Tertiary haloalkanes

Tertiary Haloalkanes. Tertiary systems eliminate (E2) with concentrated strong base and are substituted in nonbasic media (SnI). Bimolecular substitution is almost never observed, but elimination by El accompanies SnI. 

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... 

The use of a tertiary amine as an adjunct is not advised as it leads to increased formation of haloalkane the hydrogen halide generated is simply vented from the reaction system. Caution needs to be applied in handling the product alkyl (or aryl) phosphorodichloridites. They are extremely susceptible to moisture, and many are flammable upon contact with air. 

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],... 

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]. 

To illustrate the 8, 1 mechanism, consider the reaction between the tertiary haloalkane 2-bromo-2-methylpropane and the nucleophilic hydroxide ion. A study of the kinetics of the reaction reveals that it has the following rate equation rate = ic[(CH3)3CBr]. 

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. 

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,... 

Cyclopropen-1-yl sodium derivatives are also readily prepared. Thus reaction of cyclopropene with one equivalent of sodium amide in liquid ammonia leads to 1-sodiocyclopropene which is alkylated by haloalkanes 77,78 reacts with ketones to produce tertiary alcohols and opens epoxides to produce 2-cyclopropenyl-ethanols in moderate to good yields79). Moreover, on reaction with two equivalents of base followed by haloalkane, 1,2-dialkylated species are obtained sequential reactions can also be used to produce unsymmetrically substituted cyclopropenes78). Reaction with a deficiency of sodium amide can also cause addition of the cyclopro-penyl anion to unreacted cyclopropene, leading to products derived from the 2-cyclo-propylcydopropen-l-yl anion and to 1,2-dicyclopropylcyclopropene 77). 

In the SnI solvolysis reaction of 2-chloro-2-methylpropane, leading mainly to t-butanol and t-butyl ethers together with some f-butene, the term solvolysis is normally restricted to the reaction in water and other HBD solvents. In non-HBD solvents, however, the only reaction product is f-butene. For convenience, the term solvolysis is often used in the literature to cover both types of reaction, solvolysis and dehydrohalogenation of 2-chloro-2-methylpropane, because the solvent-dependent rate-determining step of both reactions, S l and El, is the same. For a detailed review on the heterolysis of tertiary haloalkanes in the gas phase and in solution, see G. F. Dvorko, E. A. Ponomareva, and N. 1. Kulik, Usp. Khim. 53, 948 (1984) Russ. Chem. Rev. 53, 547 (1984). 

Rearrangement reactions, where the first step corresponds to the ionization of a tertiary haloalkane, also proceed faster with increasing solvent polarity, as shown by the Wagner-Meerwein rearrangement of 3-chloro-2,2,3-trimethylnorbornane to 2-exo-ehlorobornane [49]. 

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]. 

The medium influence on the solvolyses of a variety of further substrates, i.e. benzylic [310-313], allylic and propargylic compounds [312], as well as very crowded tertiary haloalkanes [314], has been studied and analyzed in the framework of the extended Grunwald-Winstein equation (7-15). 

Fig. 7-6 demonstrates the correlation between itT(30) and the relative rates for the Sn2 Menschutkin reaction between a tertiary amine and a haloalkane in non-HBD solvents. The values of the second-order rate constants are taken from the compilation made by Abraham and Grellier [110]. 

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 fundamental route for the preparation of simple tetraalkylphosphonium salts is the reaction of a tertiary phosphine with a haloalkane or other substrate upon which a simple nucleophilic substitution reaction can occur. (In comparing phosphorus nucleophiles with the corresponding nitrogen-centered nucleophiles, it must be remembered that the phosphorus is significantly more nucleophilic than is the nitrogen. For example, while triphenylamine is devoid of nucleophilic character in reaction with ordinary haloalkanes, triphenylphosphine exhibits high reactivity.) Reactivity of the phosphorus in such nucleophilic substitution reactions, as with other types of nucleophiles, decreases with increasing substitution about the electrophilic site of the substrate. 

Tertiary phosphine oxides are also produced as significant by-products in several of the reactions of phosphines that have been noted previously, including the Wittig olefination and the conversions of alcohols to haloalkanes with triphenylphosphine as an adjunct reagent. The tertiary phosphine oxides produced in such reactions present a problem in chemical economics, as they themselves possess little chemical utility. The phosphine may be regenerated, but several steps are required, as previously noted with preparations of phosphines by reduction (see Section 3.2). 

Tertiary phosphine oxides and sulfides are also produced by way of the Michaelis-Arbuzov reaction beginning with phosphonous esters [R2POR ] and thiophosphonous esters [R2PSR ], when used in reaction with haloalkanes (see Section 3.5). Similarly, phosphine oxides are formed from trivalent phosphorus reagents in the Michaelis-Becker reaction as well as the conjugate addition reactions of phosphinous acid derivatives with a, -unsaturated compounds (see Section 3.5). 

It is well established that the same three-dimensional scaffolding in proteins often carries constellations of amino acids with diverse enzymatic functions. A classic example is the large family of a/jS, or TIM, barrel enzymes (Farber and Petsko, 1990 Lesk et ai, 1989). It appears that lipases are no exception to date five other hydrolases with similar overall tertiary folds have been identified. They are AChE from Torpedo calif arnica (Sussman et al., 1991) dienelactone hydrolase, a thiol hydrolase, from Pseudomonas sp. B13 (Pathak and Ollis, 1990 Pathak et al, 1991) haloalkane dehalogenase, with a hitherto unknown catalytic mechanism, from Xanthobacter autotrophicus (Franken et al, 1991) wheat serine carboxypeptidase II (Liao et al, 1992) and a cutinase from Fusa-rium solani (Martinez et al, 1992). Table I gives some selected physical and crystallographic data for these proteins. They all share a similar overall topology, described by Ollis et al (1992) as the a/jS hydrolase... 

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 lithium alkynides with aluminum trichloride leads to tri(ethynyl)aluminum intermediates, which on treatment with haloalkanes give the corresponding disubstituted acetylenes. " The reaction is successful with tertiary haloalkanes and a variety of alkynes have been prepared (Scheme 9). An interesting variation of this method has been reported by Trost and Ghadri who reacted a diethylethynylalumin-um with an allyl sulfone in the the presence of the Lewis acid aluminum trichloride. When the allyl sulfone was part of a six-membered ring, then the alkyne was introduced exclusively in a pseudo axial orientation (Scheme 10). 

Primary amines can also be synthesized by alkylaton of ammonia. Haloalkanes react with amines to give a corresponding alkyl-substituted amine, with the release of a halogen acid. Such reactions, which are most useful for alkyl iodides and bromides, are rarely employed because the degree of alkylation is difficult to control. If the reacting amine is tertiary, a quaternary ammonium cation results. Many quaternary ammonium salts can be prepared by this route with diverse R groups and many halide and pseudohalide anions. 

Thiolanes behave like dialkyl sulfides. With haloalkanes or alcohols in the presence of Bronsted acids, tertiary sulfonium salts are formed ... 

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