Primary haloalkanes

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],... 

For example, direct treatment of red phosphorus with potassium hydroxide in a mixture of dioxane and water with a phase-transfer catalyst (benzyltriethylammonium chloride) allows direct reaction with primary haloalkanes to form the trialkylphosphine oxide in moderate (60-65%) yield.1415 Allylic and benzylic halides are similarly reported to generate the corresponding tertiary phosphine oxides. When the reaction is performed with a,(o-dihalides, cyclic products are generated only with four- and five-carbon chains the third site... 

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... 

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]. 

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... 

During the hydrogenolysis of primary haloalkanes, diborane is produced and it provides a viable route for its preparation in non-ethereal solvents (see Section 11.5) [5]. 

To illustrate the Spj2 mechanism, consider the reaction between the primary haloalkane bromoethane and the nucleophilic hydroxide ion. A study of the kinetics of the reaction reveals that it has the following rate equation rate = /cfCHjCH BrllOH ]. 

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

Alkyl groups are said to have a positive inductive effect. This means they are electron-donating and can push electrons onto the positively charged carbon atom, thus stabilising the carbocation. It follows that tertiary carbocatlons, with their three alkyl groups, are the most stable species and that primary carbocatlons, with just one alkyl group, are the least stable species. This suggests that tertiary haloalkanes are most likely to react with a nucleophile via an Sj. 1 mechanism. 

The size of the alkyl groups in the haloalkane is Important. This is known as a steric effect. You will recall that, in the mechanism, the nucleophile attacks the carbon atom of the C-X bond from the side opposite to the halogen atom. In the case of a tertiary haloalkane, attack from that side is likely to be sterlcally hindered because three bulky alkyl groups will limit access to the atom. Hence tertiary haloalkanes are unlikely to react with nucleophiles via an Sj. 2 mechanism. Primary haloalkanes, on the other hand, have no more than one alkyl group attached to the halogen-bearing carbon atom and so access to the atom will be much easier. This suggests that primary haloalkanes are most likely to react with nucleophiles via an S. j2 mechanism. 

TABLE 8. Primary aliphatic organoUthiums Li—R by halogen/metal permutation between haloalkanes X—R and tert-butylUthium in diethyl ether at —75°C... 

The primary area of application of adsorption chromatography on polar stationary phases is in the separation of nonpolar to moderately polar organic compounds. A preliminary decision on whether or not this system is adequate can be based on sample solubility in such "nonpolar" solvents as aliphatic or aromatic hydrocarbons, haloalkanes, perhaps with the addition of a few percent of esters, acetonitrile, or even alcohols. When the sample is soluble or miscible with these eluents, the use of a polar stationary phase may be the best approach to chromatographic separation. 

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,... 

Because 1-bromopropane is a primary haloalkane, the reaction proceeds by either a Sn2 or E2 mechanism, depending on the basicity and the amount of steric hindrance in the nucleophile. 

Recently, a new one-pot process for the sequence (i)-(iii) has been realized under heterogeneous catalysis (Ballini et al 2007b). In fact, treating at room temperature according to the reaction in Figure 2.20 one equivalent of primary haloalkanes (57) and one equivalent of aldehyde, or conjugate enone, in the presence of IR A-402 nitrite and Amberlyst A-21, the nitroalkanols (60) or y-nitro ketones (61) were obtained, respectively, in a one-pot SN2-nitroaldol (Henry) or SN2-Michael reactions. 

Ballini, R., Barboni, L., and Palmieri, A. 2007b. A new heterogeneous one-pot process for both nitroaldol (Henry) and Michael reactions from primary haloalkanes via nitroalkanes. Synlett, 19 3019-21. 

An example of reaction type (c) in Table 5-4 is the well-known Menschutkin reaction [30] between tertiary amines and primary haloalkanes yielding quaternary ammonium salts. Its solvent dependence was studied very thoroughly by a number of investigators [51-65, 491-496, 786-789]. For instance, the reaction of tri-n-propylamine with iodomethane at 20 °C is 120 times faster in diethyl ether, 13000 times faster in chloroform, and 110000 times faster in nitromethane than in -hexane [60]. It has been estimated that the activated complex of this Menschutkin reaction should have a dipole moment of ca. 29 10 Cm (8.7 D) [23, 64], which is much larger than the dipole moments of the reactant molecules (tris- -propylamine 2.3 10 Cm = 0.70 D iodomethane 5.5 10-3 1 64 D) [64]. 

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. 

A direct approach for the preparation of phosphine oxides in reasonable yield involves the treatment of elemental phosphorus (either white or red) with primary haloalkanes in a basic (KOH) medium of water/dioxane with the presence of a phase-transfer catalyst. ... 

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). 

Treatment of primary a,u)-haloalkanes with r-butyllithium at low temperature leads to efficient production of cycloalkanes, provided at least one of the halides is an iodide. - This method provides very good yields of three-, four- and five-membered rings, but produces only minor amounts of cyclic products for 1,6-dihalides. Examples of this approach are given in equations (41) and (42). 

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