Alkyl Halide Occurrence

Synthetic organic halogen compounds are readily available by directhalogenation of hydrocarbons and by addition reactions to alkenes andalkynes. Many of these have proven useful as intermediates intraditional synthetic processes. Some halogen compounds, shown in thebox. have been used as pesticides, but their persistence in theenvironment, once applied, has led to restrictions, including banning,of their use in developed countries. Because DDT is a cheap andeffective mosquito control agent, underdeveloped countries in Africaand Latin America have experienced a dramatic increase in malariadeaths following its removal, and arguments are made for returning itto limited use. 2,4,5-T and 2,4-D are common herbicides that are soldby most garden stores. Other organic halogen compounds that have beenimplicated in environmental damage include the polychloro- andpolybromo-biphenyls (PCBs and PBBs), used as heat transfer fluids andfire retardants; and freons (e.g. CCl2F2 and other chlorofluorocarbons)used as refrigeration gases and fire extinguishing agents.



Alkyl Halide Reactions

The functional group of alkyl halides is a carbon-halogen bond,the common halogens being fluorine, chlorine, bromine and iodine. Withthe exception of iodine, these halogens have electronegativitiessignificantly greater than carbon. Consequently, this functional groupis polarized so that the carbon is electrophilic and the halogen isnucleophilic, as shown in the drawing on the right. Two characteristics other than electronegativity also have an importantinfluence on the chemical behavior of these compounds. The first ofthese is covalent bond strength. The strongest of thecarbon-halogen covalent bonds is that to fluorine. Remarkably, this isthe strongest common single bond to carbon, being roughly 30 kcal/molestronger than a carbon-carbon bond and about 15 kcal/mole stronger thana carbon-hydrogen bond. Because of this, alkyl fluorides and fluorocarbons in general are chemically and thermodynamically quite stable,and do not share any of the reactivity patterns shown by the otheralkyl halides. The carbon-chlorine covalent bond is slightly weakerthan a carbon-carbon bond, and the bonds to the other halogens areweaker still, the bond to iodine being about 33% weaker. The secondfactor to be considered is the relative stability of the corresponding halide anions,which is likely the form in which these electronegative atoms will bereplaced. This stability may be estimated from the relative aciditiesof the H-X acids, assuming that the strongest acid releases the moststable conjugate base (halide anion). With the exception of HF (pKa =3.2), all the hydrohalic acids are very strong, small differences beingin the direction HCl < HBr < HI.
Substitution and Elimination

The characteristics noted above lead us to anticipate certaintypes of reactions that are likely to occur with alkyl halides. Indescribing these, it is useful to designate the halogen-bearing carbonas alpha and the carbon atom(s) adjacent to it as beta,as noted in the first four equations shown below. Replacement orsubstitution of the halogen on the α-carbon (colored maroon) by anucleophilic reagent is a commonly observed reaction, as shown inequations 1, 2, 5, 6 & 7below. Also, since the electrophilic character introduced by thehalogen extends to the β-carbons, and since nucleophiles are alsobases, the possibility of base induced H-X elimination must also beconsidered, as illustrated by equation 3.Finally, there are some combinations of alkyl halides and nucleophilesthat fail to show any reaction over a 24 hour period, such as theexample in equation 4. Forconsistency, alkyl bromides have been used in these examples. Similarreactions occur when alkyl chlorides or iodides are used, but the speedof the reactions and the exact distribution of products will change.
In order to understand why some combinations of alkyl halides andnucleophiles give a substitution reaction, whereas other combinationsgive elimination, and still others give no observable reaction, we mustinvestigate systematically the way in which changes in reactionvariables perturb the course of the reaction. The following generalequation summarizes the factors that will be important in such aninvestigation.
One conclusion, relating the structure of the R-group to possible products, should be immediately obvious. If R- has no beta-hydrogens an elimination reaction is not possible,unless a structural rearrangement occurs first. The first four halidesshown on the left below do not give elimination reactions on treatmentwith base, because they have no β-hydrogens. The two halides on theright do not normally undergo such reactions because the potentialelimination products have highly strained double or triple bonds.
It is also worth noting that sp2 hybridized C–X compounds, such as thethree on the right, do not normally undergo nucleophilic substitutionreactions, unless other functional groups perturb the double bond(s).

Using the general reaction shown above as our reference, we can identify the following variables and observables.
VariablesR change α-carbon from 1º to 2º to 3º
if the α-carbon is a chiral center, set as (R) or (S)
X change from Cl to Br to I (F is relatively unreactive)
Nu: change from anion to neutral; change basicity; change polarizability
Solvent polar vs. non-polar; protic vs. non-protic
ObservablesProducts substitution, elimination, no reaction.
Stereospecificity if the α-carbon is a chiral center what happens to its configuration?
Reaction Rate measure as a function of reactant concentration.

When several reaction variables may be changed, it is important toisolate the effects of each during the course of study. In other words:only one variable should be changed at a time,the others being held as constant as possible. For example, we canexamine the effect of changing the halogen substituent from Cl to Br toI, using ethyl as a common R–group, cyanide anion as a commonnucleophile, and ethanol as a common solvent. We would find a commonsubstitution product, C2H5–CN, in all cases, but the speed or rate ofthe reaction would increase in the order: Cl < Br < I. Thisreactivity order reflects both the strength of the C–X bond, and thestability of X(–) as a leaving group, and leads to the generalconclusion that alkyl iodides are the most reactive members of thisfunctional class.
1. Nucleophilicity

Recall the definitions of electrophile and nucleophile: Electrophile:An electron deficient atom, ion or molecule that has an affinity for anelectron pair, and will bond to a base or nucleophile.
Nucleophile: An atom, ion ormolecule that has an electron pair that may be donated in forming acovalent bond to an electrophile (or Lewis acid).
If we use acommon alkyl halide, such as methyl bromide, and a common solvent,ethanol, we can examine the rate at which various nucleophilessubstitute the methyl carbon. Nucleophilicityis thereby related to the relative rate of substitution reactions atthe halogen-bearing carbon atom of the reference alkyl halide. The mostreactive nucleophiles are said to be more nucleophilic than lessreactive members of the group. The nucleophilicities of some commonNu:(–) reactants vary as shown in the following
Nucleophilicity: CH3CO2(–) < Cl(–) < Br(–) < N3(–) < CH3O(–) < CN(–) ≈ SCN(–) < I(–) < CH3S(–)
The reactivity range encompassed by these reagents is over 5,000 fold,thiolate being the most reactive. Note that by using methyl bromide asthe reference substrate, the complication of competing eliminationreactions is avoided. The nucleophiles used in this study were allanions, but this is not a necessary requirement for these substitutionreactions. Indeed reactions 6 & 7,presented at the beginning of this section, are examples of neutralnucleophiles participating in substitution reactions. The cumulativeresults of studies of this kind has led to useful empirical rulespertaining to nucleophilicity:
(i) For a given element, negatively charged species are more nucleophilic (and basic) than are *****alent neutral species.
(ii) For a given period of the periodic table, nucleophilicity (and basicity) decreases on moving from left to right.
(iii) For a given group of the periodic table, nucleophilicity increases from top to bottom (i.e.with increasing size), although there is a solvent dependence due tohydrogen bonding. Basicity varies in the opposite manner.

2. Solvent Effects

Solvation of nucleophilic anions markedly influences their reactivity. The nucleophilicities cited above were obtained from reactions inmethanol solution. Polar, protic solvents such as water and alcoholssolvate anions by hydrogen bonding interactions, as shown in thediagram on the right. These solvated species are more stable and lessreactive than the unsolvated "naked" anions. Polar, aprotic solventssuch as DMSO (dimethyl sulfoxide), DMF (dimethylformamide) andacetonitrile do not solvate anions nearly as well as methanol, butprovide good solvation of the accompanying cations. Consequently, mostof the nucleophiles discussed here react more rapidly in solutionsprepared from these solvents. These solvent effects are more pronouncedfor small basic anions than for large weakly basic anions. Thus, forreaction in DMSO solution we observe the following reactivity order:
Nucleophilicity: I(–) < SCN(–) < Br(–) < Cl(–) ≈ N3(–) < CH3CO2 (–) < CN(–) ≈ CH3S(–) < CH3O(–)
Note that this order is roughly the order of increasing basicity.

3. The Alkyl Moiety

Some of the most important information concerning nucleophilicsubstitution and elimination reactions of alkyl halides has come fromstudies in which the structure of the alkyl group has been varied. Ifwe examine a series of alkyl bromide substitution reactions with thestrong nucleophile thiocyanide (SCN) in ethanol solvent, we find largedecreases in the rates of reaction as alkyl substitution of thealpha-carbon increases. Methyl bromide reacts 20 to 30 times fasterthan simple 1º-alkyl bromides, which in turn react about 20times faster than simple 2º-alkyl bromides, and3º-alkyl bromides are essentially unreactive or undergoelimination reactions. Furthermore, β-alkyl substitution also decreasesthe rate of substitution, as witnessed by the failure of neopentylbromide, (CH3)3CCH2-Br (a 1º-bromide), to react.
Alkyl halides in which the alpha-carbon is a chiral center provideadditional information about these nucleophilic substitution reactions.Returning to the examples presented at the beginning of this section,we find that reactions 2, 5 & 6demonstrate an inversion of configuration when the cyanide nucleophilereplaces the bromine. Other investigations have shown this to begenerally true for reactions carried out in non-polar organic solvents,the reaction of (S)-2-iodobutane with sodium azide in ethanol beingjust one example ( in the following equation the alpha-carbon is maroonand the azide nucleophile is blue). Inversion of configuration duringnucleophilic substitution has also been confirmed for chiral1º-halides of the type RCDH-X, where the chirality is due to isotopic substitution.
(S)-CH3CHICH2CH3 + NaN3 ——> (R)-CH3CHN3CH2CH3 + NaIWe can now piece together a plausible picture of how nucleophilicsubstitution reactions of 1º and 2º-alkyl halidestake place. The nucleophile must approach the electrophilic alpha-carbon atom fromthe side opposite the halogen. As a covalent bond begins to formbetween the nucleophile and the carbon, the carbon halogen bond weakensand stretches, the halogen atom eventually leaving as an anion. Thediagram on the right shows this process for an anionic nucleophile. Wecall this description the SN2 mechanism, where S stands for Substitution, N stands for Nucleophilic and 2 stands for bimolecular(defined below). In the SN2 transition state the alpha-carbon ishybridized sp2 with the partial bonds to the nucleophile and thehalogen having largely p-character. Both the nucleophile and thehalogen bear a partial negative charge, the full charge beingtransferred to the halogen in the products. The consequence ofrear-side bonding by the nucleophile is an inversion of configurationabout the alpha-carbon. Neutral nucleophiles react by a similarmechanism, but the charge distribution in the transition state is verydifferent.
This mechanistic model explains many aspects of the reaction. First, itaccounts for the fact that different nucleophilic reagents react atvery different rates, even with the same alkyl halide. Since thetransition state has a partial bond from the alpha-carbon to thenucleophile, variations in these bond strengths will clearly affect theactivation energy, ΔE‡, of the reaction and therefore its rate. Second,the rear-side approach of the nucleophile to the alpha-carbon will besubject to hindrance by neighboring alkyl substituents, both on thealpha and the beta-carbons. The following models clearly show this"steric hindrance" effect.
The two models displayed below start as methyl bromide, on the left, and ethyl bromide, on the right.These may be replaced by isopropyl, tert-butyl, neopentyl, and benzylbromide models by pressing the appropriate buttons. (note that whenfirst activated, this display may require clicking twice on theselected button.) In each picture the nucleophile is designated by alarge violet sphere, located 3.75 Angstroms from the alpha-carbon atom(colored a dark gray), and located exactly opposite to the bromine(colored red-brown). This represents a point on the trajectory thenucleophile must follow if it is to bond to the back-side of the carbonatom, displacing bromide anion from the front face. With the exceptionof methyl and benzyl, the other alkyl groups present a steric hindranceto the back-side approach of the nucleophile, which increases withsubstitution alpha and beta to the bromine. The hydrogen (and carbon)atoms that hinder the nucleophile's approach are colored a light red.The magnitude of this steric hindrance may be seen by moving the modelsabout in the usual way, and is clearly greatest for tert-butyl andneopentyl, the two compounds that fail to give substitution reactions.

4. Molecularity

If a chemical reaction proceeds by more than one step or stage,its overall velocity or rate is limited by the slowest step, the rate-determining step.This "bottleneck concept" has analogies in everyday life. For example,if a crowd is leaving a theater through a single exit door, the time ittakes to empty the building is a function of the number of people whocan move through the door per second. Once a group gathers at the door,the speed at which other people leave their seats and move along theaisles has no influence on the overall exit rate. When we describe themechanism of a chemical reaction, it is important to identify therate-determining step and to determine its "molecularity". The molecularityof a reaction is defined as the number of molecules or ions thatparticipate in the rate determining step. A mechanism in which tworeacting species combine in the transition state of therate-determining step is called bimolecular. If a single species makes up the transition state, the reaction would be called unimolecular. The relatively improbable case of three independent species coming together in the transition state would be called termolecular.

5. Kinetics

One way of investigating the molecularity of a given reaction isto measure changes in the rate at which products are formed orreactants are lost, as reactant concentrations are varied in asystematic fashion. This sort of study is called kinetics,and the goal is to write an equation that correlates the observedresults. Such an equation is termed a kinetic expression, and for areaction of the type: A + B –––> C + D it takes the form: Reaction Rate = k[A] n[b] m, where the rate constant k is a proportionality constant that reflects the nature of the reaction, [A] is the concentration of reactant A, is the concentration of reactant B, and [b]n & m are exponential numbers used to fit the rate equation to the experimental data. Chemists refer to the sum n + m as the kinetic order of a reaction. In a simple bimolecular reaction n & m would both be 1, and the reaction would be termed second order,supporting a mechanism in which a molecule of reactant A and one of Bare incorporated in the transition state of the rate-determining step.A bimolecular reaction in which two molecules of reactant A (and no B)are present in the transition state would be expected to give a kineticequation in which n=2 and m=0 (also second order). The kineticexpressions found for the reactions shown at the beginning of thissection are written in blue in the following equations. Each differentreaction has its own distinct rate constant, k#. All the reactions save7 display second order kinetics, reaction 7 is first order.
It should be recognized and remembered that the molecularity of areaction is a theoretical term referring to a specific mechanism. Onthe other hand, the kinetic order of a reaction is an experimentallyderived number. In ideal situations these two should be the same, andin most of the above reactions this is so. Reaction 7above is clearly different from the other cases reported here. It notonly shows first order kinetics (only the alkyl halide concentrationinfluences the rate), but the chiral 3º-alkyl bromide reactantundergoes substitution by the modest nucleophile water with extensiveracemization. Note that the acetonitrile cosolvent does not function asa nucleophile. It serves only to provide a homogeneous solution, sincethe alkyl halide is relatively insoluble in pure water.
One of the challenges faced by early workers in this field was to explain these and other differences in a rational manner.
Two discrete mechanisms for nucleophilic substitution reactions will be described in the next section.