Ch 6- Alkyl Halides. Structures and Properties Halogen is connected to a tetrahedral carbon The...

Ch 6- Alkyl Halides

Structures and Properties

• Halogen is connected to a tetrahedral carbon• The carbon-halogen bond is polarized with the

carbon having a partial positive charge and the halogen having a partial negative charge

• The size of the halogen increases as you move down the group

• Consequently, the C-X bond lengths increase so the bond strength decreases

Structures and Properties

• Compounds with a halogen bonded to an sp2 carbon are called vinylic halides or phenyl halides

• Ex.

• Alkyl and aryl halides have very low solubility in water, but very stable in each other

Nucleophilic Substitution Reactions

• General Reaction:

• Examples:

• Nucleophile- a species with an unshared electron pair.– Usually has either a full or partial negative charge– It is electron rich


• The nucleophile reacts with the alkyl halide, replacing the halogen substituent

• A substitution reaction takes place and the halogen substituent, called the leaving group, departs as an ion

• Because the substitution is initiated by a nucleophile, it is called a nucleophilic substitution reaction


• In the reaction, the C-X bond undergoes heterolysis and the electron pair from the nucleophile is used to make a new bond

• There are two ways this can happen:1) The C-X bond can break then the Nu-C bond forms

2) Bond making and breaking can happen at the same time.


• When deciding which of these will occur, the decision will depend primarily on the structure of the alkyl halide.

Nucleophiles

• A nucleophile is a reagent that seeks a positive center

• Here, the positive center is the carbon bonded to the halogen which has a partial positive charge

• A nucleophile is any negative ion or any neutral molecule that has at least one unshared pair of electrons

• Ex.

Leaving Groups

• To act as a substrate, in a nucleophilic substitution reaction, a molecule must have a good leaving group

• A good leaving group is a substituent that can leave as a relatively stable, weakly basic molecule or anion.

• Recall that halogen ions are very weak bases because hydrogen halides are very strong acids

Kinetics of a Nucleophilic Substitution Reaction: An Sn2 reaction

• To understand how the rate of a reaction is measured, we will consider the following reaction:

• Reaction Rates are temperature dependant so we have to discuss the reaction at a specific temperature

H3C Cl + OH60oC

H2OH3C OH + Cl


• The rate of the reaction can be determined experimentally by measuring the rate at which chloromethane or hydroxide disappear or the rate that methanol or chloride ion appears

• We do this by taking a small sample of the reaction mixture at different times and measure the concentration of chloromethane, hydroxide, methanol, or chloride.


• We know the initial concentration of the reactants because we measured them before starting the reaction.

Experiment #

Initial [CH3OH]

Initial [OH] Initial Rate

1 .0010 1.0 4.9x10-7

2 .0020 1.0 9.8x10-7

3 .0010 2.0 9.8x10-7

4 .0020 2.0 19.6x10-7


• Notice the rate depends on both the concentration of chloromethane and hydroxide

• When we double one, the rate doubled• When we doubled both the rate goes up by a

factor of 4!• We can express this by a proportionality:

Cl] [OH]


• This proportionality can be expressed as an equation by including a proportionality constant (k) called the rate constant:

Rate = k [CH3Cl] [OH]• For this reaction at this temperature, the rate

constant equals 4.9x10-4 L/mol sec• This reaction is said to be second order overall• In order for the reaction to take place, a hydroxide

ion and a chloromethane molecule must collide


• Therefore, the reaction is bimolecular, which means 2 molecules are involved in the rate determining step

• We call this kind of reaction an Sn2 reaction, Substitution, nucleophilic, Bimolecular

Mechanism for the Sn2 reaction

• The negative hydroxide approaches the partially positive carbon from the backside

• Concerted Reaction- bond breaking and bond making happen at the same time.

• Configuration of the carbon being attacked is inverted due to the backside attact.

Stereochemistry of Sn2 reaction

• The nucleophile approaches from the backside, from the side directly opposite the leaving group

• This causes a change in configuration• The carbon being attacked inverts like an umbrella• Ex.• Inversion also always takes place with acyclic

stereogenic carbons

Reaction of t-butyl chloride with OH: Sn1 reaction

• When t-butyl chloride reacts with hydroxide in water/acetone, the kinetic results are very different than with Sn2 reactions

• The rate of formation of t-butyl alcohol is dependent on the concentration of t-butyl chloride, but it is independent of the concentration of hydroxide.

• Doubling the t-butyl chloride doubles the rate• But changing [OH] has no effect


• The t-butyl chloride reacts by substitution at virtually the same rate in pure water ([OH]=10-7 M) as it does in 0.05M aqueous sodium hydroxide!

• Thus the rate for this substitution is first order with respect to t-butyl chloride and first order overall

• From this we can conclude that the hydroxide does not participate in the transition state of the step that controls the rate of the reaction.

• Only the t-butyl chloride does


• The reaction is said to be unimolecular in the rate determining step

• It is an example of an Sn1 reaction.Substitution, nucleophilic, Unimolecular

• Because only the t-butyl chloride is present in the rate determining transition state, we can conclude that the reaction must have multiple steps

Multistep Reactions and the Rate Determining Step, RDS

• If a reaction takes place in a series of steps, and one of the steps is slower than all the others, the rate of the overall reaction will essentially be the same as that slow step

• That slow step is called the Rate-Determining Step, (RDS).

Mechanism for Sn1

• The mechanism has two intermediates

Carbocations

• Carbocations are trigonal planar• The carbon bearing the positive charge is sp2

hybridized• The carbon is electron deficient as it only has

6 electrons.

• Overall stability:

Stereochemistry of Sn1

• Because the carbocation formed in the first step is planar, the nucleophile can attach from either side.

• Often, this has no effect because the same product is formed

• However, if the starting reactant is optically active, this will always result in a racemization

• Racemization- a reaction transforms an optically active compound into a racemic form

Stereochemistry of Sn1

• Racemization takes place whenever the reaction causes chiral molecules to be converted to an achiral intermediate

• Ex• The Sn1 reaction proceeds through the

carbocation, which because it is trigonal planar, is achiral. The nucleophile can attack the carbocation from either side, thus producing both enantiomers in equal amounts.

Solvolysis

• The Sn1 reaction of an alkyl halide with water is an example of solvolysis.

• Solvolysis reaction- a nucleophile substitution in which the nucleophile is a molecule of the solvent

• The previous reaction was in water, so it is also called a hydrolysis

• If the reaction was in methanol, it would be a methanolysis.

• Examples:

Factors affecting the rates of Sn1 and Sn2 reactions

• Now we know the mechanism Sn1 and Sn2• The next thing is too explain why

chloromethane went Sn2 t-butylchloride went Sn1

• By the time we are done, you will be able to predict which pathway a reaction will undergo

Choosing between Sn2 and Sn1

• If a given alkyl halide and nucleophile react rapidly via Sn2 but slow by Sn1 then a Sn2 pathway will be followed by most of the molecules and vice versa

• A number of factors affect the relative rates of Sn1 and Sn2 reactions:

Factors that affect rates of Sn1 and Sn2

The most important are:1) Structure of the substrate

- Is it a primary, secondary, tertiery alkyl halide?

2) The concentration and reactivity of the nucleophile- For bimolecular reactions only

3) The effect of the solvent

4) The nature of the leaving group

Effect of the Structure of the Substrate

• In Sn2 reactions, simple alkyl halides have the following general order of reactivity

• The important factor behind this order is a steric effect

• Steric Effect- an effect on relative rates caused by the space-filling properties of those parts of a molecule attached at or near the reaction site

Steric Effect

• One type of steric effect is Steric Hindrance

• Steric Hindrance- the spatial arrangement of the atoms or groups at or near the reacting site of a molecule hinders or retards a reaction

Effect of the Structure of the Substrate

• In Sn1 reactions, the primary factor that determines the reactivity of a substrate is the relative stability of the carbocation that is formed.

• Because of this, only the tertiary alkyl halides react via Sn1 with reasonable rates

• There are exceptions to this that we will cover later

Effect of Concentration and Strength of the Nucleophile

• In Sn1 reaction, the nucleophile does not participate in the RDS, so the concentration and strength does not matter

• In Sn2, the rate is dependent on both the substrate and the nucleophile

• We have already seen how doubling the concentration of the nucleophile doubles the rate

• We identify good and bad nucleophiles based on their rate of reaction in similar situations

• Ex

Nucleophile Strength vs Structure

• The relative strengths of nucleophiles can be correlated with two structural features:

1) A negative charged nucleophile is always a more reactive nucleophile than its conjugate acid

2) In a group of nucleophiles in which the nucleophilic atom is the same, nucleophilicities parrallel basicities.

Solvent effects on Sn2 Reactions

• Protic Solvents- those having a Hydrogen bond to an electronegative element such as Oxygen

• These solvents can hydrogen bond to the nucleophile and hinder its reaction in an Sn2 reaction

• Hydrogen bonding effects decreases with anion size


• Nucleophilicity of halide anions in protic solvents:

• Relative Nucleophilicity in Protic Solvents:


• Aprotic Solvents- Solvents whose molecules do not have a hydrogen that is attached to an electronegative atom.

• Aprotic Solvents are especially useful for Sn2 reactions!

• Examples of Aprotic solvents:


• Aprotic Solvents dissolve ionic compounds and solvate cations well but not anions because their positive centers are well shielded.

• Because anions are not solvated, small anions react faster.

• Nucleophilicity in Aprotic Solvents:


• The rates of Sn2 reactions are vastly increased when they are carried out in polar aprotic solvents!

• Take Home: Aprotic Solvents= Sn2


• Polar protic solvents greatly increase the rate of ionization of alkyl halides

• This is the RDS, therefore it increases the rate of the Sn1 reactions.

• So, in most cases, use of a protic solvent = Sn1

Nature of Leaving Group

• The more stable an anion, the better the leaving group

• General order of stabilities:

• Some “Super” leaving groups are shown on page 269

• Also, in some cases, bad leaving groups can be converted into good leaving groups with simple acid/base chemistry

Summary of Sn1 vs Sn2

• Reactions of alkyl halides by Sn1 are favored by:– Substrates that form stable carbocations– Use of weak nucleophiles– Use of polar protic solvents

• Sn2 favored by:– Unhindered alkyl halide – Strong nucleophiles– Aprotic solvents– High concentrations of nucleophile

Final Notes on Sn2/Sn1

• Note the chart on page 272• These are all the functional group transformations

possible through Sn2/Sn1 reactions!

• Remember, Sn2 reactions always proceed with inversion of the stereocenter while Sn1 reactions proceed with the total loss of stereocenter and result in racemic mixture

• Watch for “Double Inversion”

Elimination Reations

• Elimination reactions are important reactions of alkyl halides that compete with Sn2/Sn1 reactions

• Recall, in elimination reactions, 1 thing is eliminated from each of two adjacent carbons to form a double bond

• Ex.

Elimination Reactions

• A widely used method is the elimination of HX from an Alkyl Halide

• Ex

• When the elements of a hydrogen halide are eliminated from a haloalkane, the reaction is called a dehydrohalogenation.

Elimination Reactions

• In these eliminations, as in Sn1/Sn2, there is a Leaving group and an attacking Lewis base that posses an electron pair

• They are also called β-elimination since the hydrogen that is removed is from the beta carbon

Base Used in Dehydrohalogenations

• Very strong bases are used for elimination reactions• Typically, the sodium or potassium salts of alcohols

are used• These sometimes present problems because they

can also react as nucleophile• To avoid this, the salt of t-butanol is used• t-butoxide is very bulky which prevents it from

being a good nucleophile

Mechanisms for Elimination Reactions

• Just like substitutions, there are two• One has a bimolecular T.S. = E2• One has an unimolecular T.S. = E1

• Mechanism for E2

Mechanisms for Elimination Reactions

• Mechanism for E1

• Problem!! E1 and Sn1 usually complete to give mixed products

Substitution vs Elimination

• All nucleophiles are potential bases and vice versa

• So substitution and elimination compete• Sn2 vs E2– Both favored by high concentration of

nucleophile/base

Sn2 vs E2

• 1o LG – With a 1o alkyl halide and unhindered base favors

substitution– With a hindered base, elimination is favored

• 2o LG– Strong base favors elimination due to steric hinderance

• 3o LG– No chance for Sn2 only elimination

Effect of Temperature

• Increasing the temperature favors

• Low temperature favors substitution

Sn1 vs E1• E1 favored by:– Stable cations– Poor nucleophiles– Use protic solvents– High temperatures

• Sn1- very hard to favor– Use low temperatures– Strong nucleophiles – Aprotic solvents

Overall Summary

Ch 6- Alkyl Halides. Structures and Properties Halogen is connected to a tetrahedral carbon The...

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