Tertiary alkyl halides synthesis

Section 8 13 When nucleophilic substitution is used for synthesis the competition between substitution and elimination must be favorable However the normal reaction of a secondary alkyl halide with a base as strong or stronger than hydroxide is elimination (E2) Substitution by the Sn2 mechanism predominates only when the base is weaker than hydroxide or the alkyl halide is primary Elimination predominates when tertiary alkyl halides react with any anion... 

This is not a new reaction. This is just an Sn2 reaction. We are simply using the alkoxide ion (ethoxide in this case) to function as the attacking nucleophile. But notice the net result of this reaction we have combined an alcohol and an alkyl halide to form an ether. This process has a special name. It is called the Williamson Ether Synthesis. This process relies on an Sn2 reaction as the main step, and therefore, we must be careful to obey the restrictions of Sn2 reactions. It is best to use a primary alkyl halide. Secondary alkyl halides cannot be used because elimination will predominate over substitution (as seen in Sections 10.9), and tertiary alkyl halides certainly cannot be used. 

Imidazolium salts that can be prepared by the first procedure, the alkylation of imidazole, are easy to obtain and often used for metal complex synthesis. Potassium imidazolide is reacted with the first equivalent of alkyl halide in toluene to give the 1-alkylimidazole. Subsequent alkylation in 3-position is achieved by addition of another equivalent of alkyl halide [Eq. (2)]. " A variant of this approach employs commercially available A-trimethylsilyl imidazole with 2 equiv of an alkyl chloride, under elimination of volatile MesSiCl. The drawback of these simple routes is the fact that only primary alkyl halides can be reacted in satisfactory yields because secondary and tertiary alkyl halides give substantial amounts of elimination by-products. 

McKillop and Ford synthesized a range of primary and secondary alkyl nitrates in excellent yields by treating alkyl bromides with mercury (I) nitrate in 1,2-dimethoxyethane at reflux (Equation 3.9). This method has been used to synthesize substituted nitrate esters from both a-bromocarboxylic acid and a-bromoketone substrates. Unlike metathesis with silver salts, which are widely known to promote SnI reactions, this method is not useful for the synthesis of nitrate esters from tertiary alkyl halides. 

The Gabriel synthesis of amines uses potassium phthalimide (prepared from the reaction of phthalimide with potassium hydroxide). The structure and preparation of potassium phthalimide is shown in Figure 13-13. The extensive conjugation (resonance) makes the ion very stable. An example of the Gabriel synthesis is in Figure 13-14. (The N2H4 reactant is hydrazine.) The Gabriel synthesis employs an 8, 2 mechanism, so it works best on primary alkyl halides and less well on secondary alkyl halides. It doesn t work on tertiary alkyl halides or aryl halides. 

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,... 

For synthesis of an unsymmetrical ether, the most hindered alkoxide should be reacted with the simplest alkyl halide rather than the other way round (Following fig.). As this is an SN2 reaction, primary alkyl halides react better then secondary or tertiary alkyl halides. 

The E2 reaction is the most effective for the synthesis of alkenes from alkyl halides and can be used on primary, secondary, and tertiary alkyl halides. The El reaction is not so useful from a synthetic point of view and occurs in competition with the SN1 reaction of tertiary alkyl halides. Primary and secondary alkyl halides do not generally react by this mechanism. 

The method is an extension of the well-known Grignard synthesis in ethers to the use of nonsolvating media, and is a development of procedures previously reported.2-6 A version of it has been employed with straight-chain primary alkyl chlorides, bromides, and iodides from C2 to Cu,5-7 and in solvents (or an excess of the halide) which permit reaction temperatures above 120°, with simple aryl halides such as chlorobenzene and 1-chloro-naphthalene. Branched-chain primary, secondary, and tertiary alkyl halides, allyl, vinyl, and benzyl halides either fail to react or give extensive side reactions. Better results are reported to be obtained in such cases with the use of catalytic quantities of a mixture of an alkoxide and an ether such as diethyl ether or tetrahydrofuran in a hydrocarbon medium, but the products are not, of course, completely unsolvated.4... 

The method works best with primary halides because a competitive 1 elimination reaction can occur when a secondary or tertiary alkyl halide I used (Section 11.15). Nevertheless, some unhindered secondary halid react well. An example occurs in the commercial synthesis of fenoprofen, nonsteroidal anti-inflammatory drug, or NSAID, marketed under the tradi name Mylan. (See Aspirin and Other Aromatic NSAID s at the end of Chap- ] ter 15.)... 

The range of electrophiles is very large.20 Alkylation with tertiary alkyl halides, e.g. 99, and Lewis acid catalysts allows the synthesis of molecules with two adjacent quaternary centres,28 such as 100 from 87. 

Coh(I)alamin is a powerful nucleophile, 40 000 times as reactive as the thiolate anion.Its intrinsic chemical reactivity as a nucleophile makes it an important species in the nonenzymatic synthesis of alkylcohalamins. Coh(I)alamin is easily alkylated at ambient temperatures by primary alkyl halides, alkenes, and alkynes. Secondary and tertiary alkyl halides either do not react or form unstable products because of steric crowding with the macrocyclic cobamide. Nonenzymatic alkylation by an alkyl halide is illustrated in Equation (6), where X is Cl, Br, or I. 

The ability to open the furan ring by oxidation has also been utilized for synthesis of trialkylacetic acids A 2-furoic ester is first subjected to a Friedel-Crafts reaction with a tertiary alkyl halide, and the 5-alkyl-2-furoic acid obtained from the product by hydrolysis is then oxidized by alkaline permanganate to the trialkylacetic acid 154... 

If, however, you want to synthesize tert-butyl ethyl ether, the starting materials must be an ethyl halide and ferf-butoxide ion. If you tried to use a tert-butyl halide and ethoxide ion as reactants, you would obtain the elimination product and little or no ether because the reaction of a tertiary alkyl halide under Sn2/E2 conditions forms primarily the elimination product. So, in carrying out a Williamson ether synthesis, the... 

The resulting thiolate anion is then capable of displacing halogen from a second equivalent of alkyl halide. This produces the corresponding thioether (dibutyl sulfide, Equation 8.59). In practice, thiol synthesis via the Sn2 process is best undertaken using a large excess of hydrosulfide anion so that the relative concentration of thiolate anion is minimized and thioether formation (Equation 8.59) is repressed. However, even under the best of circumstances, elimination competes with substitution. Alkenes can even be the major product and with tertiary alkyl halides, it is common to find that only alkenes result. 

Ethers can be readily prepared from the reaction between an alkoxide ion and an alkyl halide, a process called a Williamson ether synthesis. This process works best for methyl or primary alkyl halides. Secondary alkyl halides are significantly less efficient, and tertiary alkyl halides cannot be used. 

One of the most popular approaches to the laboratory scale synthesis of ethers is the addition of alkoxides and phenoxides to a suitable substrate such as an alkyl bromide. This reaction is known as the Williamson ether synthesis. For primary substrates, this approach tended to work quite well, and a host of ethers have been prepared using this method. The chemistry is less straightforward when secondary or tertiary alkyl halides were used due to competing elimination processes. As a representative example, the successful synthesis of an alkyl aryl ether is shown in Example 2.2 [14]. The reaction was carried out in acetone using allyl bromide and a functionalized phenol as the substrates and potassium carbonate as the base. While many bases have been used in Williamson ether syntheses, a mild base was critical for this work since it was needed to deprotonate the phenol without deprotonating the alkyne. This was critical for the success of the chemistry as the alkyne was needed for later steps in the reaction. In related work, potassium carbonate promoted the synthesis of photo-activatable fluorescein derivatives through a Williamson ether synthesis (Scheme 2.11) [15]. It also promoted the synthesis of a morphine precursor as well (Example 2.3) [16]. 

The Gabriel synthesis is limited to the formation of primary amines because secondary and tertiary alkyl halides undergo competitive elimination reactions. Aryl halides cannot be used because they do not undergo nucleophilic substitution under these reaction conditions. 

Show a synthesis of each target starting from a tertiary alkyl halide and any reagents containing three or fewer carbons. 

No. Preparation of this amine via the Gabriel synthesis would require the use of a tertiary alkyl halide, which will not imdergo an Sn2 process. 

Since an Sn2 process is employed, a tertiary allgrl halide cannot be used, because tertiary alkyl halides are too sterically hindered to undergo an Sn2 process. It is a coimnon mistake to attempt to use a tertiary alkyl halide in a Gabriel synthesis, because it is easy to forget the restrictions that apply. Keep this in mind for all reactions that you study. Make sure that you understand the circumstances under which each reaction can or cannot be used. 

A method that achieves the same end result as that desired by alkylation of ammonia but which avoids the formation of secondary and tertiary amines as byproducts is the Gabriel synthesis Alkyl halides are converted to primary alkylamines without contam mation by secondary or tertiary amines The key reagent is the potassium salt of phthal imide prepared by the reaction... 

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