Haloalkanes and Alcohols

Compounds with a halogen atom bonded to an sp -hybridized carbon atom are called halo-alkanes. Halogens can also bond to an sp -hybridized carbon atom of an aromatic compound or an alkene. However, since the chemistry of these compounds is very different, we will not consider them in this chapter. Compounds with the halogen atom bonded to an sp-hybridized carbon atom, which are very unstable, are seldom encountered. We will primarily focus on the chemistry of chloro and bromo compounds. lodo compounds are less stable. The chemistry of fluoro compounds is somewhat different from the other halogen compounds, and we will not discuss fluoro compounds in this text. 

Alcohols contain a hydroxyl group bonded to an sp -hybridized carbon atom. Com-poimds in which a hydroxyl group is bonded to the sp -hybridized carbon atom of a benzene ring are called phenols. The distinction between an alcohol and a phenol is illustrated by the two isomeric structmes shown below. We will discuss the chemistry of phenols, which differs from that of alcohols, in Chapter 23. 

This hydroxyl group is bonded to an sp -hybridized carbon atom. The compound is a phenol. 

Haloalkanes and alcohols are classified as primary (1°), secondary (2°), or tertiary (3°) according to the number of alkyl groups bonded to the carbon atom bearing the halogen or hydroxyl group. 

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Before we examine other classes of compounds and their properties, we need to learn more about the structures and, in particular, the geometric shapes of organic molecules. In Chapter 4 we discuss compounds that contain atoms in rings and in Chapter 5 we study additional forms of isomerism. The ideas we introduce are a necessary background as we begin a systematic study in the chapters that follow of polar reactions of haloalkanes and alcohols. 

In Section 6-1 we invoked the polarity of the haloaUcanes to explain why their boiling points are higher than those of the corresponding nonpolar alkanes. The polarity of alcohols is similar to that of the haloalkanes. Does this mean that the boiling points of haloalkanes and alcohols correspond Inspection of Table 8-1 shows that they do not Alcohols have unusually high boiling points, much higher than those of comparable alkanes and haloalkanes. 

Table 9-2 Comparison of the Boiling Points of Thiols, Haloalkanes, and Alcohols...

In this chapter, we looked at alkenes, a compound class characterized by the carbon-carbon double bond. In Chapters 7 and 9, we learned that alkenes are prepared synthetically by elimination reactions of haloalkanes and alcohols, hi this chapter, we examined these reactions in more depth. We saw that the structure of the base determines what products will form in E2 elimination from haloalkanes. Similarly, the stracture of an alcohol undergoing acid-catalyzed dehydration determines what mechanism takes place and how easily it occurs. 

Haloalkanes and alcohols are important starting materials in the synthesis of compounds with other functional groups. Primary haloalkanes react with hydroxide ion to give alcohols, although we will see that elimination reactions compete with substitution for secondary and tertiary halides. 

In Chapter 9, we introduced the basic principles of nucleophilic substitution and elimination reactions. We focused almost entirely upon the reactions of haloalkanes and alcohols. In this chapter, we will expand upon these reactions and consider a much wider range of nucleophiles, leaving groups, substrates, solvents, and their effects on nucleophilic substitution and elimination reactions. We will ask ... 

Variables a andZ are specific constants reported by Tsonopoulos for some alcohols and water (e.g., methanol a = 0.0878, b = 0.0560 and water a = 0.0279, b = 0.0229). Tsonopoulos also gives specific prediction methods for haloalkanes and water pollutants. 

Aqueous solutions are not suitable solvents for esterifications and transesterifications, and these reactions are carried out in organic solvents of low polarity [9-12]. However, enzymes are surrounded by a hydration shell or bound water that is required for the retention of structure and catalytic activity [13]. Polar hydrophilic solvents such as DMF, DMSO, acetone, and alcohols (log P<0, where P is the partition coefficient between octanol and water) are incompatible and lead to rapid denaturation. Common solvents for esterifications and transesterifications include alkanes (hexane/log P=3.5), aromatics (toluene/2.5, benzene/2), haloalkanes (CHCI3/2, CH2CI2/I.4), and ethers (diisopropyl ether/1.9, terf-butylmethyl ether/ 0.94, diethyl ether/0.85). Exceptionally stable enzymes such as Candida antarctica lipase B (CAL-B) have been used in more polar solvents (tetrahydrofuran/0.49, acetonitrile/—0.33). Room-temperature ionic liquids [14—17] and supercritical fluids [18] are also good media for a wide range of biotransformations. 

In general, the rates of reduction by the ammonium salts are slower than those attained under normal conditions with the lithium salts, but the use of a non-ethereal solvent can be an advantage. Quaternary ammonium aluminium hydrides reduce ketones and amides effectively to alcohols and amines. Nitriles are also reduced to amines, whereas haloalkanes and arenes are reductively dehalogenated to give hydrocarbons in high yield [3]. 

Reduction of conjugated carbonyl compounds using stoichiometric amounts of the ammonium salt shows little advantage over the sodium salt in acidic methanol [11] with both reagents producing allylic alcohols (58-88% for acyclic compounds and 15-64% for cyclic compounds) by selective 1,2-reduction of the conjugated systems. Aldehydes, ketones and conjugated enones are also reduced by tetra-n-butylammonium cyanoborohydride in HMPA [11, 12], whereas haloalkanes and alkanesulphonic esters are cleaved reductively under similar conditions [13]. 

It is interesting to note that boiling points of alcohols and phenols are higher in comparison to other classes of compounds, namely hydrocarbons, ethers, haloalkanes and haloarenes of comparable molecular masses. For example, ethanol and propane have comparable molecular masses but their boiling points differ widely. The boiling point of methojqmiethane is intermediate of the two boiling points. 

S)-2-Amino-3-methylbutanol [(S)-valinol] derived oxazolidinones, i.e., (S)-3-acyl-4-iso-propyl-2-oxazolidinones 1, have been used extensively for the preparation of a-alkylated acids, aldehydes and alcohols. The enolates are formed by deprotonation with lithium diisopropyl-amide or sodium hexamethyldisilazanide at low temperature in tetrahydrofuran. Subsequent addition of a haloalkane gives alkylation, which occurs from the Si-face2. The diastereoselectivities are usually good (>90 10), and the products are usually purified by flash chromatography and/or recrystallization (see Table 10). Additional examples of alkylation of 1 have been published5 l0 12- 20 22-29 39.44.-47,49.57.70-78... 

Among the fluoride ion promoted reactions which occur in dipolar non-HBD solvents are alkylations of alcohols and ketones, esterifications, Michael additions, aldol and Knoevenagel condensations as well as eliminations for a review, see reference [600]. In particular, ionic fluorides are useful in the dehydrohalogenation of haloalkanes and haloalkenes to give alkenes and alkynes (order of reactivity R4N F > K ([18]crown-6) F > Cs F K F ). For example, tetra-n-butylammonium fluoride in AjA-dimethylformamide is an effective base for the dehydrohalogenation of 2-bromo-and 2-iodobutane under mild conditions [641] cf Eq. (5-123). 

The most common functional groups with only single bonds are alcohols, haloalkanes, and amines. 

Nucleophilic Opening. A neutral hydrolysis medium, more effective than water alone is provided by the combination of water and a polar aprotic solvent eg. HMPA or NMP (N-methyl-2-pyrrolidone). Thus 15 aqueous NMP at 130°C containing NaHCO will open terminal (but not internal) epoxides to diols (>90 ) as well as convert haloalkanes to alcohols in high yields. 

The or /io-positions of the benzene ring in 4,4-dimethyl-2-phenyl-4,5-dihydrooxazole 13, prepared from benzoyl chloride and the amino alcohol 12, are activated to such an extent that lithiation is possible. On reaction with an electrophile, e.g. a haloalkane, and followed by hydrolysis, 2-substituted or 2,6-disubstituted benzoic acids 14 or 15 are obtained [78] ... 

It is ab.solutcly necessary to know the.se interconversion patterns, because they provide the framework fttr designing synthetic strategy. Suppose we wish to synthesize an alcohol starling with an alkane. From this chart, we. see immediately that we have no direct method for converting tilkanes to alcohols. We must first itiake a haloalkane and then use it in another reaction to make an alcohol. We set up the proposed synthesis in just that way and insert the specific reagents necessary to carry out the two synthetic steps ... 

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