Secondary haloalkanes

Secondary Haloalkanes. Secondary alkyl systems undergo, depending on conditions, both eliminations and substitutions by either possible pathway uni- or bimolecular. Good nucleophiles favor Sn2, strong bases result in E2, and weakly nucleophilic polar media give mainly SnI and El. 

The haloalkane is a 2° haloalkane. Secondary haloalkanes undergo substitution reactions by either the Sisjl or Sisj2 depending on the nucleophile and solvent. (See Table 27.2.)... 

Modifying the reaction medium to involve liquid ammonia with metallic lithium, f-butyl alcohol, and white phosphorus, to which is added the haloalkane, is reported to provide the primary alkylphos-phine derived from the haloalkane.19 Similar results are reported for the reaction of red phosphorus with sodium acetylides20 and by treatment of red phosphorus with sodium metal in an organic medium followed by the addition of two equivalents of f-butyl alcohol and the haloalkane.21 The latter approach is noteworthy in that moderate yields (45%) are obtained for primary phosphines derived from secondary haloalkanes (Figure 2.6). Mixtures of tertiary phosphines bearing one or two acetylenic linkages are produced in low yield ( 15%) by the reaction of lithium acetylides with white phosphorus in liquid ammonia followed by addition of a haloalkane.22... 

Step 1 is fundamentally an SN2 reaction (kinetics related to structural variations of the reactants,16 8 retention of stereochemistry at phosphorus912), except in those instances wherein a particularly stable carbocation is produced from the haloalkane component.13 A critical experiment concerned with verification of the Sn2 character of Step 1 by inversion of configuration at the carbon from which the leaving group is displaced was inconclusive because elimination rather than substitution occurred with the chiral secondary haloalkane used.14 An alternative experiment suggested by us in our prior review using a chiral primary substrate apparently has not yet been performed.2... 

Haloalkanes are the most common substrates for the Michae-lis-Becker reaction.162-170 Of course, primary and benzylic halides provide more favorable reactions than secondary halides... 

Typically, the organic substrate in these reactions is a haloalkane. Primary haloalkanes will generally give 100% substitution products, but tertiary and cyclohexyl halides usually undergo 100 % elimination, with secondary haloalkanes producing a mixture of the two. Studies of the chloride and bromide displacements of (R)-2-octyl methanesulfonate have shown that phase transfer displacements proceed with almost complete inversion of stereochemistry at the carbon centre, indicating an Sjv2-like mechanistic pathway [41],... 

Although sodium sulphide reacts readily with haloalkanes [2] and activated aryl halides (see Chapter 2) [e.g. 3-5] in the presence of a quaternary ammonium catalyst to form symmetrical thioethers (Table 4.1), a major side reaction results in the formation of disulphides owing to the oxidation of the intermediate thiols under the basic conditions. Consequently, little use has been made of this procedure for the synthesis of thioethers [3, 6], but the corresponding reaction of the a,(0-dihaloalkanes to yield cyclic thioethers has proved to be a valuable procedure for the synthesis of thietanes [7] (Table 4.2). The ring closure with the secondary dihaloalkanes is considerably more difficult to effect than is the reaction of the primary dihaloalkanes. 1,3-Dihydrobenzo[c]thiophene (89%) is produced in the reaction of 1,2-bis(bromomethyl)benzene with sodium sulphide (Scheme 4.1) [8]. The direct... 

The catalysed two-phase alkylation of carboxamides has the advantages of speed and simplicity over the traditional procedures and provides a valuable route to secondary and tertiary amines by hydrolysis or reduction of the amides, respectively. The procedure appears to be limited, however, to reactions with primary haloalkanes and dialkyl sulphates, as secondary haloalkanes are totally unreactive [6, 7]. The use of iodoalkanes should be avoided, on account of the inhibiting effect of the released iodide ion on the catalyst. Also, the A-alkylation reaction is generally susceptible to steric effects, as seen by the low yields in the A -cthylation of (V-/-butylacetamide and of A-ethylpivalamide [6]. However, the low steric demand of the formyl group permits A,A-dialkylation and it is possible to obtain, after hydrolysis in 60% ethanolic sulphuric acid, the secondary amines having one (or, in some cases, two) bulky substituent(s) [7]. 

In contrast with the amides, which yield only A-alkylated products, the corresponding reaction of 5,5-dimethylisoxazolidin-3-one (Scheme 5.8) produces both the /V-and 0-alkylated derivatives [24] (Table 5.15). With the exception of the sec-bromobutane, the overall yields from primary and secondary haloalkanes are comparable, but there is a tendency for the secondary haloalkanes to produce slightly higher yields of the ethers. 

In a similar manner, saccharin has been A-alkylated and A-acylated (Table 5.17) [31, 32], There is good evidence that the kinetic O-alkylated product is initially formed and it is converted into the thermodynamically more stable A-alkyl derivative upon prolonged heating [31, 32], The reaction fails with secondary haloalkanes and is most successful with primary bromoalkanes [31, 32]. 

Methylenesulphones are more acidic than the simple esters, ketones and cyano compounds and are more reactive with haloalkanes [e.g. 48-57] to yield precursors for the synthesis of aldehydes [53], ketones [53], esters [54] and 1,4-diketones [55] (Scheme 6.4). The early extractive alkylation methods have been superseded by solidtliquid phase-transfer catalytic methods [e.g. 58] and, combined with microwave irradiation, the reaction times are reduced dramatically [59]. The reactions appear to be somewhat sensitive to steric hindrance, as the methylenesulphones tend to be unreactive towards secondary haloalkanes and it has been reported that iodomethylsulphones cannot be dialkylated [49], although mono- and di-chloromethylsulphones are alkylated with no difficulty [48, 60] and methylenesulphones react with dihaloalkanes to yield cycloalkyl sulphones (Table 6.5 and 6.6). When the ratio of dihaloalkane to methylene sulphone is greater than 0.5 1, open chain systems are produced [48, 49]. Vinyl sulphones are obtained from the base-catalysed elimination of the halogen acid from the products of the alkylation of halomethylenesulphones [48]. 

Haloalkanes are readily oxidized to the corresponding aldehydes or ketones. The best yields are attained with secondary alcohols and unsaturated hydroxyl groups [5]. a-Nitroketones, which are valuable intermediates in organic synthesis, are... 

Catalysed oxidation of non-activated haloalkanes by hypochlorite provides an attractive low-cost and convenient procedure for their conversion into carbonyl compounds [6] primary haloalkanes produce carboxylic acids and secondary haloalkanes are converted into ketones (Table 10.12). Secondary amines are oxidized to ketones under analogous conditions, whereas primary amines yield nitriles (Table 10.13) [1,2], o-Nitroanilines are oxidized to benzofurazan-1-oxides [15]. 

Selected examples of the oxidation of primary and secondary haloalkanes to carboxylic... 

One important factor that helps us to decide is the structure of the haloalkane, i.e. whether it is primary, secondary or tertiary. 

The reactivity order also appears to correlate with the C-X bond energy, inasmuch as the tertiary alkyl halides both are more reactive and have weaker carbon-halogen bonds than either primary or secondary halides (see Table 4-6). In fact, elimination of HX from haloalkenes or haloarenes with relatively strong C-X bonds, such as chloroethene or chlorobenzene, is much less facile than for haloalkanes. Nonetheless, elimination does occur under the right conditions and constitutes one of the most useful general methods for the synthesis of alkynes. For example,... 

Reaction of a secondary haloalkane with a basic nucleophile yields both substitution and elimination products. This is a less satisfactory method of ether preparation. 

It should be mentioned that a solvent change affects not only the reaction rate, but also the reaction mechanism (see Section 5.5.7). The reaction mechanism for some haloalkanes changes from SnI to Sn2 when the solvent is changed from aqueous ethanol to acetone. On the other hand, reactions of halomethanes, which proceed in aqueous ethanol by an Sn2 mechanism, can become Sn 1 in more strongly ionizing solvents such as formic acid. For a comparison of solvent effects on nucleophilic substitution reactions at primary, secondary, and tertiary carbon atoms, see references [72, 784]. 

Dehalogenation Dehalogenation of haloalkanes (R-X) is often carried out with trib-utyltin hydride (2.43) in the presence of AIBN (2.37). The reactivity of R-X is in the order ofR-I > R-Br > R-Cl (R-F being inert) tertiary > secondary > primary > aryl or vinyl. 

The alkynide ion can undergo alkylation with a variety of alkylating reagents, such as haloalkanes and alkyl sulfates, with the formation of a carbon-carbon bond. The alkynide ion is also strongly basic so that elimination reactions may accompany or subvert the substitution reaction. Group I metal alkynides in liquid ammonia give mainly substitution products with primary haloalkanes but secondary and tertiary haloalkanes give mainly elimination products, as do 2-substituted primary haloalkanes (equation 1). 

Lithium alkynides in tetrahydrofuran or dioxane often give substitution products with secondary haloalkanes, while alkynide Grignard reagents do not usually react with haloalkanes except in the presence of other metals such as cobalt and copper. Substitution of iodine or bromine for chlorine in the halo-alkane often leads to an increased yield of the alkylation product and alkanesulfonates may give greater yields than haloalkanes. Scheme 1 illustrates examples of alkylation of haloalkanes and alkyl sulfates with alkynides of Group I metals. 

With alkylating agents of three or more carbon atoms, the monoalkylate generally contained a mixture of isomeric alkylaromatics. Structurally, these isomers consisted of unbranched paraffin chains with the aryl residue attached at various secondary carbon atoms along the chain as in (A) and (B). With primary alcohols and haloalkanes, however, variable amounts of n-alkylaromatics (C) were formed. These patterns... 

It is evidently not possible to prepare the ((u-oxoalkyl)-phosphonic (519 R = R O) or -phosphinic diesters through direct reaction between a phosphorus(III) ester and an co-haloalkanal. However, the corresponding acetals (520 = 1 or 2) are readily available in this way precautions have to be taken to avoid overheating which can result in the loss of ethanol (when n - ) and the formation of the enol ether 521, a process which becomes more prevalent in the synthesis of the secondary compounds 522 Gentle hydrolysis of the acetals 520, using very dilute or an ion-exchange resin in the... 

After a section on industrial methods, a review covering Sn2 and S l routes to alcohols is pre.sented. Primary alcohols may be prepared by Sn2 displacement reactions of HO with appropriate substrates (e.g primary haloalkanes). This approach sometimes works for secondary systems, but elimination often interferes. To a limited extent, both secondary and teniary alcohols may be formed in S l reactions with water as the nucleophile. However, the chemistry described in the remainder of the chapter provides much more versatile and reliable means of synthesizing alcohols. 

As in Problems 32 and 33, first things first Categorize the substrate (primary, secondary, etc.) in order to identify the mechanistic pathways available to it. 1-Bromobutane is an unbranched primary haloalkane ... 

Branched primary and secondary haloalkanes are poorer substrates in SN2 reactions and undergo elimination to a significant degree. 

The substrate is a primary haloalkane Sn2 with any but tertiary alkoxides (this one is secondary). This reaction is a good Williamson ether synthesis. 

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