HALOGEN DERIVATIVES OF THE HYDROCARBONS: NOMENCLATURE, ISOMERY, METHODS OF OBTAINING, CHEMICAL PROPERTIES AND THEIR USAGE IN PHARMACY

Halogen derivatives of the hydrocarbons: nomenclature, isomery, methods of obtaining, chemical properties and their usage in pharmacy. Reaction of nucleophilic substitution and elimination. Methods of the organic compounds halogenation. Small practicum.

Isomery of the organic compounds. Spatial construction of the molecules of biologically active compounds: conformation, geometric, optical isomery.

 

We begin our study of alkyl halides by briefly reviewing what constitutes the initiation of a reaction sequence: the breaking of a covalent hydrocarbon bond. This can occur i none of two fundamentally different ways, depending on what happens to the two electrons making up the bonding pair.

1) Homolysis is chemical bond dissociation of a neutral molecule generating two species called free radicals, which are typically associated with single unpaired electrons. That is, the two electrons that are involved in the bond are distributed one by one to the two species.

                           A : B    ®    A.    +    B.

The energy involved in this process is called bond dissociation energy. Recall that we saw distinct examples of this type in Unit 1- the discussion of the halogenation reaction sequence of methane and other alkanes. 

2) Heterolysis is chemical bond cleavage of a neutral molecule generating a positively charged cation and a negatively charged anion. In this process the two electrons that make up the bond are assigned to the same fragment.

                           A : B    ®    A +    +    B: –

Thus, heterolytic reactions are those in which the bonding electrons are taken away – or provided – in pairs. The energy involved in this process is called heterolytic bond dissociation energy.  In heterolysis, additional energy is required to separate the ion pair. An ionizing solvent helps reduce this energy. In summary:

1) Homolytic chemistry is the chemistry of the odd electron. 

2) Heterolytic chemistry is the chemistry of the electron pair. 

Homolytic reactions are typically carried out in the gas phase, or in solvents whose principal function is to provide an inert medium in which the reactants can move about freely (mobility).  

Heterolytic reactions are typically carried out in solution, and the solvents exert powerful effects.  

So far, the reactions we have been chiefly concerned with were characterized by homolytic bond cleavage. We now begin our study of heterolytic chemistry – which constitutes the vast majority of chemical reactions involving hydrocarbon compounds. The reaction we shall start with is a substitution reaction. But unlike alkane halogenation, this reaction is heterolytic. It is based on substitution of one nucleophile by another, and applies only to aliphatic (vs. aromatic) compounds. 

We call it nucleophilic aliphatic substitution. 

 The nomenclature of halogenderivatives of hydrocarbons

We classify a carbon atom as primary, secondary, or tertiary according to the number of other carbon atoms attached to it. An alkyl halide is classified according to the kind of carbon that bears the halogen atom.

As members of the same family, containing the same functional group, alkyl halides of different classes tend to undergo the same kinds of reactions. They differ in rates of reaction, however, and these differences in rates may lead to other differences as well. 

Alkyl halides can be given two kinds of names: commoames (for the simpler halides) and IUPAC names, in which the compound is named as an alkane with a halogen attached as a side chain. For example:

Halogenderivatives of hydrocarbons are the products of substitution one or several atoms of hydrogen to atoms of halogens in the hydrocarbon molecules.

The names of halogenderivatives of hydrocarbons are the names of the same hydrocarbons with added prefix which means the halogen radical.

i.e.

                             

If there are several halogen radicals in the molecule of halogenderivatives of hydrocarbons, then all substutients are called in alphabetical order.

 Some halogenderivatives of hydrocarbons have trivial names:

                      

The isomery of halogenderivatives of hydrocarbons

Halogenderivatives of hydrocarbons are characterized by structural, geometrical and optical isomery.

Structural isomery is formed by different structure of carbon chain and different location of halogen atoms in the molecule of organic compound.

i.e.

 Geometrical isomery is possible for molecules of halogenderivatives which contain the carbon atoms connected with different substutients.

i.e.

                           

Optical isomery is possible for molecules of halogenderivatives which contain asymmetric carbon atom.

i.e.

 

The medico-biological importance of halogenderivatives of hydrocarbons

Because of the atom of halogen is present in the molecule, many halogenderivatives of hydrocarbons are physiologically active. For example:

C₂H₅Cl – ethyl chloride – is the means for the local anaesthetization when there are neuralgia, large superficial cuts, wounds. Because of the fast evaporation from the skin ethyl chloride causes the strong cooling and loss of painful sensitivity;

CHCl₃ – chloroform – is the means for inhalative narcosis. It is relatively toxic. In the presence of light it can oxidize with forming of HCl and phosgene () – which is very toxic compound;

CHI₃ – iodoform – is the antiseptic means. It is crystal compound, it has yellow colour. It is used as powder and ointment;

СF₃–CHBrCl – fluorotane – (2-bromo-1,1,1-trifluoro-2-chloroethane) – is one of the best means of general narcosis;

CCl₂=CHCl – trichloroethylene – is the strong narcotic means, especially for short-term narcosis.

Because of the presence of halogen atom in the benzene ring the compound is more toxic. Because of the presence of halogen atom in the side carbon chain of the benzene ring the compound is lachrymatorier.

Physical properties

Because of their greater molecular weights, alkyl halides have considerably higher boiling points than unhalogenated alkanes with the same number of carbons. For a given alkyl group, the boiling point increases with increasing atomic weight of the given halogen, so that a fluoride is the lowest boiling and an iodide the highest. For a given halogen, the boiling point rises with increasing carboumber. Branching of any kind (R group or halogen X) lowers the boiling point.  

In spite of their modest polarity, alkyl halides are insoluble in water, probably because of their inability to form hydrogen bonds. They are soluble in the typical organic solvents of low polarity, like benzene, ether, chloroform, or ligroin (petroleum ether). Iodo, bromo, and polychloro compounds are more dense than water ( > 1.0  g / cc). Thus, as molecules of low polarity, both the alkanes and alkyl halides are held together by van der Waals forces or weak dipole-dipole attractions. They are characterized by low melting points and boiling points, and are soluble ion-polar solvents. 

The halogenalkanes’ boiling point increase as the atomic mass of the halogen atoms increase, or as the number of halogen atoms increase. Effectively the mass is what determines the boiling point.

A simple explination for this is that the amount of instantaused dipole-induced interactions increase. With this increase in intermolecular force, more energy is required to break the intermolecular bonds, so the boiling point is higher.

Physical state and smell. Haloalkanes are colorless, sweet-smelling liquids. The lower members like methyl chloride, methyl bromide and ethyl chloride are colorless gases while members having very high molecular masses are solids.

Solubility. Haloalkanes are not able to form hydrogen bonds with water and, even though they are polar iature, they are practically insoluble in water. However, they are soluble in organic solvents like alcohol, ether, benzene, etc.

Density. Chloroalkanes are lighter than water while bromides and alkyl iodides are heavier. With the increase in the size of the alkyl group, the densities go on decreasing in the order of:

fluoride > chloride > bromide > iodide.

Boiling points. The boiling points of alkyl chlorides, bromides and iodides follow the order RI > RBr > RCl where R is an alkyl group. With the increase in the size of halogen, the magnitude of Van der Waals forces increases and, consequently, the boiling points increase. Also, for the same halogen atom, the boiling points of haloalkanes increase with increase in the size of alkyl groups.

The tables below show some physical data for a selection of haloalkanes.

The methods of extraction of halogenalkanes

1. Chlorinating and brominating of the saturated hydrocarbons (the reactions of radical substitution (S_R).

 As we might expect, halogenation of the higher alkanes is essentially the same as the halogenation of methane. It can be complicated, however, by the formation of mixtures of isomers. 

Under the influence of UV light or temperatures from 250 to 400 degrees C, chlorine or bromine converts alkanes into chloroalkanes (alkyl chlorides) or bromoalkanes (alkyl bromides). Reaction rates of the chlorination and bromination reactions are similar. When diluted with an inert gas, and with sufficient heat transfer for cooling, (in contrast to methane) fluorine has recently been found to give analogous results. But as with methane, iodination does not take place at all. 

Depending on which hydrogen atom is replaced, any of number of isomeric products can be formed from a single alkane. Thus, free-radical (homolytic) chlorination leads to a possible substitution at each C atom that bears an H atom. This situation essentially requires the recognition of structures that contain various numbers of non-equivalent H atoms. Since all H atoms are potential candidates for chorination, then in general, the number of non-equivalent H atoms is equal to the number of different possible substitution sites – and thus the number of potential isomers. For example: 

1)  Ethane can yield only one alkyl halide (all H atoms are equivalent) 

2)  Propane, n-butane and isobutane can yield two isomers each.

3)  n-Pentane can yield three isomers.

4)  Isopentane can yield four isomers.

Experiment has shown that on halogenation, an alkane yields a mixture of all possible isomeric products. These results indicate that all H atoms are eligible for replacement.  

For example, for chlorination: 

Bromination gives the corresponding bromides, but in greatly different proportions:

Example Problem:  Among the isomeric alkanes of molecular formula C5H12, identify the one that on photochemical chlorination yields the alkyl chloride specified in each case.

a) A single monochloride:

2,2 – Dimethylpropane (neopentane)

 

Notice that in this highly symmetrical (totally non-polar) structure, all H atoms are equivalent. Thus only one possible monochloride is possible. The same isomer will result from the substitution of any of these H atoms.

1 – Chloro – 2,2 – dimethylpropane

 

 b)  3 isomeric monochlorides

The simplest constitutional isomer neopentane, the straight-chai-Pentane, satisfies the C₅H₁₂ chemical formula requirement with 3 non-equivalent hydrogen sites.

                       n – Pentane

       

Chlorination of n-Pentane at the following 3 non-equivalent hydrogen sites yields three different structural (constitutional) isomers of monochloropentane.

 

1 – Chloropentane

2 – Chloropentane

3 – Chloropentane

c) 4 isomeric monocholrides

Another structural isomer of neopentane, 2 – Methylbutane, satisfies the C5H12 chemical formula requirement with 4 non-equivalent hydrogen sites.

First of all, note the equivalence of the following 2 substitution sites:                                                                  

 1 – Chloro – 2 – methylbutane

The other 3 non-equivalent sites for substitution in 2 -Methylbutane are in the methyl groups associated with carbon atoms C2, C3 and C4.

1- Chloro – 2 – methylbutane   

2 – Chloro – 3 – methylbutane

   

1 – Chloro – 3 – methylbutane

 

d)  2 isomeric dichlorides

In order to identify the alkanes of molecular formula C5H12 which photochemical chlorination yield 2 isomeric dichlorides, the starting alkane must have a structure that is rather symmetrical; that is, one in which most or all of the hydrogen substitution (or chlorination) sites are equivalent. The molecule from part a) that satisfies this requirement is:

 2,2 Dimethylpropane   

Again, we first note the similarities of the following 2 identical structures in 3-dimensions.

                                                 1,3 – Dichloro – 2,2 – dimethylpropane

We then illustrate the only other non-equivalent H atom substitution site as follows:

  1,3 – Dichloro – 2,2 – dimethylpropane

Based on these results, we must therefore conclude that the method of halogenation of alkanes is not a suitable technique for the laboratory preparation of alkyl halides.

We turow to more appropriate methods of preparation and synthesis.

2. The Finkelshtain reaction.

R–Cl + NaI → R–I + NaCl

 

3. Hydrohalogenation is the joining HCl, HBr or HJ to ethylene and acethylene hydrocarbons. This reaction runs by Markovnikov rule.

 

4. The substitution of the functional groups (for example, –ОН) to atom of any halogen by the action of the following reagents:

a) HCl, HBr, HJ or mixture NaCl + H₂SO_{4(concentrated)}, KBr + H₂SO_{4(concentrated)};

b) PCl₃, PCl₅, PBr₃, PBr₅ or mixture P + J₂;

c) SOCl₂, SO₂Cl₂.

i.e.

Alkyl halides are nearly always prepared form alcohols. The reaction mechanism is a nucleophilic substitution SN1.

In the laboratory, alcohols are the most common starting point for the synthesis of other aliphatic compounds. One of the most common first steps in such a synthesis is the conversion of the alcohol into an alkyl halide. Once the alkyl halide is made, the synthesis can follow any one of the myriad of possibilities available via nucleophilic aliphatic substitution – proceeding via either the SN1 or SN2 mechanism as described herein.

1) Addition of hydrogen halides to alkenes: 

An alkene is converted by hydrogen halide HX ( X = Cl, Br, or I) into the corresponding alkyl halide.

The reaction is frequently carried out by passing the dry gaseous hydrogen halide directly into the alkene. Acetic acid, a moderately polar solvent which will dissolve both the polar hydrogen halide and the non-polar alkene, is often used. (The familiar aqueous solutions of the hydrogen halides are not generally used, due to the hazards of water addition to the alkene). 

In this way, propylene is converted into isopropyl iodide, the hydrogen becoming attached to one doubly bonded carbon and the halogen to the other. Also, the bromination of propylene yields 2 products: isopropyl bromide or n-propyl bromide, depending on the orientation of addition – or which carbon atoms the H atom and X atom become attached to. Actually, only the isopropyl halide is formed. Thus, in the addition of an acid to the C=C double bond of an alkene, the H atom of the acid is regioselective. It attaches itself to the C atom already holding the largest number of H atoms. This is Markovnikov’s Rule. Thus, the formation of isopropyl iodide (vs. n-propyl iodide) and the formation of tert-butyl iodide (vs. isobutyl iodide) as follows:

A widely observed reversal of orientation caused by the presence of peroxides has come to be known as the peroxide effect. Of the reactions we are studying here, only the addition of hydrogen bromide shows evidence of the peroxide effect. As we shall see later in this Unit, both Markovnikov’s Rule and the peroxide effect can readily be accounted for in a manner consistent with our our current understanding of chemical principles.

 2) Addition of halogens to alkenes:

Alkenes are readily converted by chlorine or bromine into saturated compounds that contain two atoms of halogen attached to adjacent C atoms.

The reaction is carried out simply by mixing together the two reactants – usually in an inert (non-polar) solvent like CCl4. The addition proceeds rapidly at room temperature or below, and does not require exposure to UV light. (In fact, we deliberately avoid higher temperatures and undue exposure to light, as well as the presence of excess halogen, since under such conditions substitution might become a significant side reaction.)

This reaction is by far the best method for preparing vicinal dihalides. Also, the addition of bromine is extremely useful for detection of the C=C double bond. A solution of bromine in CCl4 is red, while the dihalide (like the alkene) is colorless. Rapid decolorization of a bromine solution is thus characteristic of compounds containing the C=C double bond.

In the first step, the reaction mechanism for the addition of halogens to alkenes differs distinctly form the previous addition reactions. In short, the cation formed is NOT believed to be a carbocation.

We refer to this cation as halonium ion – or in this case, a bromonium ion. Thus, in step (1) bromine is transferred form a bromine molecule to the alkene. In so doing, it is not transferred to just one of the doubly bonded carbons. But rather it attaches itself to both of the doubly bonded C atoms – forming a cyclic reaction intermediate called a halonium ion.

Step (1) does indeed represent electrophilic addition. Bromine is transferred as positive bromine, without a pair of electrons. The electrons are thus left behind on the newly formed bromide ion. In step (2) this bromide ion, (or more probably another just like it) reacts with the bromonium ion to yield the dibromide product. 

In search of clarity here, consider an alternative viewpoint. From the standpoint of a halogen molecule, the reaction with an alkene is nucleophilic substitution. Acting as a nucleophile, the alkene attaches itself to tone of the bromines and pushes the other bromine out as bromide ion. Bromide ion is the leaving group in this reaction scheme. And as we have seen, the bromide ion is an excellent leaving group.

Evidence includes:

1) The effect of structure of the alkene on reactivity. Thus, alkenes show the same order of reactivity toward halogens as toward the acids already studied. Electron-releasing substituents activate an alkene, and electron-withdrawing substituents deactivate. This fact supports the idea that addition is indeed electrophilic- that the alkene is acting as the electron source, and that the halogen acts as an acid.

2)  The effect of added nucleophiles on the products obtained. If a halonium ion is the intermediate, and capable of reacting with halide ion, then we might expect it to react with almost any negative ion or basic molecule we care to provide (e.g. fluoride ion, iodide ion, nitrate ion, or water). This is, indeed, the case.

Thus, when ethylene is bubbled into an aqueous solution of bromine and sodium chloride, there is formed not only the dibromo compound, but also the bromochloro compound and the bromoalcohol. Aqueous sodium chloride alone is completely inert toward ethylene. Chloride ion or water can react only after the halonium ion has been formed by the action of bromine. Similarly, bromine and aqueous sodium iodide or sodium nitrate converts ethylene into the dibromoiodo compound or the bromo nitrate, as well as the dibromo compound and the bromoalcohol. Bromine in water with no added ion yields the dibromo compound and the bromoalcohol. 

This work definitely indicates that ethylene reacts with bromine to form something that can react readily with these other nucleophiles. In order to determine more certainly that it is indeed a bromonium ion which forms as the reaction intermediate, we must turn to additional considerations of chirality and stereospecific reactions (see Unit 12: Stereochemistry II) and actual experimental observation.

 3) Addition of halogens to alkynes:

Alkynes react with halogens to yield tetrahaloalkanes. Two molecules of the halogen (chlorine or bromine) add to the triple bond as follows:

A dihaloalkane is an intermediate and is the isolated product when the alkyne and the halogen are present in equimolar amounts. Toward the addition of of halogens, alkynes are considerably less reactive than alkenes. For alkenes, as we have seen, this reaction involves the the initial formation of a cyclic halonium ion. The lower reactivity of alkynes has been attributed to the greater difficulty of forming such cyclic intermediates.

 4) Addition of hydrogen halides to alkynes:

Alkynes react with many of the same electrophilic reagents that add to the double bond of alkanes. E.G. Hydrogen halides add to the alkynes to form alkenyl halides.

The regioselectivity of addition follows Markovnikov’s rule. A proton adds to the carbon that has the greatest number of hydrogens attached to it, and a halide adds to the C atom with the fewer H atoms attached to it. For example:

To explain this, we could propose a process analogous to that of electrophilic addition to alkenes – in which the first step is the formation of a carbocation and is rate-determining. Then the second step would be nucleophilic capture of the carbocation by a halide ion as follows:

Evidence indicates, however, that alkenyl cations (aka vinylic cations) are far less stable than simple cations, and their involvement in these additions has been questioned. E.G. Although electrophilic addition of hydrogen sulfides to alkynes occurs more slowly than the corresponding additions to alkenes. The difference is not nearly as great as the difference in carbocation stabilities would suggest.

In addition, kinetic studies suggest that electrophilic addition of hydrogen halides to alkynes follows a rate law that is third-order overall and second order in hydrogen halide.

The third order rate dependence suggests a transition state involving two molecules of the hydrogen halide and one of the alkyne. The following figure depicts a one-step termolecular process using curved arrows to show the follow of electrons.

Dashed lines are to indicate the bonds being made and broken at the transition state.

 This reaction mechanism, called AdE3 for addition-electrophilic-termolecular, avoids the formation of a very unstable alkenyl cation intermediate by invoking nucleophilic participation by the halogen at an early stage. Nevertheless, because Markovnikov’s rule is observed, it seems likely that some degree of positive character develops at the C atom and controls the regioselectivity of addition. 

In the presence of excess hydrogen halide, geminal dihalides are formed by sequential addition of two molecules of hydrogen halide to the C-C triple bond.

The second mole of hydrogen halide adds to the initially formed alkenyl halide in accordance with Markovnikov’s rule. Both protons become bonded to the same carbon and both halogens to the adjacent carbon. 

Chemical properties of halogenalkanes

1.       Halogenalkanes react with water

C₂H₅Br + H₂O ↔ C₂H₅OH + HBr

2.       Halogenalkanes react with NaOH or KOH

C₂H₅Br + NaOH ↔ C₂H₅OH + NaBr

3.       Williamson reaction

C₂H₅Br + NaOC₂O₅ → C₂H₅−O−C₂H₅ + NaBr

4.       Reaction with salts of carboxylic acids

5.     Reaction with ammonium

C₂H₅Br + NH₃ → [C₂H₅NH₃]⁺Br⁻  C₂H₅NH₂

6.     Halogenalkanes react with NaCN or KCN

7.     For example, using 1-bromopropane as a typical primary halogenoalkane:

8.     

9.     You could write the full equation rather than the ionic one, but it slightly obscures what’s going on:

10

11. The bromine (or other halogen) in the halogenoalkane is simply replaced by a -CN group – hence a substitution reaction. In this example, butanenitrile is formed.

C₂H₅Br + NaCN → C₂H₅−C≡N + NaBr

12.  Reaction with salts of HNO₂

C₂H₅Br + NaNO₂ → C₂H₅NO₂ + NaBr

 

13. Finkelshtain reaction (catalyst is acetone)

C₂H₅Cl + NaI → C₂H₅I + NaCl

 

14. Reaction with NaSN (thioalkohols form) or Na₂S (thioethers form)

C₂H₅I + NaSN → C₂H₅SN + NaI

 

2C₂H₅I + Na₂S → C₂H₅−S−C₂H₅ + 2NaI

 

15. Reaction with metals

C₂H₅I + Mg → C₂H₅MgI

 

16. Reduction (the reaction runs in the presence of catalysts)

C₂H₅Cl + H₂ → C₂H₆ + HCl

Nucleophilic Substitution

What we have now established in our preliminary studies of the alkanes, alcohols, and alkyl halides is rather significant in relationship to what we intend to accomplish in this comprehensive program of studies in organic chemistry.

We have now clearly established the importance of alcohols, their relative roles as both acids and bases, and the special position they occupy in the hierarchy of organic synthesis, especially in relationship to the aliphatics.

Alternatively, we have established the extremely limited role of the alkanes as organic precursors, and must view them from here onward in a limited and “dead-end” type of framework. Their tendency for structural and functional specificity is far too loose-ended, and what we might refer to as their “structural ambiguity” (or reaction site equivalence) is simply too prevalent to lend any sense of practicality to their use in synthesis in the chemical laboratory.   

Thus, in the laboratory, alcohols are the most common starting point for the synthesis of aliphatic compounds, and the most common first step in such a synthesis is the conversion of an alcohol to an alkyl halide. Once the alky halide is produced, a number of reactions are possible, including a wide variety of both substitution and elimination reactions (see figure above).

In this section, we turn our attention to the reactions which can occur utilizing the alkyl halides as chemical precursors, with a strong emphasis on those reactions characterized by:

When methyl bromide is reacted with sodium hydroxide in a solvent that dissolves both reagents, the result is methanol (methyl alcohol) and sodium bromide. This is a simple substitution reaction, since the OH group is substituted for the halogen (Br) atom in the original compound. In this reaction, an alkyl halide has been converted into an alcohol.

The reaction as clearly heterolytic, since the departing halide ion takes with it the electron pair it has been sharing with the C atom. The OH ion brings with it the electron pair needed to bind it to the C atom. Thus, the C atom loses one pair of electrons while gaining another pair. This is a classic example of the class of reactions called nucleophilic (aliphatic) substitution.

A halide ion is an extremely weak base. This is evidenced by its readiness to release (or donate) a proton to other bases, i.e. by the high acidity of the hydrogen halides. In an alkyl halide, a halogen atom X is attached to a C atom. Just as X in an H-X acid readily releases a proton, so the X in an R-X alkyl halide readily releases a C atom – again, to other bases.  These bases possess an unshared pair of electrons and are seeking a relatively positive site. I.E. they are seeking a nucleus with which to share their electron pair.

Basic, electron-rich reagents which tend to attack the nucleus of carbon are called nucleophilic reagents, or simply nucleophiles. When this attack results in substitution, the reaction is called nucleophilic substitution. The compound containing the carbon atom that undergoes a particular kind of reaction is called the substrate, and is typically characterized by a leaving group. The leaving group becomes displaced from the C atom and departs from the molecule – taking the electron pair with it. 

Because the weakly basic halide ion is a good leaving group, the alkyl halides are good substrates for nucleophilic substitution. As illustrated in the table below, they react with a large number of nucleophilic reagents, both inorganic and organic, to yield a wide variety of important products. These reagents include not only negative ions like hydroxide and cyanide, but also neutral bases such as ammonia and water. Their characteristic feature is an unshared pair of electrons.

Nucleophilic substitution is the “work-horse” of organic synthesis. The synthesis of aliphatic compounds, we said, most often starts with alcohols. Alcohols the OH group is a very poor leaving group. It is only thru the conversion of alcohols into alkyl halides – or other compounds with good leaving groups – that we open the door to nucleophilic substitution and the vast majority of higher compounds.   

 

1) Dehydrohalogenation / Elimination

2) Preparation of a Grignard Reagent

3) Reduction by Metal and Acid

Let’s take a closer look at some of the nucleophiles we shall be working with. Many of the products formed are new to us. But at this point we need only see how the structure of a particular product is the natural result of the structure of a particular nucleophile. For now, we shall use alkyl halides as our examples of substrates.

Some nucleophiles are anions, like the OH- (hydroxide) ion, or another halide ion (Iodine, I-) which, while only weakly basic, does after all possess unshared electrons. Alternatively, the cyanide (CN-) ion is the strongly basic anion of the weakly basic HCN (hydrocyanic acid or Prussic acid).

Neutral molecules can also possess unshared electrons, have basic properties, and hence act as nucleophiles. E.G. Water attacks an alkyl halide to yield an alcohol. But the oxygen of water already has two hydrogens. And when it attaches itself to a C atom, it initially forms its conjugate acid, the protonated alcohol. This is easily changed into the alcohol by loss of the proton.    

It should be pointed out that the existence of a lone hydrogen ion (or proton, H+) is a misnomer, as it does not actually exist in solution. In aqueous solution, H+ will immediately attach itself to a water molecule in order to form the more stable positively charged species: the hydronium ion (H3O+). See above.

Regarding other leaving groups, and thus other substrates we shall encounter, the alkyl esters of sulfonic acids (ArSO2OR), are most commonly used in place of alkyl halides. Like alkyl halides, the sulfonates are made from alcohols.

Kinetics:  2nd  Order  vs. 1st  Order

Let us begin with a specific example: the reaction of methyl bromide with sodium hydroxide to yield methanol.

CH3Br    +    OH-      =      CH3OH    +    Br-

This reaction would probably be carried out in aqueous ethanol, in which both reactants are soluble. If the reaction results from collisions between an OH- ion and a CH3Br molecule, then we say that the rate depends upon the concentrations of both of these species. I.E.

Rate  =  k [CH3Br] [OH-]

and we find this to be so. Let us now look at the corresponding reaction between tert-butyl bromide and hydroxide ion:

In this reaction, however, we find there to be no dependence of the reaction rate on OH- concentration. The reaction rate is independent of [OH-]. Thus:

                                                                   Rate  =  k [RBr]

To summarize our findings, we say that the methyl bromide reaction follows second-order reaction kinetics, since its rate is dependent upon the concentration of 2 substances. Alternatively, the tert-butyl bromide reaction follows first-order reaction kinetics, since its rate is dependent upon the concentration of only one substance. 

In 1935, E. D. Hughes and Sir Christopher Ingold studied nucleophilic substitution reactions of alkyl halides and related compounds. Initially, the overall rate of the nucleophilic substitution was a little puzzling:

                                   CH₃X > primary > secondary < tertiary

The reaction kinetics appeared to change from second order to first order. They proposed that there were two main mechanisms at work, both of them competing with each other. The two main mechanisms are the SN1 reaction and the SN2 reaction. S stands for chemical substitution, N stands for nucleophilic, and the number represents the kinetic order of the reaction (see Unit 29: Chemical Equilibrium).

The following illustration constitutes a graph showing the relative reactivities of the different alkyl halides towards SN1 and SN2 reactions. The minimum in rate is attributed to the crossing of two opposing curves. I.E. The minimum in the curve is attributed to a shift in the reaction mechanism form SN₂ to SN₁.

Thus, as one passes along the series, reactivity by the SN2 mechanism decreases from CH3 to primary C atoms, and at a secondary C atom is so low that the SN1 begins to contribute significantly, rising sharply to tertiary C atoms. 

In order to decipher this quandary, we need to understand the different factors influencing these 2 different reaction mechanisms: SN1 and SN2.

SN2 – Mechanism of Reaction

SN2 reactivity rates follow the trend:

                             CH₃X > primary > secondary > tertiary                        

The simplest way to account for the second-order reaction kinetics is to assume that the reaction requires a collision between a hydroxide ion and a methyl bromide molecule. It is known that in its attack the OH ion stays as far away as possible from the bromine atom (i.e. it attacks the molecule from the rear). The reaction is believed to take place as follows, with a complete inversion of the molecular tetrahedral geometry taking place. This allows the distance between the (OH-) and (Br-) to be maximized.  

The transition state can be pictured as structure in which carbon is partially bonded to both OH and Br. The C-OH bond is not completely formed, and the C-Br bond is not completely broken. The OH has a diminished negative charge, since it has begun to share its electrons with the C atom. Bromine has developed a partial negative charge, since it has begun to remove a pair of electrons from a C atom.  

Most importantly, the OH and Br are located as far apart as possible. The three H atoms and the C atom lie within a single plane (are coplanar) with all bond angles set at 120 degrees – due to the trigonal planar overlap of three sp2 orbitals. 

The partial bonds to the leaving group and the nucleophile are formed through overlap of the remaining p orbitals: 180 degrees apart, and perpendicular to the plane of the sp2 orbitals.  Thus, the C-H bonds are radial (as in the spokes of a wheel) while the C-OH and C-Br bonds lie horizontally (along the axle of the wheel). This is the mechanism that is called 

SN₂:  Substitution Nucleophilic Bimolecular

The strongest evidence for this reaction mechanism is based on the inversion of the reaction intermediate. A reaction that yields a product whose configuration is opposite (chiral) to that of a reactant is said to proceed with inversion of configuration. I.E. The reactants and products are enantiomers. Indeed, we find this to be the case as all SN₂ reactions proceed with complete stereochemical inversion.

Additional evidence for this mechanism is provided in the form of steric hindrance among alkyl groups. Direct measurement of SN2 rates for a series of substrates in DMF (dimethylformamide – a pro-active SN2 solvent) gives results like the following, where the bottom figures represent relative rates of reaction:

These trends in reactivity match the relative rates as quoted above:

                                 CH₃X > primary > secondary > tertiary       

We now need to compare the structure of the reactants to the structure of the transition state. In contrast to free radical substitution, the structure of the transition state is not intermediate between the structures of the reactants and products. Thus, we cannot simply expect that factors stabilizing the product will also stabilize the transition state.

We might begin by investigating the redistribution of charge on forming the transition state, as very often reactivity depends upon how easily the molecule accommodates that charge. Accommodation of charge, in turn, depends upon how well the substituents tend to withdraw or release electrons. What we find in the SN2 transition state, however, is that while the OH ion has brought electrons to the C atom, the halide ion has equally taken them away. Thus, there should be no net change in the electronegativity of the central C atom. Therefore, it is highly unlikely that the reactivity sequence results from the polar effects of substituent groups.

Let us next compare transition state and reactants with regard to shape and form, starting with the methyl bromide reaction. What we find as H atoms are replaced by an increasing number of methyl groups is an increasing crowding about the central carbon atom. In fact, the alkyl groups will be strategically situated on the backside of the molecule; directly opposite of the halide (Br) atom. In short, the backside of the molecule will be increasingly difficult to access for partial bonding and/or molecular tetrahedral inversion.   

Thus we must conclude that differences in rates between two SN2 reactions are due chiefly to steric factors and not to polar factors. I.E. Differences in rates are related to the bulk of the substituents and not to their effect on the electron distribution (or distribution of charge). As the number of substituents attached to the carbon bearing halogens is increased, the reactivity toward SN2 substitution decreases, as experimental data has evidenced.

SN1 – Mechanism of Reaction

The reaction between tert-butyl bromide and hydroxide ion to yield tert-butyl alcohol follows first-order reaction kinetics. I.E. The reaction rate depends upon the concentration of only one reactant: tert-butyl bromide. How are we to interpret the fact that the rate is independent of [OH-] ? Our only conclusion can be that the reaction whose rate we are measuring does not involve the OH- ion.

These observations are quite consistent with the following reaction mechanism. Tert-butyl bromide slowly dissociates (step 1) into a bromide ion and a cation derived form the tert-group, called a carbocation. This carbocation then combines rapidly (step 2) with a hydroxide ion to yield tert-butyl alcohol.

The rate of the overall reaction is determined by the slow breaking of the C-Br bond to form the carbocation. Once formed, the carbocation reacts rapidly to form the product. It is step 1 that we are actually measuring. This step does not involve OH-, and thus its rate does not depend on [OH-]. A single step whose rate determines the overall rate of a stepwise reaction is called  a rate-determining step

It is not surprising that the (slow) rate-determining step in this reaction sequence is the one that involves the breaking of a bond, as this is a process which requires energy. We recognize this particular bond-breaking as an example of heterolysis: cleavage in which both bonding electrons go to the same fragment. This cleavage process takes even more energy than its alternative (homolysis – the formation of 2 free radicals).   

Nor is it surprising that the combining of the carbocation with a hydroxide ion is a very rapid step, since it involves only the formation of a bond, which is fundamentally an exothermic (energy-releasing) process – and could easily be projected as a simultaneous event (no activation energy necessary).

We recognize this latter step as an acid-base reaction in the Lewis sense. We are already familiar with the OH ion as a strong base. We shall learn to recognize carbocations as extremely powerful Lewis acids.

This is the mechanism that is called:

SN₁:  Substitution Nucleophilic Unimolecular

Our primary evidence that alkyl halides can (and will) react by the SN₁ mechanism is that the mechanism is consistent with the first-order reaction kinetics we have presented here. Thus, in general, an SN₁ reaction follows first-order kinetics. 

The rate of the entire reaction is determined solely by how fast the alkyl halide ionizes, and hence depends only upon the concentration of alkyl halide.

In review: 

SN₁ reactivity rates follow the trend:

                            CH₃X < primary < secondary < tertiary

In the SN₂ reaction, the addition of the nucleophile and the elimination of leaving group take place simultaneously. SN2 occurs where the central carbon atom is easily accessible to the nucleophile. By contrast the SN1 reaction involves two steps.

SN1 reactions tend to be important when the central carbon atom of the substrate is surrounded by bulky groups. This is due to the following two facts:

1) Bulky functional groups introduce steric interference with the SN2 reaction 

2) A highly substituted carbon forms a stable carbocation.

Let us consider the nature of carbocations. Just what exactly are they, and why is their role so critical in the reaction of alkyl halides to form alcohols via the SN1 mechanism?

SN1 Mechanism – Carbocations

A carbocation is an ion with a positively-charged C atom. The charged carbon atom in a carbocation has only six electrons in its outer valence shell instead of the eight valence electrons that ensures maximum stability. Therefore the carbon cation is unstable and very reactive, seeking to fill its octet of valence electrons as well as regain its neutral charge. 

Carbocations (or carbonium ions) are classified as primary, secondary, or tertiary depending on the number of carbon atoms bonded to the ionized carbon. Primary carbocations have one or zero carbons attached to the ionized carbon, secondary carbocations have two carbons attached to the ionized carbon, and tertiary carbocations have three carbons attached to the ionized carbon.

         The carbocation has sp2 hybridization with a trigonal planar molecular geometry.

As we have seen in the methyl free radical (Unit 1: Methane), sp2 orbitals lie in a single plane, that of the carboucleus, and are directed towards the corners of an equilateral triangle (trigonal planar configuration, 120 degree bond angles). This part of the ion is flat, with the electron-deficient C atom and its 3 radial H atoms all coplanar.

A p orbital is situated with its two lobes lying above and below the plane of the sigma bonds. I Na carbocation, the p orbital is empty. But even in its unoccupied state, it is intimately involves in the chemistry of carbocations. This results from an overlap of the p orbital with other nearby orbitals – overlap that is made possible by the flatness of the carbocation (as confirmed by NMR, as well as Infrared and Raman spectroscopy).

We turn our attentioow to the stereochemistry of the SN1, where we find that a typical reaction product is a biased mixture (favoring the inversion) of the the inverted compound and the racemic modification – a condition we refer to as partial racemization. I.E. The inverted product and its enantiomer are both present in the final solution.

How do we account for this?

In an SN₂ reaction, we saw that the nucleophile attacks the substrate molecule itself, and the complete inversion observed is a direct consequence of that action. I.E. The leaving group is still attached to the C atom during the attack, which directs the attack to the backside every time.

In an SN1 reaction, the nucleophile attacks not the substrate, but the reaction intermediate (or transition state): the carbocation. In this case, the leaving group has already been detached in the rate-determining step, and thus cao longer have an influence on the spatial orientation of the attack.

Thus, the nucleophilic reagent Z attaches itself to the carbocation. But it may attach itself to either face of the planar trigonal cation, and, depending upon which face, yield one or the other of the two enantiomeric products. Together, the two enantiomers constitute the racemic modification. The racemization that accompanies these reactions is consistent with the SN1 mechanism and the formation of an intermediate carbocation as the transition state for the reaction.

If the attack on the two faces of the cation were purely random, we would expect equal amounts of the two enantiomers. But in general, the inverted product exceeds the enantiomer. I.E. The reaction proceeds with racemization plus some net inversion.

How do we accommodate even this limited net inversion? How do we account for the fact that the attack on the carbocation is not purely random? Clearly, the excess of inversion is due in some way to the leaving group, which is somehow still exerting some measure of control over the reaction’s stereochemistry. *Note: In the complete absence of the leaving group, the flat cation would lose all sense of chirality.

We might speculate that before complete ionization occurs, the anion clings more or less closely to the front side of the carbocation and thus shields this side form attack. As a result, the backside is preferred – as evidenced experimentally. This explanation supports the experimental evidence, and therefore stands. Thus, unlike an SN2 reaction which precedes with complete inversion, an SN1 reaction proceeds with racemization.

Relative Stabilities of Carbocations can best be measured by comparing the respective bond dissociation energies (the energy required to convert a mole of alkyl bromide molecules into carbocations and bromide ions). What we find is that the energy needed to form the various classes of carbocations decreases in the order:

                                   CH₃X > primary > secondary > tertiary            

If less energy is needed to form one carbocation than another, then it can only mean that, relative to the alkyl bromide from which it was formed, the one carbocation contains less energy than the other. I.E. It is more stable. Thus, the relative stability of the carbocation increases with the number of alkyl groups bonded to the charge-bearing carbon.  

                                    CH₃X < primary < secondary < tertiary

Tertiary carbocations are more stable (and form more readily) than secondary carbocations. Primary carbocations are highly unstable because, while ionized higher-order carbons are stabilized by hyperconjugation, unsubstituted (primary) carbons are not. Therefore, reactions such as the SN1 reactioormally do not occur if a primary carbocation would be formed.

[Exception to this occurs when there is a carbon-carbon double bond next to the ionized carbon, such as that found in alkenes or aromatic compounds. E.G. Such cations as the allyl cation CH₂=CH-CH₂⁺ and benzyl cation C₆H₅-CH₂⁺ are more stable than most other carbocations. Molecules which can form allyl or benzyl carbocations are especially reactive.]

Differences in stability between carbocations are much, much larger that between free radicals (say 100 kcals vs. 10-20 kcals). We thus see much larger effects on reactivity via SN1.

How do we account for these trends in relative stability in carbocations?

I. Dispersal of charge 

The relative stability of a carbocation is determined largely by how well it accommodates its electron deficiency and its corresponding positive charge.

According to the laws of electrostatics, the stability of a charged system is increased by dispersal of charge. Any factor, therefore, that tends to spread out the positive charge of the electron-deficient carbon and redistribute it over the rest of the ion will tend to stabilize a carbocation.

Consider a substituent G attached to an electron-deficient carbon in place of an H atom. Compared to hydrogen, G may either release withdraw electrons, inducing polarity in either case? 

An electron-releasing substituent tends to reduce the positive charge at the electron-deficient C atom. In doing so, the substituent itself becomes somewhat more positive. The overall effect is a net dispersal of charge, which tends to stabilize the entire system – mainly the carbocation. 

An electron withdrawing substituent tends to intensify the positive charge on the electron deficient C atom, thus destabilizing the system and carbocation. 

The order of stability of carbocations, we have just seen, is:

                              CH₃X < primary < secondary < tertiary

Thus, the greater the number of alkyl groups, the more stable the carbocation.

It would therefore appear reasonable to conclude that, with regard to dispersal of charge, alkyl groups must act to release electrons here. In fact, there is increasing evidence that alkyl groups often tend to stabilize both cations and anions, indicating electron release or withdrawal on demand.

II. Rearrangement 

It is noteworthy that our reactivity sequence leads directly to an identical sequence showing the relative rates of formation of carbocations. I.E. the more stable the carbocation, the faster it is formed. This is likely the most useful generalization about structure and reactivity that exists in the field of organic synthesis. Carbocations are formed form many compounds other than alkyl halides, and in reactions quite different from nucleophilic substitution. Yet in all these reactions in which carbocations are formed, carbocation stability plays the leading role in governing reactivity and mechanism orientation. 

How can we account for the fact that the rate of formation of a carbocation depends upon its stability?

In an SN1 reaction of an alkyl halide, the carbocation is formed by the heterolytic cleavage of the substrate molecule via its covalent C-H bond. In the reactant, an electron pair is shared by the C and H atoms. Except for a modest polarity, these atoms are neutral. In the products, the halogen has taken away the electron pair, and the carbon is left with only a sextet. The halide bears a full negative charge, and the carbocation bears a full positive charge, which is centered on the C atom.

In the transition state, the C-X bond must be partially broken, the halogen having begun to pull the electron pair away from the C atom. Thus, the halogen atom has begun to take on the negative charge it is to carry as a halide anion. More importantly, the C atom has begun to take on the positive charge it is to carry in the carbocation.

In 1979, Edward Arnett and Paul Schleyer compared values of activation energy of SN1 reactions with heats of ionization in super-acid solutions, and found a direct quantitative dependence of rate of formation of carbocations on carbocation stability. The more stable the carbocation, the found, the faster it is formed.  

As we encounter other reactions in which carbocations are formed, we must, for each of these reactions, examine the structure of the transition state. In most ( if not all) of these reactions, we shall find that the transition state differs form the reactants chiefly in being more similar to the product. What are we seeing here is evidence for a distinct pattern of behavior? The most striking feature of this pattern is the occurrence of rearrangements within the carbocation itself.             

Carbocations undergo rearrangement from less stable structures to equally stable or more stable ones with rate constants in excess of 10 ^ 9 per second. Iucleophilic substitution via SN1, for example, it is sometimes observed that the entering group, Z, becomes attached to a different carbon than the ones that originally held the leaving group, X. 

In each of the above cases, we see that, in order to accommodate Z in the new position, there must be a rearrangement of H atoms in the substrate. The transformation of an n-propyl group into an isopropyl group, for example, requires the removal of one H atom from C-2 and attachment of one H atom to C-1. 

This complicates synthetic pathways to many compounds. Sometimes there is even a rearrangement of the carbon skeleton.

Rearrangement lends powerful support to the particular form of the SN1 mechanism – the intermediacy of carbocations – by linking this mechanism to the mechanisms of those other kinds of reactions where rearrangements are observed. The correlation between rearrangement and intermediate cations is so strong that, i the absence of other information about a particular nucleophilic substitution reaction, rearrangement is generally taken as evidence that the reaction mechanism is indeed SN1.

On this basis, then, we can account for the observed products in the following way.

1) A n-propyl substrate yields the n-propyl cation. This rearranges to the isopropyl cation, which combines to give the isopropyl product. 

 2) The isobutyl cation rearranges to give the tert-butyl cation. 

3)  The 3-methyl-2-butyl cation rearranges to the 2-methyl-2-butyl cation

4) The neopentyl cation (2,2-dimethylpropane) rearranges to the tert-pentyl cation.

5)  The 3,3-dimethyl-2-butyl cation rearranges to the 2,3-dimethyl-2-butyl cation

We can see in each case that rearrangement takes place in such a way that a less stable carbocation is converted into a more stable one. (e.g. a primary into a secondary, a primary into a tertiary, or a secondary into a tertiary.) Another way of saying this is that if the degree on the electron-deficient carbon can increase, then it will.

Frank Whitmore pictured rearrangement as taking place this way. An H atom or alkyl group migrates with a pair of electrons form an adjacent C atom to the electron-deficient C atom. The C atom that loses the migrating group acquires a positive charge. This is referred to as a hydride shift or an alkyl shift. These are just 2 examples of the most common type of rearrangement, the 1,2-shifts. These are rearrangements in which the migrating group moves form one atom to the nearest atom. 

In the case of the n-propyl cation, for example, a shift of the H atom yields the more stable isopropyl cation. Migration of a methyl group would simply form a different n-propyl cation.

In the case of the isobutyl cation, a hydride shift yields a tertiary cation, and hence is preferred over a methyl shift, which would only yield a secondary cation.

In the case of the 3,3-dimethyl-2-butyl cation, on the other hand, a methyl shift can yield a tertiary cation and is the rearrangement that takes place.

Just as the reality of carbocations has been verified, so has the reality of their rearrangement. Carbocations have actually been observed to rearrange utilizing various spectroscopic techniques, with rates of rearrangement being measured in excess of 10^9 per second. Here again, we are observing as discrete processes the individual steps proposed for the SN1 mechanism – this time with rearrangement.

In short, we have now seen two of the actions or types of behavior which carbocations are capable of. A carbocation may either: 

1) Combine with a nucleophile or rearrange to a more stable carbocation.

2) Rearrange it to form a more stable configuration.

It is worth noting that, in rearrangement, as in every other reaction of a carbocation, the electron-deficient C atom gains a pair of electrons, this time at the expense of a neighboring C atom – one that can better accommodate the positive charge.

SN2  vs.  SN1

We now turn to the obvious questions which are surely burning inside even the brightest of bulbs in the academic box: 

1) For a given substrate under a given set of conditions, which reaction will be followed?

2) What (if anything) can be done to encourage one reaction mechanism over the other?

In order to answer these questions, let us consider just what can happen to a molecule of substrate. It can either suffer backside attack by the nucleophile, or undergo heterolysis to form a carbocation. Whichever of these two processes goes faster determines which mechanism predominates. (Remember: Heterolysis is the first – and rate determining – step of the  SN1 mechanism.) Once again we must turn to the matter of relative rates of competing reaction. 

The role of the substrate in this competition is combination of influences by both the alkyl group and the leaving group. The nature of the leaving group is, of course, vital to the very occurrence of substitution. Whichever process is taking place (SN2 or SN1) the bond to the leaving group is being broken. The easier it is to break the bond (i.e. the better the leaving group) the faster the reaction occurs. A better leaving group thus speeds up reactions by both mechanisms – and, as it happens, to about the same degree. Thus, the nature of the leaving group is largely inconsequential.

In contrast, the nature of the alkyl group, R, of the substrate exerts a profound effect on which mechanism is to be followed. In R, two structural factors are at work: 

I.  Steric hindrance – which largely determines the ease of the backside attack. 

II. Charge dispersibility – the capacity of the R group to accommodate and redistribute a positive charge – which largely determines the ease of heterolysis.  

As we proceed along the simple alkyl series, CH3, primary, secondary, tertiary, the group R becomes more branched. The number of substituents on the C atom increases – bulky, electron-releasing constituents. Steric hindrance increases. Backside attack becomes difficult and thus slower. Charge dispersibility increases. Heterolysis becomes easier and faster.  

The result is the pattern we saw earlier. For methyl and primary substrates, SN2 is favored. For tertiary substrates, SN1 is favored. Secondary substrates show mixed tendencies.

Our remaining influence over the experimental outcome relies almost entirely on our control of the experimental conditions. For example, we have control over the concentration of the nucleophile, which directly effects the rate of the SN2 reaction. Thus, an increase in [Z] speeds up the 2nd-oreder reaction but has no effect on the 1st-order reaction. The fraction of reaction by SN2 increases. A decrease in [Z] has just the opposite effect.  The fraction of reaction by SN2 decreases.

The net result is that, other experimental factors being equal, a high concentration of nucleophile favors the SN2 reaction, while a low concentration of nucleophile favors the SN1 reaction.

In a similar fashion, the rate of SN2 depends upon the nature of the nucleophile. A stronger nucleophile attacks the substrate faster. The rate of SN1 is not affected by this factor. So, other things being equal, a strong nucleophile favors the  SN2 reaction mechanism, and a weak nucleophile favors the SN1 reaction mechanism.

Role of the Solvent

The last, but possibly most important experimental condition which we have under our control is the nature of the solvent. One unavoidable conclusion is that it is the nature of the substrate and the nucleophile that determine what product is formed. The major effect of the solvent is on the rate of nucleophilic substitution – not on what the products are.

Thus we need to consider two related questions:

I. What properties of the solvent influence the rate most?

II. How does the rate-determining step of the mechanism respond to this property of the solvent?

It has been amply demonstrated experimentally that the rate of ionization of tert-butyl chloride increases dramatically as the polarity of the solvent increases. In the SN1 reaction, polar and non-polar solvents are similar in their interaction with the alkyl halide reactants, but differ dramatically in how they affect the intermediates characteristic of the transition state. A non-polar solvent has little effect on the intermediate species, while strongly polar solvent acts to stabilize the charge separated transition state. In summary, polar solvents increase the rate of the SN1 reaction.

Polar solvents are required in typical bimolecular substitutions (e.g. SN2) because ionic substances are not sufficiently soluble ion-polar solvents to give a high enough concentration of the nucleophile to allow the reaction to proceed at a sufficiently rapid rate. And while it has been shown that the effect of solvent polarity on the rate of the SN2 reaction is negligible, what is more important is whether or not the polar solvent is protic or aprotic.

Protic solvents carry hydrogen attached to oxygen as in a hydroxyl group, nitrogen as in an amine group, or, more generally, any molecular solvent which contains dissociable H+, such as hydrogen fluoride. The molecules of such solvents can donate an H+ (proton). Examples include water, alcohols, carboxylic acids, amines, hydrogen halides, and polyprotic acids with multiple dissociable protons such as sulfuric acid, H2SO4 and phosphoric acid, H3PO4. Conversely, aprotic solvents cannot donate hydrogen bonds.

Experiments have clearly indicated that the reaction rate by SN2 is seriously limited by polar protic solvents, and can be accelerated markedly with the use of polar aprotic solvents such as dimethyl sulfoxide. Alternatively, reaction by SN1 is favored by polar protic solvents that help to pull out the leaving group of the molecule.

Solvolysis. The most controversial aspect of nucleophilic substitution centers around the special case in which the nucleophile is the solvent: solvolysis.

                            R – X   +   :S    ->    R – S   +   :X-

There is no added strong nucleophile. And so, for many substrates, solvolysis falls into the category we have called SN1. That is, the reaction proceeds by tow or more steps, with the intermediate formation of an organic cation. It is this intermediate that lies at the center of the problem.

And what exactly is the role of the solvent ? Our choices are as follows:

1) The solvent molecules will cluster around the carbocation and the anion (and the transition state leading to their formation) and thus aid in heterolysis through the formation of ion-dipole bonds.   

2) The solvent molecules will act as nucleophiles and help to eliminate the leaving groups from the substrate molecules.

Since the solvent concentration is fixed, we cannot use reaction kinetics to determine the order (and thus the mechanism) of the reaction.

It does seem clear that the solvent can give nucleophilic assistance to solvolysis. The strength of this assistance will depend on:

1) The nucleophilic power of the solvent;

2) How badly the assistance is needed;

3) How accessible (sterically) carbon is to the assisting molecule.

E.G. Water, methanol, and ethanol are strongly nucleophilic (for solvents). Acetic Acid (CH₃COOH) is weaker and formic acid (HCOOH) is weaker yet. Fluoro acids and fluoro alcohols are very weak, since the highly electronegative F atom pulls electrons strongly form oxygen, lowering its basicity and nucleophilic power.

Reactivity of tertiary substrates is found to depend little upon the nucleophilic power of the solvent and chiefly upon its ionizing power. Formation of tertiary cations is relatively easy and needs little nucleophilic assistance. In any case, crowding would discourage such assistance.

Reactivity of secondary substrates is found to depend upon both the nucleophilic power and the ionizing power of the solvent. Formation of secondary cations is more difficult, and needs much nucleophilic assistance.

With most primary substrates, the reaction is probably straightforward SN2: a single step with the solvent acting as a nucleophile.

Let us focus for now on secondary alkyl substrates. What is meant by the term “nucleophilic assistance”?

1) It differs form the typical SN2 kind of attack in that it leads to the formation, not of the product, but of an intermediate cation.

2) It differs form general solvation in that a single molecule is involved – not a cluster of molecules. The solvent molecule attacks the substrate at the backside and, acting as a nucleophile, helps to push the leaving group out the front side.

There is formed a carbocation – or something quite similar to a carbocation. 

              

Clinging to its backside is the solvent molecule and to the front side, the leaving group. The geometry is similar to that of the SN2 transition state. But the difference is that this is a reaction intermediate, and thus corresponds to an energy minimum in a progress-of-reaction plot.

 

If the leaving group is an anion, and if the solvent is of only moderate polarity, then bonding between cation and anion may be chiefly electrostatic iature. One would thus speak of an ion pair.

This cationic intermediate – this nucleophilically saturated carbocation – now reacts. It has open to it the wide variety of reactions, as we shall see, carbocations may undergo. In this case, it combines with the solvent molecule – with the formation of a full-fledged bond – to yield product.

If, at the time of reaction, the leaving group is still bonded to the front side (or still lurking there) reaction with solvent occurs at the backside. Alternatively, if the cation has lasted long enough for a leaving group to be exchanged for a second solvent molecule- thus forming a symmetrical reaction intermediate – reaction is equally likely on either side (front or back). Thus, solvolysis can occur with complete inversion or with inversion plus varying degrees of racemization.  

Thought still widely debated, it is generally accepted that the safest description of the mechanism of solvolysis is that of a modification of SN1. There is a cationic intermediate formed which presumably has all the same capabilities of a carbocation. Dispersal of the developing positive charge provides much of the driving force for the reaction.

We shall refer to the reaction as one following the SN1 mechanism with nucleophilic assistance from the solvent. We shall call the intermediate a nucleophilically solvated carbocation (or “encumbered” carbocation). The critical factors which need to be recognized in this description are:

1) Nucleophilic attack, with its susceptibility to steric hindrance

2) Dispersal of charge, by substituents and by the solvent.

Bear in mind here that most of what we say has to do strictly with secondary alkyl substrates. The differences in stability between the various classes of carbocations are great enough that, by and large, reactions fall into three separate groups:

1) For primary substrates, single-step SN2

2) For tertiary substrates, SN1 with an intermediate that approximates our idea of a simple (solvated) carbocation

3) For secondary substrates, a two-step reaction that is SN1-like to the extent that there is a cationic intermediate, but one formed with nucleophilic assistance and still encumbered with nucleophile (solvent) and leaving group.

Nucleophilic assistance is an important factor in determining the relative reactivities among secondary substrates, and their reactivities in various solvents. But so also is the ionizing power of the solvent. And nucleophilic assistance is not so powerful a factor as the dispersal of charge that makes tertiary substrates react (without any nucleophilic assistance) more rapidly than secondary substrates.

 

Spatial structure of biologically active compounds: conformative, geometrical and optical isomery.

Isomery is the phenomenon of existence of compounds which are similar by qualitative and quantitive structures but are different by locations of bonds in molecule. Different compounds that have the same molecular formula are called isomers. If they are different because their atoms are connected in a different order, they are called constitutional isomers. They can have different properties.

Stereochemistry is the study of the 3-dimensional structure of molecules. Isomers are molecules with the same chemical formula and often with the same kinds of bonds between atoms, but in which the spatial arrangement of atoms differs. Isomers are grouped into two broad classes. (Most of the non-substituted cycloalkanes have conformational isomers, or diastereomers also known as conformers.)

Formamide (left) and formaldoxime (right) are constitutional isomers; both have the same molecular formula (CH₃NO), but the atoms are connected in a different order. 

Isomery of Carbon chain is formed by different sequence of atoms in the molecule of the organic compound.

i.e.

C₄H₁₀             

For cyclic compounds the isomery can change the Carbon cycle in the molecule of the isomer.

i.e.

C₆H₁₂          

Isomery of the location of the functional group is formed by different locations of identical functional groups and double or triple bonds.

i.e.

C₃H₇Cl                 

C₆H₁₀Cl₂               

 

C₄H₈                

Isomery of the functional group is formed by different functional groups in the molecules.

i.e.

C₂H₆O             

Conformation is the different spatial localization of atoms or atom groups in the molecule as a result of its rotation around s-bonds. Hydrogen peroxide is formed in the cells of plants and animals but is toxic to them. Consequently, living systems have developed mechanisms to rid themselves of hydrogen peroxide, usually by enzyme-catalyzed reduction to water. An understanding of how reactions take place, be they reactions in living systems or reactions in test-tubes, begins with a thorough knowledge of the structure of the reactants, products, and catalysts. Even a simple molecule such as hydrogen peroxide may be structurally more complicated than you think. Suppose we wanted to write the structural formula for H202 in enough detail to show the positions of the atoms relative to one another. We could write two different planar geometries A and B that differ by a 180 rotation about the O—O bond. We could also write an infinite number of nonplanar structures, of which C is but one example that differ from one another by tiny increments of rotation about the O—O bond.

Structures A, B, and C represent different conformations of hydrogen peroxide. Conformations are different spatial arrangements of a molecule that are generated by rotation about single bonds. Although we can’t tell from simply looking at these structures, we now know from experimental studies that C is the most stable conformation.

There is also the conformation in the structure of molecules of organic compounds (alkanes and cycloalkanes). Ethane is the simplest hydrocarbon that can have distinct conformations. Two, the staggered conformation and the eclipsed conformation, deserve special mention and are illustrated with molecular models below.

In the staggered conformation, each C—H bond of one carbon bisects an H—C—H angle of the other carbon. In the eclipsed conformation, each C—H bond of one carbon is aligned with a C—H bond of the other carbon.

The staggered and eclipsed conformations interconvert by rotation around the C—C bond, and do so very rapidly. Among the various ways in which the staggered and eclipsed forms are portrayed, wedge-and-dash, sawhorse, and Newman projection drawings are especially useful. These are shown staggered and eclipsed conformation of ethane.

     

Here it is illustrated the structural feature that is the spatial relationship between atoms on adjacent carbons. Each H—C—C—H unit in ethane is characterized by a torsion angle or dihedral angle, which is the angle between the H—C—C plane and the C—C—H plane. The torsion angle is easily seen in a Newman projection of ethane as the angle between C—H bonds of adjacent carbons.

Eclipsed bonds are characterized by a torsion angle of 0⁰. When the torsion angle is approximately 60⁰, it means that the spatial relationship is gauche; and when it is 180⁰ it is called anti. Staggered conformations have only gauche or anti relationships between bonds on adjacent atoms.

For characteristic of optical isomery the optical activity and chirality are very important.

1)Constitutional isomers (structural isomers) differ in their bonding sequence. Thus their atoms and constituents (or functional groups) are connected differently.

 2) Stereoisomers have the same bonding sequence, but they differ in the spatial orientation or geometric relationships between their atoms and groups. 

The concept of chirality is essential for understanding  stereoisomers and  optically active enantiomers. We can tell whether an object is chiral by looking at its mirror image. Every physical object has a mirror image. Objects with mirror images which are identical to themselves are achiral. But a chiral object has a mirror image different from the original object. This is due to its lack of symmetry along a given plane. I.E. There is something on one side of the object which differs from that on the other side of the object (e.g. the thumb of a hand, the pocket on a shirt, the heart in the chest, the steering wheel of a car, etc.). These objects all have chirality.     

If molecules contain internal planes of symmetry, then their mirror images can be superimposed, and they are achiral. However, just because we cannot find an internal plane of symmetry does not mean that molecule must be chiral (typical examples are aromatic compounds). If two of the four groups on a carbon atom are the same, then the molecule is not chiral. A carbon atom with two identical constituents usually has an internal plane of symmetry which splits the molecule down the middle along the plane between the 2 common constituents. When rotated by 180 degrees, the mirror images of such structures can be superimposed on each other. Thus, these type of molecules are achiral.

The most common feature that lends the property of chirality to an organic molecule is a carbon atom that is bonded to four different groups. Such a carbon atom is called an asymmetric carbon atom or a chiral carbon atom, and is often designated by an asterisk. An asymmetric carbon atom is the most common example of a chirality center. Chirality centers belong to an even broader group called stereocenters.  A stereocenter is any atom at which the interchange of 2 groups gives a stereoisomer.

Thus, if a compound has no asymmetric carbon, it is usually achiral. If a compound has just one symmetric compound, it is chiral. If a compound has more than one asymmetric carbon, it may or may not be chiral. 

Stereoisomers have the same bonding sequence, but they differ in the spatial orientation or geometric relationships between their atoms and groups. 

This class includes chiral enantiomers which are non-superimposable mirror-images of each other, as well as diastereomers which are not mirror images. Thus, diastereomers are stereoisomers that are not mirror images. This group can be subdivided into conformational isomerism (conformers) when isomers can interconvert by chemical bond rotations and cis-trans isomerism when this is not possible. (Note: Although conformers can be referred to as having a diastereomeric relationship, these isomers over all are not diastereomers, since bonds in conformers can be rotated to make them mirror images.)  Most diastereomers contain 2 or more chirality centers.

Fischer projections are used to visually describe various isomers of the same compound in two dimensions. They are also used as a basic test for optical activity (or chirality). The Fischer projection looks like a cross, with the (invisible) asymmetric carbon located at the points where the lines cross. The horizontal lines are taken to be wedges, or bonds that project out of the plane of the paper. The vertical lines are taken to project away form the viewer, or back below the plane of the paper, as dashed lines.

Fischer projections that differ by a 180 degree rotation are the same. This is due to the fact that the vertical lines remain forward, and the horizontal lines remain recessed into the page. Alternatively, 90 degree rotations change the spatial characteristics of the molecule by switching the forward and reverse arrangements of the chiral center. This typically results in a chiral enantiomer of the original configuration. (Flipping them over has a similar effect). 
The mirror image of a Fischer projection is created simply by interchanging the groups on the horizontal part of the cross. This effectively reverses left and right, while leaving the vertical portion of the configuration unchanged.
 

“Enantiomers are conformations of the same molecule whose mirror images cannot be superimposed on one another.”

Testing for chirality (and thus enantiomerism) is particularly simple using Fischer projections. If the mirror image cannot be made to look the same as the original structure with a 180 degree rotation in the plane of the paper, the two mirror images are enantiomers. If the original structure can be obtained using a 180 degree rotation of the mirror image, then the structure is achiral.

Mirror planes of symmetry are particularly easy to identify using Fischer projections. Molecules with symmetry planes cannot be chiral.

Diastereomers are stereoisomers not related through a reflection operation. These often have multiple chiral centers, and include meso compounds, cis-trans (E-Z) isomers, and non-enantiomeric optical isomers. Diastereomers seldom have the same physical properties. In the example shown below, the meso form of tartaric acid (on the right) forms a diastereomeric pair with both levo and dextro tartaric acids (on the left) , which form an enantiomeric pair.

Tartaric Acid

 

Everything has a mirror image, but not all things are superimposable on their mirror images. Mirror-image superimposability characterizes many objects we use every day. Cups and saucers, forks and spoons, chairs and beds are all identical with their mirror images. Many other objects though – and this is the more interesting case – are not. Your left hand and your right hand, for example, are mirror images of each other but can’t be made to coincide point for point, palm to palm, knuckle to knuckle, in three dimensions. In 1894, William Thomson (Lord Kelvin) coined a word for this property. He defined an object as chiral if it is not superimposable on its mirror image. Applying Thomson’s term to chemistry, we say that a molecule is chiral if its two mirror-image forms are not superimposable in three dimensions. The word chiral is derived from the Greek word cheir, meaning “hand,” and it is entirely appropriate to speak of the “handedness” of molecules. The opposite of chiral is achiral. A molecule that is superimposable on its mirror image is achiral.

In organic chemistry, chirality most often occurs in molecules that contain a carbon that is attached to four different groups. An example is bromochlorofluoromethane (BrClFCH).

As shown in figure, the two mirror images of bromochlorofluoromethane cannot be superimposed on each other. Because the two mirror images of bromochlorofiuoromethane are not superimposable, BrClFCH is chiral.

The mirror images of bromochlorofluoromethane have the same constitution. That is, the atoms are connected in the same order. But they differ in the arrangement of their atoms in space; they are stereoisomers. Stereoisomers that are related as an object and its nonsuperimposable mirror image are classified as enantiomers. The word enantiomer describes a particular relationship between two objects. Just as an object has one, and only one, mirror image, a chiral molecule can have one, and only one, enantiomer. 

A molecule of chlorodifluoromethane (ClF2CH), in which two of the atoms attached to carbon are not chiral. Figure shows two molecular models of ClF2CH drawn so as to be mirror images. As is evident from these drawings, it is a simple matter to merge the two models so that all the atoms match. Because mirror-image representations of chlorodifluoromethane are superimposable on each other, ClF2CH is achiral.

The surest test for chirality is a careful examination of mirror-image forms for superimposability. Working with models provides the best practice in dealing with molecules as three-dimensional objects and is strongly recommended.

Molecules of the general type are chiral when w, x, y, and z are different. In 1996, the IUPAC recommended that a tetrahedral carbon atom that bears four different atoms or groups be called a chirality center, which is the term that we will use. Several earlier terms, including “asymmetric center”, “asymmetric carbon”, “chiral center”, “stereogenic center” and “stereocenter”, are still widely used.

Noting the presence of one (but not more than one) chirality center is a simple, rapid way to determine if a molecule is chiral. For example, the second atom of carbon C-2 is a chirality center in 2-butanol; it bears a hydrogen atom and methyl, ethyl, and hydroxyl groups as its four different substituents. By way of contrast, none of the carbon atoms bear four different groups in the achiral alcohol 2-propanol.

Carbons that are part of a double bond or a triple bond can’t be chirality centers.

A carbon atom in a ring can be a chirality center if it bears two different substituents and the path traced around the ring from that carbon in one direction is different from that traced in the other. The carbon atom that bears the methyl group in 1,2-epoxypropane, for example, is a chirality center. The sequence of groups is O—CH2 as one proceeds clockwise around the ring from that atom, but is CH2—O in the counter clockwise direction. Similarly, C-4 is a chirality center in limonene.

A molecule may have one or more chirality centers. When a molecule contains two chirality centers, as does 2,3-dihydroxybutanoic acid, there are possible several stereoisomers.

Stereoisomers that are not related as an object and its mirror image are called diastereomers; diastereorners are stereoisomers that are not enantiomers.

To convert a molecule with two chirality centers to its enantiomer, the configuration at both centers must be changed. Reversing the configuration at only one chirality center converts it to a diastereomeric structure. Enantiomers must have equal and opposite specific rotations. Diastereomers can have different rotations, with respect to both sign and magnitude. Thus, as figure shows, the (2R,3R) and (2S,3S) enantiomers (I and II) have specific rotations that are equal in magnitude but opposite in sign. The (2R,3S) and (2S,3R) enantiomers (III and IV) likewise have specific rotations that are equal to each other but opposite in sign. The magnitudes of rotation of I and II are different, however, from those of their diastereomers III and IV.

In writing Fischer projections of molecules with two chirality centers, the molecule is arranged in an eclipsed conformation for projection onto the page. Horizontal lines in the projection represent bonds coming toward you; vertical bonds point away.

Organic chemists use an informal nomenclature system based on Fischer projections to distinguish between diastereomers. When the carbon chain is vertical and like substituents are on the same side of the Fischer projection, the molecule is described as the erythro diastereomer. When like substituents are on opposite sides of the Fischer projection, the molecule is described as the threo diastereomer. Thus, as seen in the Fischer projections of the stereoisomeric 2,3-dihydroxybutanoic acids, compounds I and II are erythro stereoisomers and III and IV are threo.

 

 Because diastereomers are not mirror images of each other, they can have quite different physical and chemical properties. For example, the (2R,3R) stereoisomer of 3-amino-2-butanol is a liquid, but the (2R,3S) diastereomer is a crystalline solid.

 

Stereochemistry is an excellent example of the importance of structural symmetry iature. Some 50 % of all organic compounds have chiral centers. E.G. When the amino acid alanine is synthesized in the laboratory, a mixture of the two possible structures is formed. However, when alanine is produced in a living cell, only one of the two forms is seen. The naturally occurring form of alanine is called L-alanine, and its mirror image is called D-alanine. Comparison of the 20 common amino acids will show that only the “L” form is used in protein synthesis.
Receptors have a distinct three-dimensional structure whose surface consists of grooves and cavities. They can interact only with three-dimensional molecules which have a complementary structure. Depending on the form of the molecule that links to the receptor, the biological results may vary significantly.

Thus, receptors usually display of preference for binding a specific structure. Through selective metabolism, a membrane can also displace selective intake by providing a specific transport mechanism that only recognizes only a single enantiomer. Toxic effects include non-specific receptors that can bind the drug, thus lowering the available concentration for specific receptors.

The enzymatic machinery used in protein synthesis has an asymmetric binding site the amino acids must fit into. Your right hand won’t fit properly into a left handed glove, and an amino acid of the wrong shape won’t fit into an enzyme. Of all the naturally occurring amino acids in proteins, only Glycine (NH2-CH2-COOH) has a plane of symmetry (along its “spine”).

Our bodies only create and digest carbohydrates and amino acids of a certain stereochemistry. Thus, all the proteins that make up our hair, skin, organs, brain, and tissues, are composed of a single stereoisomer of amino acids. We can synthesize and digest starch (e.g. bread & potatoes) but not wood pulp or cellulose (plant fibers) even though both are stereoisomers of polymerized glucose.

Stereochemistry is also very important from the point of view of synthetic pharmaceuticals and their mechanism of action in the body. Since so many biochemical compounds consist of stereoisomers (e.g. amino acids, nucleotides, carbohydrates & phospholipids) it makes sense that synthetic drugs also have chiral centers. But while one stereoisomer may have positive effects on the body, another stereoisomer may be toxic – or even lethal.

Thus, a drug upon administration undergoes a series of steps (aside form official FDA approval) before exerting its activity. At each step the molecular structure of the compound and hence its chirality influences the further metabolism. Because of this, a great deal of work done by synthetic organic chemists today is in devising methods to synthesize compounds that are purely one stereoisomer.

Thalidomide was a drug used during the 1950s to suppress morning sickness. The drug was prescribed as a racemic mixture – that is, it contained a 50:50 mixture of its mirror images – and while one stereoisomer of the drug actively worked on controlling morning sickness, the other stereoisomer caused serious birth defects. Ultimately the FDA pulled it from the marketplace.

The binding of Ibuprofin, a common pain reliever. While one stereoisomer of the compound has the right three-dimensional shape to bind to the protein receptor, the other does not and cannot bind, and is therefore ineffective as a pain reliever.

Another example is Vitamin E (an essential component in our immune system) which contains three asymmetric carbons. This allows for up to eight possible isomeric structures to be formed. Iature, due to unique specificity, only one form is produced. In the synthetic formulation, however, all eight forms are created, thus diluting the natural form to only 12.5% of the vitamin added.

http://www.mazuri.com/Llama-VitaminE.htm?Animal=Llama

The current policies of FDA in drug approval is that the inactive stereoisomer (or enantiomer) in the racemic drug has to be shown to be devoid of any toxicity or undesired side-effects.

This note is regarding the ramifications of racemic mixtures in synthetic pharmaceuticals. According to the article referenced below (which can be downloaded in PDF format) the 2 enantiomers of a chiral drug may differ significantly in their bioavailability, rate of metabolism, excretion, potency and selectivity for receptors, transporters and/or enzymes, and toxicity.

Single-enantiomer formulations of (S)-albuterol (asthma inhibitor: Ventalin, Proventil) and (S)-omeprazole (acid reflux inhibitor: Prilosec) have both exhibited superiority to their racemic formulations in clinical trials.
Alternatively, one enantiomer of Sotalol has both beta-blocker and antiarrhythmic activity, while the other enantiomer has antiarrythmic properties but lacks beta-adranergic antagonism. In addition, one enantiomer of fluoxetine (Prozac), at its highest dosage, let to statistically significant prolongation of cardiac repolarization.

Other drugs often used in psychiatric practice (zopiclone, methylphenndate, and some phenothiazines) are also available as racemates. Of these, single-enantiomer formulations are being developed for buproprion (Wellbutrin) and zopiclone, as well as methylphenidate (Ritalin, Concerta) or d-methylphenidate.

In both citalopram and fluoxetine, one enantiomer appeared to have superior in vivo properties.

In the case of citalopram, the -enantiomer is primarily responsible for antagonism of seratonin uptake, while the (S)-enantiomer is 30 time less potent. In clinical trials, both racemic (R,S)-citalopram (Celexa) and the (S)-enantiomer version (Lexapro) were significantly better than placebo for improving depression.

In the case of fluoxetine (Prozac), the attempt to develop a single-enantiomer formulation for the treatment of depression was unsuccessful. While the R and S enantiomers of fluoxetine are are similarly effective at blocking the uptake of seratonin, they are metabolized differently. The use of the R enantiomer was expected to result in less variable plasma levels of fouxetine and its active metabolites than observed with racemic fluoxetine. In addition, the -fluoxetine and its metabolites inhibit certain target enzymes to a lesser extent than (S)-fluoxetine and its metabolites.

As previously mentioned, one enantiomer of fluoxetine, at its highest dosage, let to statistically significant prolongation of cardiac repolarization (but studies were terminated). Although racemic fluoxetine has proven to be both safe and effective for over 15 years, the -enantiomer formulation was not viable due to safety concerns.

It would appear obvious now that when both a single-enantiomer and a racemic formulation of a drug are available, the information from both trial and experience should be used to decide which formulation is most appropriate on a case-by-case basis.

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