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In a substitution reaction, a functional group in a particular chemical compound is replaced by another group. In organic chemistry, the electrophilic and nucleophilic substitution reactions are of prime importance. Organic substitution reactions are classified in several main organic reaction types depending on whether the reagent that brings about the substitution is considered an electrophile or a nucleophile, whether a reactive intermediate involved in the reaction is a carbocation , a carbanion or a free radical or whether the substrate is aliphatic or aromatic. Detailed understanding of a reaction type helps to predict the product outcome in a reaction. It also is helpful for optimizing a reaction with regard to variables such as temperature and choice of solvent.
A good example of a substitution reaction is the photochemical chlorination of methane forming methyl chloride.
In organic and inorganic chemistry, nucleophilic substitution is a fundamental class of substitution reaction in which an "electron rich" nucleophile selectively bonds with or attacks the positive or partially positive charge of an atom attached to a group or atom called the leaving group; the positive or partially positive atom is referred to as an electrophile.
The most general form for the reaction may be given as:
Nuc: + R-LG â†’ R-Nuc + LG:
The electron pair (:) from the nucleophile (Nuc) attacks the substrate (R-LG) forming a new bond, while the leaving group (LG) departs with an electron pair. The principal product in this case is R-Nuc. The nucleophile may be electrically neutral or negatively charged, whereas the substrate is typically neutral or positively charged. An example of nucleophilic substitution is the hydrolysis of an alkyl bromide, R-Br, under alkaline conditions, where the attacking nucleophile is the OHâˆ’ and the leaving group is Br-. R-Br + OHâˆ’ â†’ R-OH + Brâˆ’
Nucleophilic substitution reactions are commonplace in organic chemistry, and they can be broadly categorised as taking place at a saturated aliphatic carbon or at (less often) a saturated aromatic or other unsaturated carbon centre.
A nucleophile reacts with an aliphatic substrate in a nucleophilic aliphatic substitution reaction. These substitutions can be produced by two different mechanisms:
unimolecular nucleophilic substitution (SN1) and
bimolecular nucleophilic substitution (SN2).
The SN1 mechanism has two steps. In the first step, the leaving group departs, forming a carbocation. In the second step, the nucleophilic reagent attacks the carbocation and forms a sigma bond. This mechanism can result in either inversion or retention of configuration.
An SN2 reaction has just one step. The attack of the reagent and the expulsion of the leaving group happen simultaneously. This mechanism always results in inversion of configuration.
Nucleophilic substitution reactions:
There are many reactions in organic chemistry that involve this type of mechanism. Common examples include:
Organic reductions with hydrides, for example
R-X â†’ R-H using LiAlH4 Â (SN2)
hydrolysis reactions such as:
R-Br + OHâˆ’ â†’ R-OH + Brâˆ’ (SN2) or
R-Br + H2O â†’ R-OH + HBr Â (SN1)
Williamson ether synthesis:
R-Br + OR'âˆ’ â†’ R-OR' + Brâˆ’ Â (SN2)
The Wenker synthesis, a ring-closing reaction of aminoalcohols.
The Finkelstein reaction, a halide exchange reaction. Phosphorus nucleophiles appear in the Perkow reaction and the Michaelis-Arbuzov reaction.
The Kolbe nitrile synthesis, the reaction of alkyl halides with cyanides.
Nucleophilic substitution reaction at carbon:
According to hughes and ingold ca.1940:
It was found that:
Most primary compounds undergo SN2 reaction with second order kinetics.
And most tertiary compounds undergo SN1 reaction with first order kinetics.
Most nucleophilic substitution reactions fit one or the other of these two paterns.
Following are the important things which we consider in case of SN1 reactions:
fastest for tertiary substrates
needs a good leaving group
product will be racemic
Following are the important things which we consider in case of SN2 reactions:
fastest for methyl and primary substrates
needs a strong nucleophile
leaving group does not need to be primarily good
Nucleophilic substitution at unsaturated carbon centres:
Nucleophilic substitution via the SN1 or SN2 mechanism does not generally occur with vinyl or aryl halides or related compounds. Under certain conditions nucleophilic substitutions may occur, via other mechanisms such as those described in the nucleophilic aromatic substitution article.
When the substitution occurs at the carbonyl group, the acyl group may undergo nucleophilic acyl substitution. This is the normal mode of substitution with carboxylic acid derivatives such as acyl chlorides, esters and amides.
AROMATIC SUBSTITUTION REACTION
Substitution Reactions of Benzene and Other Aromatic Compounds:
The remarkable stability of the unsaturated hydrocarbon benzene has been discussed in an earlier section. The chemical reactivity of benzene contrasts with that of the alkenes in that substitution reactions occur in preference to addition reactions, as illustrated in the following diagram.
Many other substitution reactions of benzene have been observed, the five most useful are listed below (chlorination and bromination are the most common halogenation reactions). Since the reagents and conditions employed in these reactions are electrophilic, these reactions are commonly referred to as Electrophilic Aromatic Substitution. The catalysts and co-reagents serve to generate the strong electrophilic species needed to effect the initial step of the substitution. The specific electrophile believed to function in each type of reaction is listed in the right hand column.
Electrophile Â E(+)
+ Â Cl2 & heat
Â Â FeCl3 catalyst
C6H5Cl Â + Â HCl
Cl(+) or Br(+)
+ Â HNO3 & heat
Â Â H2SO4 catalyst
C6H5NO2 Â + Â H2O
+ Â H2SO4 + SO3
Â Â & heat
C6H5SO3H Â + Â H2O
+ Â R-Cl & heat
Â Â AlCl3 catalyst
C6H5-R Â + Â HCl
+ Â RCOCl & heat
Â Â AlCl3 catalyst
C6H5COR Â + Â HCl
An Aryl Ketone
A Mechanism for Electrophilic Substitution Reactions of Benzene
A two-step mechanism has been proposed for these electrophilic substitution reactions. In the first, slow or rate-determining, step the electrophile forms a sigma-bond to the benzene ring, generating a positively charged benzenonium intermediate. In the second, fast step, a proton is removed from this intermediate, yielding a substituted benzene ring. The following four-part illustration shows this mechanism for the bromination reaction. Also, an animated diagram may be viewed.
Bromination of Benzene - An Example of Electrophilic Aromatic Substitution
This mechanism for electrophilic aromatic substitution should be considered in context with other mechanisms involving carbocation intermediates. These include SN1 and E1 reactions of alkyl halides, and Brønsted acid addition reactions of alkenes.
To summarize, when carbocation intermediates are formed one can expect them to react further by one or more of the following modes:
1. The cation may bond to a nucleophile to give a substitution or addition product.
2. The cation may transfer a proton to a base, giving a double bond product.
3. The cation may rearrange to a more stable carbocation, and then react by mode #1 or #2.
SN1 and E1 reactions are respective examples of the first two modes of reaction. The second step of alkene addition reactions proceeds by the first mode, and any of these three reactions may exhibit molecular rearrangement if an initial unstable carbocation is formed. The carbocation intermediate in electrophilic aromatic substitution (the benzenonium ion) is stabilized by charge delocalization (resonance) so it is not subject to rearrangement. In principle it could react by either mode 1 or 2, but the energetic advantage of reforming an aromatic ring leads to exclusive reaction by mode 2 (ie. proton loss).
Substitution Reactions of Benzene Derivatives:
When substituted benzene compounds undergo electrophilic substitution reactions of the kind discussed above, two related features must be considered:
The first is the relative reactivity of the compound compared with benzene itself. A nitro substituent decreases the ring's reactivity by roughly a million. This activation or deactivation of the benzene ring toward electrophilic substitution may be correlated with the electron donating or electron withdrawing influence of the substituents, as measured by molecular dipole moments. In the following diagram, electron donating substituents (blue dipoles) activate the benzene ring toward electrophilic attack, and electron withdrawing substituents (red dipoles) deactivate the ring (make it less reactive to electrophilic attack).
ELECTROPHILIC SUBSTITUTION OF DISUBSTITUTED BENZENE RINGS
When a benzene ring has two substituent groups, each exerts an influence on subsequent substitution reactions. The activation or deactivation of the ring can be predicted more or less by the sum of the individual effects of these substituents. The site at which a new substituent is introduced depends on the orientation of the existing groups and their individual directing effects. We can identify two general behavior categories, as shown in the following table. Thus, the groups may be oriented in such a manner that their directing influences act in concert, reinforcing the outcome; or are opposed (antagonistic) to each other. Note that the orientations in each category change depending on whether the groups have similar or opposite individual directing effects.
Orientational Interaction of Substituents
Antagonistic or Non-Cooperative
Reinforcing or Cooperative
D = Electron Donating Group (ortho/para-directing)
W = Electron Withdrawing Group (meta-directing) Â
The products from substitution reactions of compounds having a reinforcing orientation of substituents are easier to predict than those having antagonistic substituents. For example, the six equations shown below are all examples of reinforcing or cooperative directing effects operating in the expected manner. Symmetry, as in the first two cases, makes it easy to predict the site at which substitution is likely to occur. Note that if two different sites are favored, substitution will usually occur at the one that is least hindered by ortho groups.
RADICAL SUBSTITUTION REACTION
InÂ organic chemistry, aÂ radical substitution reactionÂ is aÂ substitution reactionÂ involvingÂ free radicalsÂ as aÂ reactive intermediateÂ .
The reaction always involves at least two steps, and possibly a third.
In the first step calledÂ initiationÂ (2,3) aÂ free radicalÂ is created byÂ homolysis. Homolysis can be brought about by heat or light but also byÂ radical initiatorsÂ such asÂ organic peroxidesÂ orazo compounds. Light is used to create two free radicals from one diatomic species. The final step is calledÂ terminationÂ (6,7) in which the radicalÂ recombinesÂ with another radical species. If the reaction is not terminated, but instead the radical group(s) go on to react further, the steps where new radicals are formed and then react is collectively known aspropagationÂ (4,5) because a new radical is created available for secondary reactions.
Radical substitution reactions
InÂ free radical halogenationÂ reactions radical substitution takes place withÂ halogenÂ reagents andÂ alkaneÂ substrates. Another important class of radical substitutions involveÂ aryl radicals. One example is the hydroxylation ofÂ benzeneÂ byÂ Fenton's reagent. Many oxidation and reduction reactions in organic chemistry have free radicalÂ intermediates, for example the oxidation ofÂ aldehydesÂ toÂ carboxylic acidsÂ withÂ chromic acid.Â Coupling reactionsÂ can also be considered radical substitutions. Certain aromatic substitutions takes place byÂ radical-nucleophilic aromatic substitution.Â Auto-oxidationÂ is a process responsible for deterioration of paints and food and lab hazards such asÂ diethyl ether peroxide.
More radical substitutions are listed below:
TheÂ Barton-McCombie deoxygenationÂ is a way to substitute aÂ hydroxylÂ group for a proton.
TheÂ Wohl-Ziegler reactionÂ involves the allylic bromination of alkenes.
TheÂ Hunsdiecker reactionÂ converts silver salts of carboxylic acids to alkyl halides.
TheÂ Dowd-Beckwith reactionÂ involves ring expansion of cyclic Î²-keto esters.
TheÂ Barton reactionÂ involves synthesis of nitrosoalcohols from nitrites.
Nucleophilic Substitution, Elimination & Addition Reactions of Benzene Derivatives
An early method of preparing phenol (the Dow process) involved the reaction of chlorobenzene with a concentrated sodium hydroxide solution at temperatures above 350 °C. The chief products are phenol and diphenyl ether (see below). This apparent nucleophilic substitution reaction is surprising, since aryl halides are generally incapable of reacting by either an SN1 or SN2 pathway.
C6H5-Cl Â +Â NaOH solution
C6H5-OH Â +Â C6H5-O-C6H5 Â +Â NaCl
The presence of electron-withdrawing groups (such as nitro) ortho and para to the chlorine substantially enhance the rate of substitution, as shown in the set of equations presented on the left below. To explain this, a third mechanism for nucleophilic substitution has been proposed. This two-step mechanism is characterized by initial addition of the nucleophile (hydroxide ion or water) to the aromatic ring, followed by loss of a halide anion from the negatively charged intermediate.
Addition-elimination processes generally occur at sp2 or sp hybridized carbon atoms, in contrast to SN1 and SN2 reactions. When applied to aromatic halides, as in the present discussion, this mechanism is called SNAr. Some distinguishing features of the three common nucleophilic substitution mechanisms are summarized in the following table.
Number of Steps
Bond Formation Timing
After Bond Breaking
Prior to Bond Breaking
There is good evidence that the synthesis of phenol from chlorobenzene does not proceed by the addition-elimination mechanism (SNAr) described above. For example, treatment of para-chlorotoluene with sodium hydroxide solution at temperatures above 350 °C gave an equimolar mixture of meta- and para-cresols (hydroxytoluenes). Chloro and bromobenzene reacted with the very strong base sodium amide (NaNH2 at low temperature (-33 °C in liquid ammonia) to give good yields of aniline (aminobenzene). However, ortho-chloroanisole gave exclusively meta-methoxyaniline under the same conditions. These reactions are described by the following equations.
The explanation for this curious repositioning of the substituent group lies in a different two-step mechanism we can refer to as an elimination-addition process. The intermediate in this mechanism is an unstable benzyne species, as displayed in the above illustration by clicking the "Show Mechanism" button. In contrast to the parallel overlap of p-orbitals in a stable alkyne triple bond, the p-orbitals of a benzyne are tilted ca.120° apart, so the reactivity of this incipient triple bond to addition reactions is greatly enhanced. In the absence of steric hindrance (top example) equal amounts of meta- and para-cresols are obtained. The steric bulk of the methoxy group and the ability of its ether oxygen to stabilize an adjacent anion result in a substantial bias in the addition of amide anion or ammonia.
Although it does so less readily than simple alkenes or dienes, benzene adds hydrogen at high pressure in the presence of Pt, Pd or Ni catalysts. The product is cyclohexane and the heat of reaction provides evidence of benzene's thermodynamic stability. Substituted benzene rings may also be reduced in this fashion, and hydroxy-substituted compounds, such as phenol, catechol and resorcinol, give carbonyl products resulting from the fast ketonization of intermediate enols. Nickel catalysts are often used for this purpose, as noted in the following equations.
Benzene is more susceptible to radical addition reactions than to electrophilic addition. We have already noted that benzene does not react with chlorine or bromine in the absence of a catalyst and heat. In strong sunlight or with radical initiators benzene adds these halogens to give hexahalocyclohexanes. It is worth noting that these same conditions effect radical substitution of cyclohexane, the key factors in this change of behavior are the pi-bonds array in benzene, which permit addition, and the weaker C-H bonds in cyclohexane. The addition of chlorine is shown below; two of the seven meso-stereoisomers will appear if the "Show Isomer" button is clicked.