Reactivity order

If it is necessary to reduce one group in a given molecule without affecting any other unprotected reducible group, the following reactivity orders for ease of reduction toward catalytic hydrogenation, LiAlH, and diborane may serve as a guideline. 

The reactivity order parallels the ease of carbocation formation Increasing rate of elimination by the El mechanism... 

What structural features are responsible for the reactivity order of carboxylic acid derivatives Like the other carbonyl containing compounds that we ve studied they all have a planar arrangement of bonds to the carbonyl group Thus all are about the same in offering relatively unhindered access to the approach of a nucleophile They differ m the degree to which the atom attached to the carbonyl group can stabilize the carbonyl group by electron donation... 

Pivalates. The selective pivaloylation of sucrose with pivaloyl (2,2-dimethylpropionyl) chloride has been thoroughly investigated (56). The reactivity of sucrose toward pivaloylation was shown to be significantly different from other sulfonic or carboxyflc acid chlorides. For example, reaction of sucrose with four molar equivalent of toluene-/)-sulfonyl chloride in pyridine revealed, based on product isolation, the reactivity order ofO-6 0-6 > 0-1 > 0-2 (57). In contrast, a reactivity order for the pivaloylation reaction, under similar reaction conditions, was observed to be 0-6 0-6 > 0-1 > 0-4. 

The second-order rate constants for the reaction of a number of amines with benzyl chloride are tabulated below. Calculate A// and A5 from the data. Offer an explanation for the relative reactivity order for the amines. What trends do you observe in A// with reactivity ... 

In fee absence of fee solvation typical of protic solvents, fee relative nucleophilicity of anions changes. Hard nucleophiles increase in reactivity more than do soft nucleophiles. As a result, fee relative reactivity order changes. In methanol, for example, fee relative reactivity order is N3 > 1 > CN > Br > CP, whereas in DMSO fee order becomes CN > N3 > CP > Br > P. In mefeanol, fee reactivity order is dominated by solvent effects, and fee more weakly solvated N3 and P ions are fee most reactive nucleophiles. The iodide ion is large and very polarizable. The anionic charge on fee azide ion is dispersed by delocalization. When fee effect of solvation is diminished in DMSO, other factors become more important. These include fee strength of fee bond being formed, which would account for fee reversed order of fee halides in fee two series. There is also evidence fiiat S( 2 transition states are better solvated in protic dipolar solvents than in protic solvents. 

The reaction of substituted 1-arylethyl chlorides with K OC(CH3)3 in DMSO does not follow a Hammett correlation. Instead, the reactivity order is />-N02 > p-MeO > P-CF3 > P-CH3 > H > p-Cl. What explanation can you offer for the failure to observe a Hammett relationship ... 

One important experimental fact is that the rate of reaction of alcohols with hydrogen halides increases in the order methyl < primary < secondary < tertiary. This reactivity order parallels the caibocation stability order and is readily accommodated by the mechanism we have outlined. 

The position of aniline in the above reactivity order deserves special comment. Aniline is less basic than pyridine by a relatively small factor, 0.65 pA units, but is appreciably more polarizable it then seems likely that the inverted order of reactivity is caused by the polarizability term in accordance with Edwards equation. If this is correct, in the reactivity order piperidine > aniline > pyridine, inversion with respect to basicity appears to result from an abnormally high reactivity of aniline rather than from a particularly low reactivity of pyridine. This view differs from that based on relative steric requirements of the reagents, but other factors besides basicity and polarizability may well contribute to the quantitative experimental picture. 

On both experimental and theoretical grounds there is little doubt of the importance of polarizability as a major factor in determining the commonly encountered, though variable, high RS /RO ratios. Were thermodynamic carbon affinities mainly responsible for the usual reactivity order RS > RO, the peculiar behavior of chloroquinolines would be very difficult to understand. There is some indication, however, that carbon affinities roughly parallel basicities (hydrogen affinities), In the latter case, lower RS /RO ratios could be explained in terms of the intermediate complex mechanism, ... 

It may be unsafe to carry this discussion further until more data are available. Knowledge of the activation parameters would be especially desirable in several respects. Reactivity orders involving different reagents or substrates may be markedly dependent on temperature. Thus, in Table IV both 2- and 4-chloroquinolines appear to be about equally reactive toward sodium methoxide at 86,5°. However, the activation energies differ by 3 kcal/mole (see Section VII), and the relative rates are reversed below and above that temperature. Clearly, such relative rates affect the rs-/ ro- ratios. 

Different mineral acids showed the following reactivity order toward grafting in the TBHP-mineral acid system ... 

From these and similar reactions, it s possible to calculate a reactivity order toward chlorination for different sorts of hydrogen atoms in a molecule. Take the butane chlorination, for instance. Butane has six equivalent primary hydrogens (-CH3) and four equivalent secondary hydrogens (-CH2-). The fact that butane yields 30% of 1-chlorobutane product means that each one of the six primary hydrogens is responsible for 30% -e 6 = 5% of the product. Similarly, the fact that 70% of 2-chlorobutane is formed means that each of the four secondary hydrogens is responsible for 70% -e 4 = 17.5% of the product. Thus, reaction of a secondary hydrogen happens 17.5% + 5% = 3.5 times as often as reaction of a primary hydrogen. 

What are the reasons for the observed reactivity order of alkane hydrogens toward radical chlorination A look at the bond dissociation energies given previously in Table 5.3 on page 156 hints at the answer. The data in Table 5.3 indicate that a tertiary C—H bond (390 kj/mol 93 kcal/mol) is weaker than a secondary C-H bond (401 kj/mol 96 kcal/mol), which is in turn weaker than a primary C H bond (420 kj/mol 100 kcal/mol). Since less energy is needed to break a tertiary C-H bond than to break a primary or secondary C-H bond, the resultant tertiary radical is more stable than a primary or secondary radical. 

Simple alkyl halides can be prepared by radical halogenation of alkanes, but mixtures of products usually result. The reactivity order of alkanes toward halogenation is identical to the stability order of radicals R3C- > R2CH- > RCH2-. Alkyl halides can also be prepared from alkenes by reaction with /V-bromo-succinimide (NBS) to give the product of allylic bromination. The NBS bromi-nation of alkenes takes place through an intermediate allylic radical, which is stabilized by resonance. 

Although nor shown in the preceding reactivity order, vinylic halides (R2C=CRX) and aryl halides are unreactive toward Sn2 reaction. This lack of reactivity is probably due to steric factors, because the incoming nucleophile... 

I Nucleophilicity usually increases going down a column of the periodic table. Thus, HS- is more nucleophilic than HO-, and the halide reactivity order is I- > Br- > Cl-. Going down the periodic table, elements have their valence electrons in successively larger shells where they are successively farther from the nucleus, less tightly held, and consequently more reactive. The matter is complex, though, and the nucleophilicity order can change depending on the solvent. 

What s going on here Clearly, a nucleophilic substitution reaction is occurring, yet the reactivity order seems backward. These reactions can t be taking place... 

The reaction is an F.1 process and occurs through the three-step mechanism shown in Figure 17.6). As usual for El reactions (Section 11.10), only tertiary alcohols are readily dehydrated with acid. Secondary alcohols can be made to react, but the conditions are severe (75% H2S04,100 °C) and sensitive molecules don t survive. Primary alcohols are even less reactive than secondary ones, and very harsh conditions are necessary to cause dehydration (95% H2S04,150 °C). Thus, the reactivity order for acid-catalyzed dehydrations is... 

As a consequence of these reactivity differences, it s usually possible to convert a more reactive acid derivative into a less reactive one. Acid chlorides, foi instance, can be directly converted into anhydrides, thioesters, esters, and amides, but amides can t be directly converted into esters, thioesters, anhydrides, or acid chlorides. Remembering the reactivity order is therefore a way tc keep track of a large number of reactions (Figure 21.2). Another consequence, a noted previously, is that only acyl phosphates, thioesters, esters, and amides are... 

The reaction of an alcohol with an acid chloride is strongly affected by steric hindrance. Bulky groups on either partner slow down the reaction considerably, resulting in a reactivity order among alcohols of primary > secondary > tertiary. As a result, it s often possible to esterify an unhindered alcohol selectively in the presence of a more hindered one. This can be important in complex syntheses... 

The reactivity of an acid derivative toward substitution depends both on the steric environment near the carbonyl group and on the electronic nature of the substituent, Y. The reactivity order is acid halide > acid anhydride > thioester > ester > amide. 

The following reactivity order has been found for the basic hydrolysis of p-substituted methyl benzoates ... 

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