There Are Two Fundamental Events in a Nucleophilic Substitution Reaction

Overall a nucleophilic susbtitution can be represented as follows:

There are two fundamental events in a nucleophilic substitution reaction:

1. formation of the new s bond to the nucleophile 2. breaking of the s bond to the leaving group

Depending on the relative timing of these events, two different mechanisms are possible:

• Bond breaking to form a carbocation preceeds the formation of the new bond : SN1 reaction • Simultaneous bond formation and bond breaking : SN2 reaction

A third possibility, where the nucleophile adds then the leaving group departs can't occur because it would require that the electrophilic C become pentavalent.

However, it is also useful to appreciate that the overall outcome of the transformation (i.e. the substitution) is often the same regardless of whether it is SN1 or SN2, though they may be differences in regiochemistry and / or stereochemistry (which can provide some evidence as to which mechanistic path is occuring).

IMPORTANT

In general terms the C bearing the LG needs to the sp3 hybridized in order for these reactions to occur. This is important since students often want to make use of nucleophilic substitution reactions of vinyl or aryl systems which are not generally effective. The reasons for this are that the adjacent p bonds are electron rich and will repel - the Nu and / or that the vinyl and phenyl carbocations are not very favorable.

SN1 indicates a substitution, nucleophilic, unimolecular reaction, described by the expression rate = k [R-LG]. This implies that the rate determining step of the mechanism depends on the decomposition of a single molecular species.

This pathway is a multi-step process with the following characteristics:

step 1: slow loss of the leaving group, LG, to generate a carbocation intermediate, then step 2 : rapid attack of a nucleophile on the electrophilic carbocation to

form a new s bond

Multi-step reactions have intermedia tes and a several transition states (TS).

In an SN1 there is loss of the leaving group generates an intermedia te carbocatio n which is then

undergoes a rapid reaction with the nucleophil e..

General case S 1 reaction N

Lets look at how the various components of the reaction influence the reaction pathway:

R- Reactivity order : (CH3)3C- > (CH3)2CH- > CH3CH2- > CH3-

In an SN1 reaction, the rate determining step is the loss of the leaving group to form the intermediate carbocation. The more stable the carbocation is, the easier it is to form, and the faster the SN1 reaction will be. Some students fall into the trap of thinking that the system with the less stable carbocation will react fastest, but they are forgetting that it is the generation of the carbocation that is rate determining.

The following images show a selection of alkyl bromides and their relative rates of reaction in an SN1 hydrolysis. Try to correlate the structure of the alkyl bromide with the type of carbocation that will be formed. If you need help, click the L button to show you where the carbocation will be formed.

Relative rate of hydrolysis 1 2 43 100,000,000 L button highlights C+ center, R button resets

You should have found that the carbocations get more stable as you go left to right in the table. As the carbocation gets easier to form, so the rate of reaction increases.

-LG The only event in the rate determining step of the SN1 is breaking the C-LG bond. Therefore, there is a very strong dependence on the nature of the leaving group, the better the leaving, the faster the SN1 reaction will be.

Nu Since the nucleophile is not involved in the rate determining step, the nature of the nucleophile is unimportant in an SN1 reaction. However, the more reactive the nucleophile, the more likely an SN2 reaction becomes. Stereochemistry

In an SN1, the nucleophile attacks the planar carbocation. Since there is an equally probability of attack on each face there will be a loss of stereochemistry at the reactive center as both products will be observed.

Solvent Polar solvents which can stabilize carbocations which can favour the SN1 reaction (e.g. H2O, ROH)

Since a carbocation intermediate is formed, there is the possibility of rearrangements (e.g. 1,2-hydride or 1,2-alkyl shifts) to generate a more stable carbocation. This is usually indicated by a change in the position of the alkene or a change in the carbon skeleton of the product when compared to the starting material.

This pathway is most common for systems with good leaving groups, stable carbocations and weaker nucleophiles. A typical example is the reaction of HBr with a tertiary alcohol.

SN1 MECHANISM FOR REACTION OF ALCOHOLS WITH HBr

Step 1: An acid/base reaction. Protonation of the alcoholic oxygen to make a better leaving group. This step is very fast and reversible. The lone pairs on the oxygen make it a Lewis base.

Step 2: Cleavage of the C-O bond allows the loss of the good leaving group, a neutral water molecule, to give a carbocation intermediate. This is the rate determining step (bond breaking is endothermic)

Step 3: Attack of the nucleophilic bromide ion on the electrophilic carbocation creates the alkyl bromide.

SN1 MECHANISM FOR REACTION OF ALKYL HALIDES WITH H2O

Step 1: Cleavage of the already polar C-Br bond allows the loss of the good leaving group, a halide ion, to give a carbocation intermediate. This is the rate determining step (bond breaking is endothermic)

Step 2: Attack of the nucleophile, the lone pairs on the O atom of the water molecule, on the electrophilic carbocation creates an oxonium species.

Step 3: Deprotonation by a base yields the alcohol as the product.

Note that this is the reverse of the reaction of an alcohol with HBr.

In principle, the nucleophile here, H2O, could be replaced with any nucleophile, in which case the final deprotonation may not always be necessary.

Stability: The general stability order of simple alkyl carbocations is: (most stable) 3o > 2o > o 1 > methyl (least stable)

This is because alkyl groups are weakly electron donating due to hyperconjugation and inductive effects. Resonance effects can further stabilize carbocations when present.

Structure:

Alkyl carbocations are sp2 hybridized, planar systems at the cationic C center. The p-orbital that is not utilized in the hybrids is empty and is often shown bearing the positive charge

since it represents the orbital available to accept electrons.

Reactivity:

As they have an incomplete octet, carbocatio ns are excellent electrophil es and react readily with nucleophile s. Alternativel y, loss of + H can generate a p bond.

The electrostati c potential diagrams clearly show the cationic center in blue, this is where the nucleophile will attack.

Rearrangements: Carbocations are prone to rearrangement via 1,2-hyride or 1,2-alkyl shifts if it generates a more stable carbocation

Reactions involving carbocations: 1. Substitutions via the SN1 2. Eliminations via the E1 + 3. Additions to alkenes and alkynes (HX, H3O )

SN2 indicates a substitution, nucleophilic, bimolecular reaction, described by the expression rate = k [Nu][R-LG]. This implies that the rate determining step involves an interaction between these two species, the nucleophile and the organic substrate.

This pathway is a concerted process (single step) as shown by the following reaction coordinate diagrams, where there is simultaneous attack of the nucleophile and displacement of the leaving group.

The nucleophile attacks at the carbon with the partial positive charge as a result of the polar s bond to the electronegative atoms in the leaving group. Single step reactions have no intermediat es and a single transition state (TS).

In an SN2 there is simultaneo us formation of the carbon- nucleophil e bond and breaking of the carbon- leaving group bond,

hence the reaction proceeds via a TS in which the central C is partially bonded to five groups. General case S 2 reaction N

Let's look at how the various components of the reaction influence the reaction pathway:

R- Reactivity order : CH3- > CH3CH2- > (CH3)2CH- > (CH3)3C- In an SN2 reaction, the transition state has 5 groups around the central C atom. As a consequence of the steric requirements at this center, less highly substituted systems (i.e. more smaller H groups) will favour an SN2 reaction by making it easier to achieve the transition state.

The following two series of images show four alkyl bromides and a chloride ion as a potential nucleophile. Relative rate of reaction data for an SN2 reaction with iodide is also given. Use the lower row of space filling models (which are great for seeing steric effects) to rotate the molecules to look at the electrophilic C center from the side opposite to the leaving group (which is where the nucleophile attacks from) to see how much of it the electrophilic center you can see. If you need help recognising the electrophilic center, use the L button to highlight it.

- Relative rate of reaction with I 221,000 1,350 1 »0 L button highlights E+ center, R button resets

Notice how as the steric crowding increases around the electrophilic center that the rate of reaction with iodide decreases.

-LG The C-LG bond is broken during the rate determining step so the rate does depend on the nature of the leaving group. However, if a leaving group is too good, then an SN1 reaction may result.

Nu Since the nucleophile is involved in the rate determining step, the nature of the nucleophile is very important in an SN2 reaction. The more reactive the nucleophile, the more likely the reaction will be SN2 rather than SN1.

Stereochemistry When the nucleophile attacks in an SN2 it is on the opposite side to the position of the leaving group. As a result, the reaction will proceed with an inversion of configuration.

Solvent Polar aprotic solvents can be used to enhance the reactivity of the nucleophile and help promote an SN2 reaction.

Summary This pathway is most common for systems with poorer leaving groups, 1o or 2o substrates and stronger nucleophiles. A typical example is the reaction of NaI with primary alkyl halides or tosylates.

Nucleophiles

Nucleophile means "nucleus loving" which describes the tendency of an electron rich species to be attracted to the positive nuclear charge of an electron poor species, the electrophile .

The nucleophilicity expresses the ability of the nucleophile to react in this fashion.

In general terms this can be appreciated by considering the availability of the electrons in the nucleophile. The more available the electrons, the more nucleophilic the system. Hence the first step should be to locate the nucleophilic center. At this point we will be considering Nu that contain lone pairs and may be anionic, however the high electron density of a C=C is also a nucleophile.

A collection of important nucleophiles are shown to the left.

Nucleophilicity trends (compared with basicity)

- 1. Across a row in the periodic table nucleophilicity (lone pair donation) C > N- > O- > F- since increasing electronegativity decreases the lone pair availability. This is the same order as for basicity. 2. If one is comparing the same central atom, higher electron density will increase the nucleophilicity,

e.g. an anion will be a better Nu (lone pair donor) than a neutral atom such - as HO > H2O. This is the same order as for basicity.

3. Within a group in the periodic table, increasing polarization of the nucleophile as you go down a group enhances the ability to form the new C-X bond and increases the nucleophilicity, so I- > Br- > Cl- > F-. The electron density of larger atoms is more readily distorted i.e. polarized, since the electrons are further from the nucleus.

Note that is the opposite order to basicity (acidity increases down a group) where polarisability is much less important for bond formation to the very small proton. Here is a table of relative nucleophilicities as measured in methanol (CH3OH):

- - - Very Good I , HS , RS - - - - - Good Br , HO , RO , NC , N3 - - - Fair NH3, Cl , F , RCO2 Weak H2O, ROH

Very Weak RCO2H

Nucleophilicity and basicity are very similar properties in that species that are - - nucleophiles are usually also bases (e.g. HO , RO ).

This is not too surprising since in the LEWIS sense, they are functioning as LONE PAIR donors (i.e. both are LEWIS BASES), compare the two pairs of reactions mechanisms shown below to convince yourself.

However, it can avoid confusion by keeping these two types of reactivity separated because there are important differences....

1. Nucleophilicity:

Both these reactions depict a nucleophil

e reacting with an electrophili c C atom

Kinetically controlled reactions of lone pair donor with an electrophilic carbon (usually) atom resulting in the formation a new C-X bond. 2. Basicity:

Both these reactions

depict a base reacting with an electrophilic H atom, a proton

Equilibrium (thermodynamic) reaction of the lone pair donor with a proton, forming a new H-X bond

The following general reaction mechanisms show you why it is important to appreciate the differences, since an anion that is reacting as a nucleophile will result in a substitution, but if it reacts as a base, then elimination will result, be it on a carbocation (SN1 vs E1) or with the loss of a leaving group (SN2 vs E2).

SN 1 Substituti

ons

SN 2

Eliminati ons

A leaving group , LG, is an atom (or a group of atoms) that is displaced as stable species taking with it the bonding electrons. Typically the leaving group is - an anion (e.g. Cl ) or a neutral molecule (e.g. H2O). The better the leaving group, the more likely it is to depart.

A "good" leaving group can be recognized as being the conjugate base of a strong acid.

What do we mean by this ? First we should write the chemical equations for the two processes:

These two equations represent Bronsted acid dissociation and loss of a leaving group in a SN1 type reaction. Note the similarity of the two equations: both show heterolytic cleavage of a s bond to create an anion and a cation.

For acidity, the more stable A- is, then the more the equilibrium will favor dissociation, and release of protons meaning that HA is more acidic.

- For the leaving group, the more stable LG is, the more it favors "leaving".

- - Hence factors that stabilize A also apply to the stablization of a LG .

Here is a table classifying some common leaving groups that we will eventually meet......

- Excellent TsO , NH3 - Very Good I , H2O - Good Br - Fair Cl - Poor F - - - Very Poor HO , NH2 , RO

Note, once again, that HO- is a poor leaving group (remember from the reactions of alcohols ?).... after all it is the conjugate base of water.... and when we turn on a tap in the kitchen, we aren't usually trying to get a strong acid to drink ! But water itself, H2O, is a good leaving group, since it is the conjugate base of + H3O , which is a strong acid.

In general terms, the choice of solvent can have a significant effect on the performance of a reaction.

Factors when chosing a solvent are:

• solubility : need to get reagents in the same phase, the molecules need to collide to react ! • usually, the solvent needs to be unreactive towards the reagents

(except in reactions where the solvent is the Nu : "solvolysis")

• how will the solvent affect the rate of reaction ?

For an SN1 reaction, the polarity and ability of the solvent to stabilize the intermediate carbocation is of paramount importance, as shown by the relative rate data for the solvolysis of t-BuCl.

Solvent Dipole moment Dielectric Constant Relative Rate

CH3CO2H 1.74 6 1

CH3OH 1.7 33 4

H2O 1.85 78 150,000

For an SN2 reaction, the effect of solvent polarity is usually much less, but the ability (or really lack there of) of the solvent to solvate the nucleophile is the important criteria, as shown by the relative rate data for the SN2 reaction of n- - BuBr with N3 .

Solvent Dipole moment Dielectric Constant Relative Rate Type

CH3OH 1.7 33 1 protic

H2O 1.85 78 7 protic DMSO 3.96 49 1,300 aprotic DMF 3.82 37 2,800 aprotic

CH3CN 3.92 38 5,000 aprotic

POLAR PROTIC SOLVENTS (polar and ability to be H-bond donor)

• have dipoles due to polar bonds • have H atoms that can be donated into a H-bond • examples are the more common solvents like H2O and ROH • remember basicity is also usually measured in water • anions will be solvated due to H-bonding, inhibiting their ability to function as a Nu

POLAR APROTIC SOLVENTS (polar but no ability to be H-bond donor)

• have dipoles due to polar bonds • don't have H atoms that can be donated into a H-bond • examples are acetone, acetonitrile, DMSO, DMF • anions are not solvated and are "naked" and reaction is not inhibited

Overall

• All nucleophiles will be more reactive in aprotic than protic solvents • Those species that were most strongly solvated in polar protic solvents - will "gain" the most reactivity in polar aprotic (e.g. F ). • Polar aprotic solvents are typically only used when a polar protic - - - solvent gives poor results due to having a weak Nu, (esp. F , CN, RCO2 )

Substitution and elimination reactions are strongly influenced by many factors. Some of the more important factors are outlined in the following table. The significance of the effect is stated first, then the system that will favor the reaction is stated. This should help you deal with the questions.... 1. When does an anion function as a Nu and when does it function as a B ?, and therefore, 2. When to I get substitution and when do I get elimination ?

Leaving Typical Reaction Solvent Nu or Base Substrate Group Conditions Very Strong Weak Strong Strong o AgNO3 / aq. SN1 Polar Good Nu and 3 or resonance Good LG EtOH solvents weak base stabilized Strong Strong Strong Strong SN2 Polar aprotic Good Nu and o NaI / Acetone Good LG Methyl or 1 solvents weak base Very Strong Strong Weak Strong o E1 Polar 3 or resonance H2SO4, heat Weak base Good LG solvents stabilized Strong Strong Strong Strong E2 Polar aprotic Poor Nu and o KOH, heat, Good LG 3 solvents strong base

• Unless the -OH group is converted into a better leaving group, then alcohols are poor substrates for substitution reactions. • Protonation to convert the leaving group into H2O has limited utility as not all substrates or nucleophiles can be utilized under acidic conditions without unwanted side reactions. • An alternative is to convert the alcohol into a tosylate, which has a much better leaving group and will react with nucleophiles without the need for the acid.

Reactions

• Preparation and Reaction of Tosylates • Reaction of Alcohols with Hydrogen Halides • Reaction of Alcohols with SOCl2, PCl3, PBr3

Preparation and Reaction of Tosylates

Reaction type: Nucleophilic Substitution (usually SN2)

Summary:

• Alcohols can be converted into tosylates using tosyl chloride and a base to "mop-up" the HCl by-product. • Tosylates are good substrates for substitution reactions. o o • Used mostly for 1 and 2 ROH (SN2 reaction). • The -OH reacts first as a nucleophile, attacking the electrophilic center of tosylate, displacing a Cl. • Tosylates have a much better leaving group : the conjugate base of tosic acid, pKa = -2.8 • The advantage of this method is that the substitutions reactions are not under the strongly acidic conditions. • Tosylates will react with nucleophiles in much the same way as alkyl halides. • Alternatives to tosylates are mesylates (use CH3SO2Cl) and triflates (use CF3SO2Cl)

This is the reagent used to prepare the tosylate ester. It maybe referred to by any of the terms shown. The tosylate ester is shown. Note that the oxygen atom from the original alcohol is retained. In the reactions of tosylates, the displaced group is the resonance stabilized anion shown which is a good leaving group.

Note that the preparation of the tosylate is similar to the reaction of an alcohol with SOCl2.

Reaction of Alcohols with Hydrogen Halides (review of chapter 4)

Reaction type: Nucleophilic Substitution (SN1 or SN2)

Summary:

• When treated with HBr or HCl alcohols typically undergo a nucleophilic substitution reaction to generate an alkyl halide and water. o o o • Alcohol relative reactivity order : 3 > 2 > 1 > methyl. • Hydrogen halide reactivity order : HI > HBr > HCl > HF (paralleling acidity order). • Reaction usually proceeds via an SN1 mechanism which proceeds via a carbocation intermediate, that can also undergo rearrangement. • Methanol and primary alcohols will proceed via an SN2 mechanism since these have highly unfavorable carbocations. • The reaction of alcohols with HCl in the presence of ZnCl2 (catalyst) forms the basis of the Lucas test for alcohols. SN1 MECHANISM FOR REACTION OF ALCOHOLS WITH HBr

Step 1: An acid/base reaction. Protonation of the alcoholic oxygen to make a better leaving group. This step is very fast and reversible. The lone pairs on the oxygen make it a Lewis base.

Step 3: Attack of the nucleophilic bromide ion on the electrophilic carbcation creates the alkyl bromide.

Reaction of Alcohols with other Halogenating agents (SOCl2, PX3) (review of chapter 4)

Reaction type: Nucleophilic Substitution (SN1 or SN2)

Summary:

• Alcohols can also be converted to alkyl chlorides using thionyl chloride, SOCl2, or phosphorous trichloride, PCl3. • Alkyl bromides can be prepared in a similar reaction using PBr3. o o • Used mostly for 1 and 2 ROH (SN2 reaction) • In each case a base is used to "mop-up" the acidic by-product. • Common bases are triethylamine, Et3N, or pyridine, C6H5N. • In each case the -OH reacts first as a nucleophile, attacking the electrophilic center of the halogenating agent. • A displaced halide ion then completes the substitution displacing the leaving. • Note that it is not -OH that leaves, but a much better leaving group. • The advantage of these reagents is in that the reaction is not under the strongly acidic conditions like using HCl or HBr.

• Alkyl chlorides, bromides and iodides are good substrates for substitution reactions. • A variety of nucleophiles can be used to generate a range of new functional groups. • The following diagram reflects some of the more important reactions you may encounter. • For practice, make sure you can draw the mechanisms that lead to these products.

Reactions