2 Structures and Properties Halogen is connected to a tetrahedral carbonThe carbon-halogen bond is polarized with the carbon having a partial positive charge and the halogen having a partial negative chargeThe size of the halogen increases as you move down the groupConsequently, the C-X bond lengths increase so the bond strength decreases
3 Structures and Properties Compounds with a halogen bonded to an sp2 carbon are called vinylic halides or phenyl halidesEx.Alkyl and aryl halides have very low solubility in water, but very stable in each other
4 Nucleophilic Substitution Reactions General Reaction:Examples:Nucleophile- a species with an unshared electron pair.Usually has either a full or partial negative chargeIt is electron rich
5 Nucleophilic Substitution Reactions The nucleophile reacts with the alkyl halide, replacing the halogen substituentA substitution reaction takes place and the halogen substituent, called the leaving group, departs as an ionBecause the substitution is initiated by a nucleophile, it is called a nucleophilic substitution reaction
6 Nucleophilic Substitution Reactions In the reaction, the C-X bond undergoes heterolysis and the electron pair from the nucleophile is used to make a new bondThere are two ways this can happen:The C-X bond can break then the Nu-C bond formsBond making and breaking can happen at the same time.
7 Nucleophilic Substitution Reactions When deciding which of these will occur, the decision will depend primarily on the structure of the alkyl halide.
8 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 chargeA nucleophile is any negative ion or any neutral molecule that has at least one unshared pair of electronsEx.
9 Leaving GroupsTo act as a substrate, in a nucleophilic substitution reaction, a molecule must have a good leaving groupA 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
10 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
11 Kinetics of a Nucleophilic Substitution Reaction: An Sn2 reaction 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 appearsWe do this by taking a small sample of the reaction mixture at different times and measure the concentration of chloromethane, hydroxide, methanol, or chloride.
12 Kinetics of a Nucleophilic Substitution Reaction: An Sn2 reaction We know the initial concentration of the reactants because we measured them before starting the reaction.Experiment #Initial [CH3OH]Initial [OH]Initial Rate1.00101.04.9x10-72.00209.8x10-732.0419.6x10-7
13 Kinetics of a Nucleophilic Substitution Reaction: An Sn2 reaction Notice the rate depends on both the concentration of chloromethane and hydroxideWhen we double one, the rate doubledWhen we doubled both the rate goes up by a factor of 4!We can express this by a proportionality:𝑅𝑎𝑡𝑒 ∝[ 𝐶𝐻 3 Cl] [OH]
14 Kinetics of a Nucleophilic Substitution Reaction: An Sn2 reaction 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 secThis reaction is said to be second order overallIn order for the reaction to take place, a hydroxide ion and a chloromethane molecule must collide
15 Kinetics of a Nucleophilic Substitution Reaction: An Sn2 reaction Therefore, the reaction is bimolecular, which means 2 molecules are involved in the rate determining stepWe call this kind of reaction an Sn2 reaction, Substitution, nucleophilic, Bimolecular
16 Mechanism for the Sn2 reaction The negative hydroxide approaches the partially positive carbon from the backsideConcerted Reaction- bond breaking and bond making happen at the same time.Configuration of the carbon being attacked is inverted due to the backside attact.
17 Stereochemistry of Sn2 reaction The nucleophile approaches from the backside, from the side directly opposite the leaving groupThis causes a change in configurationThe carbon being attacked inverts like an umbrellaEx.Inversion also always takes place with acyclic stereogenic carbons
18 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 reactionsThe 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 rateBut changing [OH] has no effect
19 Reaction of t-butyl chloride with OH: Sn1 reaction 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 overallFrom 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
20 Reaction of t-butyl chloride with OH: Sn1 reaction The reaction is said to be unimolecular in the rate determining stepIt is an example of an Sn1 reaction.Substitution, nucleophilic, UnimolecularBecause only the t-butyl chloride is present in the rate determining transition state, we can conclude that the reaction must have multiple steps
21 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 stepThat slow step is called the Rate-Determining Step, (RDS).
22 Mechanism for Sn1The mechanism has two intermediates
23 Carbocations Carbocations are trigonal planar The carbon bearing the positive charge is sp2 hybridizedThe carbon is electron deficient as it only has 6 electrons.Overall stability:
24 Stereochemistry of Sn1Because 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 formedHowever, if the starting reactant is optically active, this will always result in a racemizationRacemization- a reaction transforms an optically active compound into a racemic form
25 Stereochemistry of Sn1Racemization takes place whenever the reaction causes chiral molecules to be converted to an achiral intermediateExThe 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.
26 SolvolysisThe 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 solventThe previous reaction was in water, so it is also called a hydrolysisIf the reaction was in methanol, it would be a methanolysis.Examples:
27 Factors affecting the rates of Sn1 and Sn2 reactions Now we know the mechanism Sn1 and Sn2The next thing is too explain why chloromethane went Sn2 t-butylchloride went Sn1By the time we are done, you will be able to predict which pathway a reaction will undergo
28 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 versaA number of factors affect the relative rates of Sn1 and Sn2 reactions:
29 Factors that affect rates of Sn1 and Sn2 The most important are:Structure of the substrate- Is it a primary, secondary, tertiery alkyl halide?The concentration and reactivity of the nucleophile- For bimolecular reactions onlyThe effect of the solventThe nature of the leaving group
30 Effect of the Structure of the Substrate In Sn2 reactions, simple alkyl halides have the following general order of reactivityThe important factor behind this order is a steric effectSteric 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
31 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
32 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 ratesThere are exceptions to this that we will cover later
33 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 matterIn Sn2, the rate is dependent on both the substrate and the nucleophileWe have already seen how doubling the concentration of the nucleophile doubles the rateWe identify good and bad nucleophiles based on their rate of reaction in similar situationsEx
34 Nucleophile Strength vs Structure The relative strengths of nucleophiles can be correlated with two structural features:A negative charged nucleophile is always a more reactive nucleophile than its conjugate acidIn a group of nucleophiles in which the nucleophilic atom is the same, nucleophilicities parrallel basicities.
35 Solvent effects on Sn2 Reactions Protic Solvents- those having a Hydrogen bond to an electronegative element such as OxygenThese solvents can hydrogen bond to the nucleophile and hinder its reaction in an Sn2 reactionHydrogen bonding effects decreases with anion size
36 Solvent effects on Sn2 Reactions Nucleophilicity of halide anions in protic solvents:Relative Nucleophilicity in Protic Solvents:
37 Solvent effects on Sn2 Reactions 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:
38 Solvent effects on Sn2 Reactions 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:
39 Solvent effects on Sn2 Reactions The rates of Sn2 reactions are vastly increased when they are carried out in polar aprotic solvents!Take Home: Aprotic Solvents= Sn2
40 Solvent effects on Sn1 Reactions Polar protic solvents greatly increase the rate of ionization of alkyl halidesThis is the RDS, therefore it increases the rate of the Sn1 reactions.So, in most cases, use of a protic solvent = Sn1
41 Nature of Leaving Group The more stable an anion, the better the leaving groupGeneral order of stabilities:Some “Super” leaving groups are shown on page 269Also, in some cases, bad leaving groups can be converted into good leaving groups with simple acid/base chemistry
42 Summary of Sn1 vs Sn2Reactions of alkyl halides by Sn1 are favored by:Substrates that form stable carbocationsUse of weak nucleophilesUse of polar protic solventsSn2 favored by:Unhindered alkyl halideStrong nucleophilesAprotic solventsHigh concentrations of nucleophile
43 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 mixtureWatch for “Double Inversion”
44 Elimination ReationsElimination reactions are important reactions of alkyl halides that compete with Sn2/Sn1 reactionsRecall, in elimination reactions, 1 thing is eliminated from each of two adjacent carbons to form a double bondEx.
45 Elimination Reactions A widely used method is the elimination of HX from an Alkyl HalideExWhen the elements of a hydrogen halide are eliminated from a haloalkane, the reaction is called a dehydrohalogenation.
46 Elimination Reactions In these eliminations, as in Sn1/Sn2, there is a Leaving group and an attacking Lewis base that posses an electron pairThey are also called β-elimination since the hydrogen that is removed is from the beta carbon
47 Base Used in Dehydrohalogenations Very strong bases are used for elimination reactionsTypically, the sodium or potassium salts of alcohols are usedThese sometimes present problems because they can also react as nucleophileTo avoid this, the salt of t-butanol is usedt-butoxide is very bulky which prevents it from being a good nucleophile
48 Mechanisms for Elimination Reactions Just like substitutions, there are twoOne has a bimolecular T.S. = E2One has an unimolecular T.S. = E1Mechanism for E2
49 Mechanisms for Elimination Reactions Mechanism for E1Problem!! E1 and Sn1 usually complete to give mixed products
50 Substitution vs Elimination All nucleophiles are potential bases and vice versaSo substitution and elimination competeSn2 vs E2Both favored by high concentration of nucleophile/base
51 Sn2 vs E21o LGWith a 1o alkyl halide and unhindered base favors substitutionWith a hindered base, elimination is favored2o LGStrong base favors elimination due to steric hinderance3o LGNo chance for Sn2 only elimination
52 Effect of Temperature Increasing the temperature favors Low temperature favors substitution
53 Sn1 vs E1 E1 favored by: Sn1- very hard to favor Stable cations Poor nucleophilesUse protic solventsHigh temperaturesSn1- very hard to favorUse low temperaturesStrong nucleophilesAprotic solvents