of which was hydrolyzed and decarbox-ylated to 2,3 -bipyridin-6-one. Several modifications and extensions of... 

Telomers 422 (n = 2) and other 4-halogeno-l,3-dioxolan-2-ones were shown288 to react readily with ammonia or primary aliphatic amines, with formation of 4-hydroxy-2-oxazolidones (460). The latter, for which the trans arrangement of the hydrogen atoms of the oxazoli-done ring was deduced from H-n.m.r. data, readily underwent replacement of the hydroxyl group by a phenyl group on reaction with... 

Bis(bromomethyl)propane-l,3-diol can be produced by replacement of the hydroxyl groups of pentaerythritol with bromide (National Toxicology Program, 1996). 

Chitin is a linear homopolysaccharide composed of Af-acetylglucosamine residues in /3 linkage (Fig. 7-18). The only chemical difference from cellulose is the replacement of the hydroxyl group at C-2 with an acety-lated amino group. Chitin forms extended fibers similar to those of cellulose, and like cellulose cannot be digested by vertebrates. Chitin is the principal component of the hard exoskeletons of nearly a million species of arthropods—insects, lobsters, and crabs, for example— and is probably the second most abundant polysaccharide, next to cellulose, in nature. 

These results suggest that the replacement of the hydroxyl group at C-l by chlorine occurs by way of an intermediate chlorosulfate, resulting in an overall inversion of configuration moreover, they show that anomerization does not occur to any significant extent under the reaction conditions. 

One of the most useful ways of introducing fluorine into organic compounds is the replacement of the hydroxyl group in alcohols hydroxy compounds, and carboxylic acuis Methyl alcohol reacts with anhydrous hydrogen fluoride at 100 500 °C in the presence of aluminum fluoride [60, 61], zinc fluoride [62] chromium fluonde [63], or a mixture of aluminum and chromium fluorides [64] to give a 20-78% yield of fluoromethane Attempted fluonnations of higher alcohols by this method failed [60]... 

A functional derivative of a carboxylic acid is a substance formed by replacement of the hydroxyl group of the acid by some other group, X, such that it can be hydrolyzed back to the acid in accord with Equation 18-7 ... 

Replacement of the hydroxyl group in a phenol by halogen cannot be accomplished by reaction with the hydrogen halides as in the case of alcohols, and reaction with phosphorus halides gives only low yields of halogenobenzenes (except in the case of nitrophenols), the main product being a phosphite or phosphate ester. 

The direct replacement of the hydroxyl group in simple phenols by an amino or substituted amino group requires drastic conditions and the method is not suitable for laboratory preparations. With the polyhydric phenols, and more particularly with the naphthols, such replacements occur more readily. Thus 2-naphthol is converted into 2-naphthylamine by heating with ammoniacal ammonium sulphite solution at 150°C in an autoclave. The reaction (the Bucherer reaction) depends upon the addition of the hydrogen sulphite ion to the keto form of the naphthol and the subsequent reaction with ammonia. 

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