CHAPTER 6

Properties and Reactions of Haloalkanes:

Bimolecular Nucleophilic Substitution

Physical Properties of Haloalkanes 6-1

The bond strength of C-X decreases as the size of X increases.

A halogen uses a p orbital to overlap an sp2 orbital on a carbon atom.

As the size of the halogen p orbital increases (F < Cl < Br < I), the percentage overlap with the smaller sp2 carbon orbital is less and the bond strength decreases.

The C-X bond is polarized. Because halogens are more electronegative that carbon, carbon-halogen bonds are polarized.

The halogen atom possesses a partial negative (δ-) and the carbon atom a partial positive (δ+) charge.

The electrophilic δ+ carbon atom is subject to attack by anions and other nucleophilic species.

Cations and other electron-deficient species attack the halogen atom.

Haloalkanes have higher boiling points than the corresponding alkanes.

Boiling points of haloalkanes are higher than those of the parent alkanes mainly due to dipole-dipole interactions between the haloalkane molecules:

As the size of the halogen increases there are also larger London forces between the haloalkane molecules.

Larger atoms are more polarizable and interact more strongly through London forces.

Nucleophilic Substitution 6-2 Haloalkanes can react with nucleophiles at their electrophilic carbon atom.

The mucleophile can be charged, as in :OH- or neutral, as in :NH3.

In nucleophilic substitution of haloalkanes, the nucleophile replaces the halogen atom.

Nucleophilic Substitution 6-2

Nucleophiles attack electrophillic centers. Nucleophilic substitution of a haloalkane can be described by two general equations:

In both cases, the leaving group is the halide anion, X-.

In describing reactions, the organic starting material is called the substrate of the reaction.

Here, the substrate is being attacked by a nucleophile.

Nucleophililc substitution exhibits considerable diversity.

Rxn 1: OH- (KOH) displaces Cl- to produce an alcohol.

Rxn 2: OCH3- displaces Cl- to produce an ether.

Rxn 3: I- displaces Cl- to produce a different haloalkane.

Rxn 4: CN- (NaCN) displaces Cl- to form a new C-C bond.

Rxn 5: The S analog of Rxn 2 forming a thioether.

Rxn 6: Neutral :NH3 produces a cationic ammonium salt

Rxn 7: Neutral :PH3 produces a cationic phosphonium salt.

Halides can serve as nucleophiles and as leaving groups in nucleophilic substitution reactions. These reactions are reversible.

Strong bases, such as HO- and CH3O-, however do not serve as good leaving groups. Substitution reactions involving these species are not reversible.

Reaction Mechanisms Involving Polar Functional Groups: Using “Electron-Pushing” Arrows

6-3

Curved arrows depict the movement of electrons.

The oxygen lone pair of electrons ends up being shared between the oxygen and the hydrogen.

The bonding pair electrons in the HCl molecule ends up as a lone pair on the chloride ion.

Mechanisms in organic chemistry are described by curved “electron pushing” arrows.

Notice that in the 1st and 3rd examples, the destination of the moving electrons is a carbon atom with a filled outer shell.

In these nucleophilic substitution and addition reactions, room must be made in the outer shell of the carbon atom to put the incoming electrons.

A Closer Look at the Nucleophilic Substitution Mechanism: Kinetics

6-4

Consider the reaction between chloromethane and sodium hydroxide:

This experimental data showing the reactants, products, and reaction conditions, gives no information on how the chemical reaction occurred or how fast it occurred.

By measuring the rate product formation beginning with several different sets of reactant concentrations, a rate equation or rate law can be determined.

A Closer Look at the Nucleophilic Substitution Mechanism: Kinetics

6-4

The reaction of chloromethane with sodium hydroxide is bimolecular.

The rate of a reaction can be measured by observing the appearance of one of the products, or by the disappearance of one of the reactants.

In the case of reaction between chloromethane and hydroxide ion:

doubling the hydroxide concentration (keeping the chloromethane concentration fixed) doubles the reaction rate.

doubling the chloromethane concentration (keeping the hydroxide concentration fixed) also doubles the reaction.

These observations are consistent with a second-order process whose rate law is:

Rate = k[CH3Cl][HO-] mol L-1 s-1.

All of the nucleophilic substitution reactions show earlier follow this rate law (with different values of k).

The mechanism consistent with a second order rate law involves the interaction of both reactants in a single step (a collision).

Two molecules interacting in a single step is call a bimolecular process.

Bimolecular nucleophilic substitution reactions are abbreviated SN2.

Bimolecular nucleophilic substitution is a concerted, on-step process.

A SN2 substitution is a one step process.

The bond formation between the nucleophile and the carbon atom occurs at the same time that the bond between the carbon atom and the electrophile is breaking.

This is an example of a concerted reaction.

There are two distinct stereochemical alternatives for an SN2 concerted reaction: frontside displacement and backside displacement:

In SN2 nucleophilic substitution reactions, the transition state of the reaction is simply the geometric arrangement of reactants and products as they pass through the point of highest energy in the single-step process.

Frontside or Backside Attack? Stereochemistry of the SN2 Reaction

6-5

The SN2 reaction is stereospecific. When (S)-2-bromobutane reacts with iodide ion, there are two possible theoretical products:

Frontside displacement: the stereochemistry at C2 is retained. The product is (S)-2-iodobutane.

Backside displacement: the stereochemistry at C2 is inverted. The product is (R)-2-iodobutane.

Only (R)-2-iodobutane is observed as a product. All SN2 proceed with inversion of configuration.

A process in which each stereoisomer of the starting material is transformed into a specific stereoisomer of product is called stereospecific.

The same reaction shown with Spartan molecular models and with electrostatic potential maps is:

Halfway through the course of an SN2 reaction, the sp3 hybridization of the carbon atom has changed to the planar sp2 hybridization (transition state).

As the reaction proceeds to completion the carbon atom returns to the tetrahedral sp3 hybridization.

The transition state of the SN2 reaction can be described in an orbital picture.

Consequences of Inversion in SN2 Reactions 6-6 We can synthesize a specific enantiomer by using SN2 reactions.

When (R)-2-Bromooctane is reacted with HS-, only (S)-2-octanethiol is obtained:

If we had started with the S enantiomer of 2-bromooctane, only the R enantiomer of 2-octanethiol would have been produced.

In order to retain the R configuration of the starting 2-bromooctane, a sequence of two SN2 reactions is used:

The double inversion sequence of two SN2 processes results in a net retention of configuration.

When a substrate contains more than one stereocenter, inversion takes place only at the stereocenter being attacked by the nucleophile.

Note that in the first case a meso product is formed.

Structure and SN2 Reactivity: The Leaving Group 6-7 The rates of SN2 reactions depend upon:

• Nature of the leaving group.

• Reactivity of the nucleophile

• Structure of the alkyl portion of the substrate.

Leaving-group ability is a measure of the ease of displacement.

The leaving group ability of a leaving group can be correlated to its ability to accommodate a negative charge.

For halogens, iodide is a good leaving group, while fluoride is a poor leaving group in SN2 reactions. SN2 reactions of fluoroalkanes are rarely observed.

Leaving-Group Ability

(best) I- > Br- > Cl- > F- (worst)

Other good leaving groups that can be displaced by nucleophiles in SN2 reactions are:

Weak bases are good leaving groups. Leaving group ability is inversely related to base strength.

Weak bases are best able to accommodate negative charge and are the best leaving groups. (Weak bases are the conjugate bases of strong acids.)

Note the sequence: I- > Br- > Cl- > F-

Structure and SN2 Reactivity: The Nucleophile 6-8

Nucleophilicity of the nucleophile depends upon:

• Charge

• Basicity

• Solvent

• Polarizability

• Nature of substituents

Increasing negative charge increases nucliophilicity.

Consider these experiments:

Conclusion: Comparing nucleophiles having the same reactive atom, the species with the negative charge is the more powerful nucleophile.

A base is always more nucleophilic than its conjugate acid.

Nucleophilicity decreases to the right in the periodic table.

Consider these experiments:

Conclusion: Nucleophilicity correlates with basicity.

As we proceed from left to right across the periodic table, nucleophilicity decreases.

(best) H2N- > HO- > NH3 > F- > H2O (worst nucleophile)

Should basicity and nucleophilicity be correlated?

Basicity is a thermodynamic property:

Nucleophilicity is a kinetic phenomenon:

Despite this difference in definition, there is a good correlation between nucleophilicy and basicity in the cases of charged versus neutral nucleophiles along a row in the periodic table.

Solvation impedes nucleophilicity. Consider these experiments:

Conclusion: Nucleophilicity increases in the progression down a column of the periodic table which is opposite the trend predicted by the basicity of the nucleophiles tested.

When a solid dissolves in a polar solvent the molecules or ions are surrounded by solvent molecules and are said to be solvated.

Generally solvation weakens a nucleophile by forming a shell of solvent molecules around the nucleophile which impedes its ability to attack an electrophile.

Smaller ions are more tightly solvated in a polar solvent than larger ones, thus F- is much more heavily solvated than in I-.

Aprotic solvents lack positively polarized hydrogen atoms and are also often used in SN2 reactions:

Protic and aprotic solvents: the effect of hydrogen bonding.

Protic solvents are those containing a hydrogen atom attached to an electronegative atom and are capable of hydrogen bonding.

Because aprotic solvents do not form hydrogen bonds, they solvate anionic nucleophiles relatively weakly.

This results in an increase in the nucleophiles reactivity.

Bromomethane reacts with KI 500 times faster in propanone than in methanol.

Consider the reaction of iodomethane with chloride:

The rate of the reaction is more than 106 times greater in the aprotic solvent DMF than in methanol.

Switching to an aprotic solvent increases the reactivity of all anions, however the effect is the largest for the smallest anion.

The differences in nucleophilic reactivity between the halides are substantially reduced in aprotic solvents, and can sometimes even be reversed.

This effect is due to the larger polarizability of the larger atom at the bottom of the periodic table

The larger electron clouds allow for more effective overlap in the SN2 transition state.

Increasing polarizability improves nucleophilic power.

The degree of nucleophilicity increases down the periodic table, even for uncharged nucleophiles, for which the solvent effects would be much weaker.

H2Se > H2S > H2O, and PH3 > NH3

Sterically hindered nucleophiles are poorer reagents.

Nucleophiles having large bulky substituents are not as reactive as unhindered nucleophiles:

Sterically bulky nucleophiles react more slowly.

Nucleophilic substitutions may be reversible. Halide ions (except F-) are both good nucleophiles and good leaving groups.

The SN2 reactions of these halides are reversible.

The solubility of the sodium halides dramatically decreases in the order: NaI > NaBr > NaCl.

NaCl is virtually insoluble in propanone so reactions involving the displacment of Cl- can be made go to completion by using the sodium salt of the attacking nucleophile:

When the nucleophile in a SN2 reaction is a strong base (HO-, CH3O-, etc.) it becomes a very poor leaving group, and SN2 reactions involving strong bases as nucleophiles are essentially irreversible.

The relative reaction rate of iodomethane with a variety of nucleophiles illustrates the previous points:

Structure and SN2 Reactivity: The Substrate 6-9 Branching at the reacting carbon decreases the rate of the SN2 reaction.

The effects of substituents on the reacting carbon can be seen in the following data:

The transition states of the reaction of OH- with methyl, primary, secondary and tertiary carbon centers explain the decrease in activity:

The steric hindrance caused by adding successive methyl groups to the electrophilic carbon decreases the transition state stability to the point that substitution at a tertiary carbon does not occur at all.

(fast) Methyl > primary > secondary > tertiary (does not occur)

(very slow)

Lengthening the chain by one or two carbons reduces SN2 reactivity.

Replacement of one hydrogen in chloromethane by a methyl group to form chloroethane reduces the rate of SN2 displacement of the chlorine atom by about a factor of 100.

Replacement of the hydrogen by an ethyl group to form chloropropane reduces the rate of SN2 displacement of the chlorine atom by another factor of 2.

The gauche conformer in the 1-propyl case has similar reactivity to the ethyl case.

Replacement of a hydrogen in a halomethane by a carbon chain of 3 or more atoms shows no additional effect over a carbon chain of 2 atoms.

Multiple substitution at the position next to the electrophilic carbon causes a dramatic decrease in reactivity in SN2 substitution reactions.

1-Bromo-2,2-dimethylpropane is virtually inert.

Branching next to the reacting carbon also retards substitution.

The explanation for the decrease in reactivity is in the stabilities of the transition states involved:

In 1-bromo-2-methylpropane two gauche methyl-halide interactions occur in the only conformation permitting nucleophilic attach by the OH-.

In 1-bromo-2,2-dimethylpropane there is no conformation allowing easy approach of the OH- and the reaction is blocked almost completely.

Important Concepts 6

1.  Haloalkane – An alkyl halide, an alkyl group and a halogen

2.  Haloalkane Properties – Strongly affected by the C-X bond polarization and the polarizability of X.

3.  Nucleophilic – When a lone pair of electrons on a reagent attacks a positively polarized (or electrophilic) center. If a substituent is replaced, the reaction is termed a nucleophilic substitution. The substituent replaced is called the leaving group.

4.  Nucleophilic Substitution Kinetics – For primary and most secondary haloalkanes the reaction is 2nd order. These reactions are termed SN2. They are concerted reactions where bonds are simultaneously made and broken.

Important Concepts 6

5.  SN2 Reactions are Stereospecific - These reactions proceed by backside displacement. The configuration at the reacting center is inverted.

6.  SN2 Transition State – •  sp2 carbon center •  Partial bond making at nucleophile and electrophilic carbon. •  Partial bond breaking at leaving group and electrophilic carbon •  Both nucleophile and leaving group bear partial charges.

7.  Leaving Group Ability - Roughly proportional to the strength of the conjugate acid (especially good leaving groups: chloride, bromide, iodide, sulfonates).

8.  Nucleophilicity – Increases: •  With negative charge •  Farther to the left and down in periodic table •  In aprotic solvents.

Important Concepts 6

9.  Polar Aprotic Solvents - Accelerate SN2 reactions.

10. Branching At The Reactive Center - (or at the carbon next to it) sterically hinders the transition state and decreases the rate of SN2 substitution.