Secondary from alkyl halides

Both C-alkylation products and the corresponding O-alkyl nitronates were detected in the reaction mixture prepared by the reactions of above mentioned salt with primary alkyl halides (Scheme 3.9, Eq. 1). However, isoxazolidines (1) are the main identified products of the reactions with secondary or tertiary alkyl halides. The possible pathway of their formation is shown in Scheme 3.9. Here, the key event is generation of the corresponding olefins from alkyl halides. These olefins can be trapped with O-nitronates that are simultaneously formed in [3 + 2]-cycloaddition reactions. Presumably, these olefins are generated through deprotonation of stabilized cationic intermediates (see Scheme 3.9). 

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 target is now cyclopentanol. Alcohols can be prepared from alkyl halides by reaction with hydroxide ion as the nucleophile. Again, however, the combination of a strongly basic nucleophile and a secondary alkyl halide will result in an unacceptable amount of elimination. A better plan is to treat bromocyclopentane with acetate ion in an aprotic solvent such as DM SO. followed by cleavage of the ester to cyclopentanol ... 

Urethanes. Methyl carbamates (1) can be prepared from primary or secondary amines, alkyl halides, and carbon dioxide in a reaction promoted by copper(I) /-butoxide (equation I). The ligand t-butyl isocyanide can be replaced with tri-n-butylphosphine. Copper(I) f-butoxide is more effective than other copper salts. In the case of diethylamine, the intermediates a and b were isolated and b was converted to the methyl carbamate in 86% yield. 

Many high-molecular-weight branched acids are best prepared from alkyl halides by this method. Monoalkylation of malonic ester proceeds readily (75 90%) with primary and some secondary halides. The second hydrogen atom may be replaced by an alkyl group in 60-85% yield. Even a-naphthylmalonic ester may be further alkylated in 55-80% yields when R equals CHj to Excess malonic ester favors the formation of... 

Carbonium ions can be generated at a variety of oxidation levels. The alkyl carbocation can be generated from alkyl halides by reaction with a Lewis acid (RCl + AICI3) or by protonation of alcohols or alkenes. The reaction of an alkyl halide and aluminium trichloride with an aromatic ring is known as the Friedel-Crafts alkylation. The order of stability of a carbocation is tertiary > secondary > primary. Since many alkylation processes are slower than rearrangements, a secondary or tertiary carbocation may be formed before aromatic substitution occurs. Alkylation of benzene with 1-chloropropane in the presence of aluminium trichloride at 35 °C for 5 hours gave a 2 3 mixture of n- and isopropylbenzene (Scheme 4.5). Since the alkylbenzenes such as toluene and the xylenes (dimethylbenzenes) are more electron rich than benzene itself, it is difficult to prevent polysubsiitution and consequently mixtures of polyalkylated benzenes may be obtained. On the other hand, nitro compounds are sufficiently deactivated for the reaction to be unsuccessful. 

Sodium sulfhydride (NaSH) is a much better reagent for the formation of thiols (mercaptans) from alkyl halides than H2S and is used much more often. It is easily prepared by bubbling H2S into an alkaline solution, but hydrosulfide on a supported polymer resin has also been used. " The reaction is most useful for primary halides. Secondary substrates give much lower yields, and the reaction fails completely for tertiary halides because elimination predominates. Sulfuric and sulfonic esters can be used instead of halides. Thioethers (RSR) are often side products. The conversion can also be accomplished under neutral conditions by treatment of a primary halide with F and a tin sulfide, such as PhsSnSSnPhs. An indirect method for the preparation of a thiol is the reaction of an alkyl halide with thiourea to give an isothiuronium salt (119), and subsequent treatment with alkali or a... 

Lead tetra-alkyls containing one or two secondary radicles can easily be obtained by the action of lead alkyl mono- or dihalides on secondary magnesium alkyl halides, win 1st those containing three secondary radicles are derived ] )rimaril,y from the tctra-alkyls. Table XX. of the Appendix gives a list of these compounds, together with their physical constants. 

Like acetylide ion, hydroxide ion is a strong base that is, it has a strong affinity for hydrogen ion. The preparation of alcohols from alkyl halides gives good yields with primary halides, somewhat poorer yields with secondary halides it is essentially worthless for the preparation of tertiary alcohols. 

Several thiols occur naturally for example, skunk secretion contains 3-methyll-butanethiol and cut onions evolve 1-propanethiol, and the thiol group of the natural amino acid cysteine plays a vital role in the biochemistry of proteins and enzymes (see Introduction, p. 2). Primary and secondary thiols may be prepared from alkyl halides (RX) by reaction with excess sodium thiolate (SN2 nucleophilic substitution by HST) or via the Grignard reagent and reaction with sulfur. Tertiary thiols can be obtained in good yields by addition of hydrogen sulfide to a suitable alkene. Thiols can also be prepared by reduction of sulfonyl chlorides (Scheme l).la,2a... 

Tertiary carbocations may be conveniently prepared in such media from alkyl halides, alcohols, and alkenes. Secondary cations can be observed at low temperatures, but they rearrange readily to more stable tertiary ions. For such cases, special techniques of mixing the reactants, e.g. cocondensation on a cold surface ( molecular beam technique ), have been developed43. Attempts to prepare primary ions in the same manner have not been successful. Methyl and ethyl fluorides exchange halogen but do not generate observable concentrations of cations. All other simple... 

The stereochemistry of oxidative addition to the palladium(II) palladacycle was studied by Lautens using an enantioenriched secondary alkyl halide (Scheme 9) [32], From alkyl halide 23, product 24 was obtained, showing a net inversion of stereochemistry [33-35], Previous work by Stille showed that reductive elimination from palladium(IV) occurs with retention of stereochemistry [36], suggesting that oxidative addition occurs with an inversion of stereochemistry. This corresponds with the generally accepted SN2 mechanism for the reaction of palladium(O) with alkyl halides [37, 38],... 

Sulfides. Symmetrical sulfides can be prepared in high yield from the reaction of alkyl halides and sodium sulfide in water with this phase-transfer catalyst. Unsymmetrical sulfides are prepared from alkyl halides and sodium mercap-tides. Secondary alkyl halides react more slowly than primary halides bromides are more reactive than chlorides. ... 

X" = NOj- From Amberlyst A-26 or Amberlite IRA 400 From Amberlite IRA 900 (C1-) by treatment with NaNO, soln. 3 Synthesis of nitroalkanes and alkyl nitrites from alkyl halides. - a-Nitro carboxylic esters from a-bromo esters alkyl-nitro compounds from primary, secondary and benzylic bromides (formation of nitrites was not detected). ... 

Aikyl fluorides by exchange from alkyl halides or methanesulfonates. The resin used for the reaction is the F form of Amberlyst-A26 (Rohm and Haas), a macroreticular anion-exchange resin containing ammonium groups. When this material and primary alkyl halides or sulfonates are refluxed in a solvent (pentane, hexane, ether), alkyl fluorides are formed, usually in satisfactory yields. Alkenes accompany fluorides in the reaction of secondary substrates. This reaction has been conducted previously under phase-transfer catalysis (5, 322). ... 

Carbocation Generation from Alkyl Halides. Alkyl chlorides, fluorides, and bromides are convenient and frequently used precursors for generation of alkyl cations in HSOsF-SbFs systems.It should be noted, however, that the HSOsF-SbFs system is less suitable than SbFs for the generation of alkyl, especially secondary alkyl, cations from the corresponding alkyl halides. Ionization of cyclohexyl chloride In Magic Acid Is accompanied by Isomerization, 3deldlng the 1-methyl- 1-cyclopentyl cation (eq 3). ... 

The preparation of tertiary amines from alkyl halides and a secondary amine, or a primary amine in which both TV-hydre en atoms are to be replaced by identical alkyl groups, can be carried out with favourable yields in many cases, as evidenced by preparations of diethyl-n-hexadecylamine (from diethylamine) and of dimethyl-n-docosylamine (from dimethylamine) . Alkyl sulphonates have similarly been used, and the reaction extended to the preparation of cyclic tertiary amines from primary amines and appropriate terminal di-sulphonates (reaction 38) . Satisfactory conditions have been reported... 

What are the hmitations of this nvo-step procedure to produce alcohols from alkyl halides First, we need an appropriate alkyl halide. Second, the displacement of halide ion by acetate occurs by an Sj 2 process, which is efficient for primary alkyl hahdes, but occurs at a slower rate for secondary alkyl halides. The process fails for tertiary alkyl halides, which are too sterically hindered to react. 

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