Alkyl halides, relative reactivity

The conventional resinsulfonic acids such as sulfonated polystyrenes (Dowex-50, Amberlite IR-112, and Permutit Q) are of moderate acidity with limited thermal stability. Therefore, they can be used only to catalyze alkylation of relatively reactive aromatic compounds (like phenol) with alkenes, alcohols, and alkyl halides. Nafion-H, however, has been found to be a suitable superacid catalyst in the 110-190°C temperature range to alkylate benzene with ethylene (vide infra) 16 Furthermore, various solid acid catalysts (ZSM-5, zeolite /3, MCM-22) are applied in industrial ethylbenzene technologies in the vapor phase.177... 

As we have seen the nucleophile attacks the substrate m the rate determining step of the Sn2 mechanism it therefore follows that the rate of substitution may vary from nucleophile to nucleophile Just as some alkyl halides are more reactive than others some nucleophiles are more reactive than others Nucleophilic strength or nucleophilicity, is a measure of how fast a Lewis base displaces a leaving group from a suitable substrate By measuring the rate at which various Lewis bases react with methyl iodide m methanol a list of then nucleophihcities relative to methanol as the standard nucleophile has been compiled It is presented m Table 8 4... 

The relative reactivity of alkyl halides m 8 1 reactions is exactly the opposite of 8 2... 

The alkyl halide can be primary, secondary, or tertiary. Alkyl iodides are the most reactive, followed by bromides, then chlorides. Fluorides are relatively umeactive. 

Olivier and Berger335, who measured the first-order rate coefficients for the aluminium chloride-catalysed reaction of 4-nitroben2yl chloride with excess aromatic (solvent) at 30 °C and obtained the rate coefficients (lO5/ ) PhCI, 1.40 PhH, 7.50 PhMe, 17.5. These results demonstrated the electrophilic nature of the reaction and also the unselective nature of the electrophile which has been confirmed many times since. That the electrophile in these reactions is not the simple and intuitively expected free carbonium ion was indicated by the observation by Calloway that the reactivity of alkyl halides was in the order RF > RC1 > RBr > RI, which is the reverse of that for acylation by acyl halides336. The low selectivity (and high steric hindrance) of the reaction was further demonstrated by Condon337 who measured the relative rates at 40 °C, by the competition method, of isopropylation of toluene and isopropylbenzene with propene catalyzed by boron trifluoride etherate (or aluminium chloride) these were as follows PhMe, 2.09 (1.10) PhEt, 1.73 (1.81) Ph-iPr, (1.69) Ph-tBu, 1.23 (1.40). The isomer distribution in the reactions337,338 yielded partial rate factors of 2.37 /mMe, 1.80 /pMe, 4.72 /, 0.35 / , 2.2 / Pr, 2.55337 339. 

Alkylation of enamines requires relatively reactive alkylating agents for good results. Methyl iodide, allyl and benzyl halides, a-halo esters, a-halo ethers, and a-halo ketones are the most successful alkylating agents. The use of enamines for selective alkylation has largely been supplanted by the methods for kinetic enolate formation described in Section 1.2. 

Conventional alkylating agents (alkyl halides, sulfates, etc.) are rather rarely used in the synthesis of alkyl nitronates. This is associated with relatively low reactivity of these compounds which, combined with low thermal stability of nitronates (for more details, see Section 3.3.1.1), does not allow one to isolate target products in the individual state. 

To be really satisfactory, a Friedel-Crafts alkylation requires one relatively stable secondary or tertiary carbocation to be formed from the alkyl halide by interaction with the Lewis acid, i.e. cases where there is not going to be any chance of rearrangement. Note also that we are unable to generate carboca-tions from an aryl halide - aryl cations (also vinyl cations, see Section 8.1.3) are unfavourable - so that we cannot nse the Friedel-Crafts reaction to join aromatic gronps. There is also one further difficulty, as we shall see below. This is the fact that introduction of an alkyl substitnent on to an aromatic ring activates the ring towards fnrther electrophilic substitution. The result is that the initial product from Friedel-Crafts alkylations is more reactive than the... 

Especially for large-scale work, esters, may be more safely and efficiently prepared by reaction of carboxylate salts with alkyl halides or tosylates. Carboxylate anions are not very reactive nucleophiles so the best results are obtained in polar aprotic solvents54 or with crown ether catalysts.55 The reactivity for the salts is Na+ < K+ < Rb+ < Cs+. Cesium carboxylates are especially useful in polar aprotic solvents. The enhanced reactivity of the cesium salts is due both to high solubility and to the absence of ion pairing with the anion.56 Acetone has been found to be a good solvent for reaction of carboxylate anions with alkyl iodides.57 Cesium fluoride in DMF is another useful combination.58 Carboxylate alkylation procedures have been particularly advantageous for preparation of hindered esters that can be relatively difficult to prepare by the acid-catalyzed esterification method (Fischer esterification) which will be discussed in Section... 

Reactivity The mobile phase must not react with the analytical sample or column packing. This does not present a major limitation since many relatively unreactive hydrocarbons, alkyl halides, and alcohols are suitable. 

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,... 

Exercise 14-14 Whereas the order of reactivity of alkyl halides toward a given nucleophile is I > Br > Cl F, the reverse order of reactivity frequently is observed with aryl hal ides (F Cl a Br = I). What does this signify regarding the relative rates of the addition and elimination steps (Equations 14-3 and 14-4) in this kind of aromatic substitution ... 

The results obtained in the gas-phase isopropylation of various aromatic hydrocarbons with isopropyl chloride over Nafion-H catalyst showed only a relatively small variation of reactivity in going from fluorobenzene to xylenes.235 Therefore, it has been assumed that the reaction rate is controlled by the formation of a reactive electrophilic intermediate (possibly, protonated alkyl halide 61, or some form of incipient alkyl cation) rather than by cr-complex formation between the electrophile and the aromatic nucleus [Eq. (5.89)]. 

Not only trialkyltin halides, but also tetraalkyltins themselves act in this way as perturbers . Evidence for this effect was obtained47 by determination of the relative reactivities of alkyl groups in unsymmetrical tetraalkyltins. The following data are typical. 

Previous investigations (Brady, 1949 Grayson, 1952 Bonner, 1952) in the Purdue laboratories were concerned with the influence of alkyl groups on the rate of ionization of phenyldimethylcarbinyl chloride. These studies indicated that first-order rate constants could be determined with high accuracy for the solvolysis reaction. Moreover, the entropies of activation were invariant in this series of halides. These considerations led to further study of other substituted phenyldimethylcarbinyl chlorides in an attempt to gain a further understanding of the influence of substituent groups on relative reactivity and as a possible model reaction for the assessment of parameters for electron-deficient reactions. 

Aryl halides are relatively unreactive toward nucleophilic substitution reactions. This lack of reactivity is due to several factors. Steric hindrance caused by the benzene ring of the aryl halide prevents SN2 reactions. Likewise, phenyl cations are unstable, thus making SN1 reactions impossible. In addition, the carbon-halogen bond is shorter and therefore stronger in aryl halides than in alkyl halides. The carbon-halogen bond is shortened in aryl halides for two reasons. First, the carbon atom in aryl halides is sp2 hybridized instead of sp3 hybridized as in alkyl halides. Second, the carbon-halogen bond has partial double bond characteristics because of resonance. 

Anilines are generally less basic and nucleophilic than aliphatic amines, but can still be alkylated with alkyl halides under relatively mild reaction conditions under which, for instance, aliphatic alcohols will not undergo alkylation (Scheme 6.7). Monoalkylations of primary anilines with highly reactive alkylating agents can be difficult, and usually require use of excess of aniline and/or careful optimization of the reaction conditions [31-33]. 

Alkylpalladium complexes generated by oxidative addition of Pd(0) to alkyl halides with a /3 hydrogen can undergo /3-elimination to yield an alkene and a Pd-hydrido complex (as in the Heck reaction Scheme8.7). Nevertheless, this process is relatively slow compared with transmetalations and reductive eliminations, and simple alkyl halides or tosylates with /3 hydrogen can be cross-coupled with carbon nucleophiles under optimized conditions if the nucleophile is sufficiently reactive [9, 73-75] (Scheme8.6). 

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