reaction of alkyl halides :nucleophilic substututions

11. Reactions of Alkyl Halides: Nucleophilic Substitutions and Eliminations

Based on McMurry’s Organic Chemistry, 7th edition

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Alkyl Halides React with Nucleophiles and Bases Alkyl halides are polarized at the carbon-halide bond,

making the carbon electrophilic Nucleophiles will replace the halide in C-X bonds of

many alkyl halides(reaction as Lewis base) Nucleophiles that are Brønsted bases produce

elimination

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Why this Chapter?

Nucleophilic substitution, base induced elimination are among most widely occurring and versatile reaction types in organic chemistry

Reactions will be examined closely to see:- How they occur- What their characteristics are- How they can be used

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11.1 The Discovery of Nucleophilic Substitution Reactions In 1896, Walden showed that (-)-malic acid could be

converted to (+)-malic acid by a series of chemical steps with achiral reagents

This established that optical rotation was directly related to chirality and that it changes with chemical alteration Reaction of (-)-malic acid with PCl5 gives (+)-

chlorosuccinic acid Further reaction with wet silver oxide gives (+)-malic

acid The reaction series starting with (+) malic acid gives (-)

acid

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Reactions of the Walden Inversion

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Significance of the Walden Inversion The reactions alter the array at the chirality center The reactions involve substitution at that center Therefore, nucleophilic substitution can invert the

configuration at a chirality center The presence of carboxyl groups in malic acid led to

some dispute as to the nature of the reactions in Walden’s cycle

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11.2 The SN2 Reaction

Reaction is with inversion at reacting center Follows second order reaction kinetics Ingold nomenclature to describe characteristic step:

S=substitution N (subscript) = nucleophilic 2 = both nucleophile and substrate in

characteristic step (bimolecular)

The SN2 reaction (also known as bimolecular nucleophilic substitution) is a type of nucleophilic substitution, where a lone pair from a nucleophile attacks an electron deficient electrophilic center and bonds to it, expelling another group called a leaving group.

The reaction most often occurs at an aliphatic sp3 carbon center with an electronegative, stable leaving group attached to it - 'X' - frequently a halide atom.

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Kinetics of Nucleophilic Substitution Rate (V) is change in concentration with time Depends on concentration(s), temperature, inherent

nature of reaction (barrier on energy surface) A rate law describes relationship between the

concentration of reactants and conversion to products

A rate constant (k) is the proportionality factor between concentration and rate

Example: for S converting to P

V = d[S]/dt = k [S]

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Reaction Kinetics The study of rates of reactions is called kinetics Rates decrease as concentrations decrease but the

rate constant does not Rate units: [concentration]/time such as L/(mol x s) The rate law is a result of the mechanism The order of a reaction is sum of the exponents of the

concentrations in the rate law – the example is second order

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SN2 Process The reaction involves a transition state in which both reactants are

together

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SN2 Transition State

The transition state of an SN2 reaction has a planar arrangement of the carbon atom and the remaining three groups

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11.3 Characteristics of the SN2 Reaction

Sensitive to steric effects Methyl halides are most reactive Primary are next most reactive Secondary might react Tertiary are unreactive by this path No reaction at C=C (vinyl halides)

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Reactant and Transition State Energy Levels Affect Rate

Higher reactant energy level (red curve) = faster reaction (smaller G‡).

Higher transition state energy level (red curve) = slower reaction (larger G‡).

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Steric Effects on SN2 Reactions

The carbon atom in (a) bromomethane is readily accessibleresulting in a fast SN2 reaction. The carbon atoms in (b) bromoethane (primary), (c) 2-bromopropane (secondary), and (d) 2-bromo-2-methylpropane (tertiary) are successively more hindered, resulting in successively slower SN2 reactions.

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Order of Reactivity in SN2

The more alkyl groups connected to the reacting carbon, the slower the reaction

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The Nucleophile Neutral or negatively charged Lewis base Reaction increases coordination at nucleophile

Neutral nucleophile acquires positive charge Anionic nucleophile becomes neutral See Table 11-1 for an illustrative list

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Relative Reactivity of Nucleophiles

Depends on reaction and conditions More basic nucleophiles react faster Better nucleophiles are lower in a column of the

periodic table Anions are usually more reactive than neutrals

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The Leaving Group A good leaving group reduces the barrier to a

reaction Stable anions that are weak bases are usually

excellent leaving groups and can delocalize charge

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Poor Leaving Groups If a group is very basic or very small, it is prevents reaction

Alkyl fluorides, alcohols, ethers, and amines do not typically undergo SN2 reactions.

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The Solvent Solvents that can donate hydrogen bonds (-OH or –NH)

slow SN2 reactions by associating with reactants Energy is required to break interactions between reactant

and solvent Polar aprotic solvents (no NH, OH, SH) form weaker

interactions with substrate and permit faster reaction

Types of solvent…

In chemistry a protic solvent is a solvent that has a hydrogen atom bound to an oxygen (as in a hydroxyl group) or a nitrogen (as in an amine group). In general terms, any molecular solvent that contains dissociable H+ is called a protic solvent. The molecules of such solvents can donate an H+ (proton). Conversely, aprotic solvents cannot donate hydrogen.

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Polar protic solvent Polar protic solvents are solvents that share ion dissolving

power with aprotic solvents but have an acidic hydrogen. In general, these solvents have high dielectric constants and high polarity.

Common characteristics of protic solvents : solvents display hydrogen bonding solvents have an acidic hydrogen (although they may be very

weak acids) solvents are able to stabilize ions

cations by unshared free electron pairs anions by hydrogen bonding

Examples are water, methanol, ethanol, formic acid, hydrogen fluoride, and ammonia.

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Polar aprotic solvent Polar aprotic solvents are solvents that share ion

dissolving power with protic solvents but lack an acidic hydrogen. These solvents generally have intermediate dielectric constants and polarity.

Common characteristics of aprotic solvents: solvents do not display hydrogen bonding solvents do not have an acidic hydrogen solvents are able to stabilize ions Examples are dimethyl sulfoxide, dimethylformamide,

dioxane and hexamethylphosphorotriamide, tetrahydrofuran.

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Polar protic solvents are favorable for SN1 reactions, while polar aprotic solvents are favorable for SN2 reactions.

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The solvent affects the rate of reaction because solvents may or may not surround a nucleophile, thus hindering or not hindering its approach to the carbon atom. Polar aprotic solvents, like tetrahydrofuran, are better solvents for this reaction than polar protic solvents because polar protic solvents will be solvated by the solvent hydrogen bonding to the nucleophile and thus hindering it from attacking the carbon with the leaving group.

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11.4 The SN1 Reaction Tertiary alkyl halides react rapidly in protic solvents

by a mechanism that involves departure of the leaving group prior to addition of the nucleophile

Called an SN1 reaction – occurs in three distinct steps while SN2 occurs with both events in same step

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SN1 Energy Diagram

Rate-determining step is formation of carbocation

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Rate-Limiting Step

The overall rate of a reaction is controlled by the rate of the slowest step

The rate depends on the concentration of the species and the rate constant of the step

The highest energy transition state point on the diagram is that for the rate determining step (which is not always the highest barrier)

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Mechanism of SN1 reaction…

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Stereochemistry of SN1 Reaction

The planar intermediate leads to loss of chirality A free

carbocation is achiral

Product is racemic or has some inversion

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SN1 in Reality Carbocation is biased to react on side opposite

leaving group Suggests reaction occurs with carbocation loosely

associated with leaving group during nucleophilic addition

Alternative that SN2 is also occurring is unlikely

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Effects of Ion Pair Formation If leaving group

remains associated, then product has more inversion than retention

Product is only partially racemic with more inversion than retention

Associated carbocation and leaving group is an ion pair

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11.5 Characteristics of the SN1 ReactionSubstrate Tertiary alkyl halide is most reactive by this mechanism

Controlled by stability of carbocation Since the rate-limitings tep in a n SN1 reaction is the spontaneous, unimolecular

dissociation of the substrate to yield a carbocation, the reaction is favored whenever a stabilized carbocation intermediate is formed.

The more stable the carbocation intermediate, the faster the SN1 reaction.

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An allyl group is a substituent with the structural formula H2C=CH-CH2R, where R is the connection to the rest of the molecule. It is made up of a methylene (-CH2-), attached to a vinyl group (-CH=CH2).

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Allylic and Benzylic Halides

Allylic and benzylic intermediates stabilized by delocalization of charge (resonance-stabilized) Primary allylic and benzylic are also more reactive

in the SN2 mechanism allylic and benzylic catbocatious are unusually

stable because the unpaired electron can be delocalized over an extended orbital system

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Effect of Leaving Group on SN1

Critically dependent on leaving group Reactivity: the larger halides ions are better

leaving groups p-Toluensulfonate (TosO-) is excellent leaving group

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Nucleophiles in SN1

Since nucleophilic addition occurs after formation of carbocation, reaction rate is not normally affected by nature or concentration of nucleophile

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Solvent in SN1

Solvent effects in the SN1 reaction are due largely to stabilization or destabilization of the transition state

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Polar Solvents Promote Ionization Polar, protic and unreactive Lewis base solvents facilitate

formation of R+ Solvent polarity is measured as dielectric polarization (P)

Nonpolar solvents have low P Polar solvents have high P values

Solvent effect of SN1 rxn…

Since the SN1 reaction involves formation of an unstable carbocation intermediate in the rate-determining step, anything that can facilitate this will speed up the reaction. The normal solvents of choice are both polar (to stabilize ionic intermediates in general) and protic (to solvate the leaving group in particular). Typical polar protic solvents include water and alcohols, which will also act as nucleophiles.

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11.6 Biological Substitution Reactions SN1 and SN2 reactions are well known in

biological chemistry Unlike what happens in the laboratory,

substrate in biological substitutions is often organodiphosphate rather than an alkyl halide

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11.7 Elimination Reactions of Alkyl Halides: Zaitsev’s Rule Elimination is an alternative pathway to substitution Opposite of addition Generates an alkene Can compete with substitution and decrease yield,

especially for SN1 processes

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Zaitsev’s Rule for Elimination Reactions In the elimination of HX from an alkyl halide, the more

highly substituted alkene product predominates

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Mechanisms of Elimination Reactions Ingold nomenclature: E – “elimination” E1: X- leaves first to generate a carbocation

a base abstracts a proton from the carbocation E2: Concerted transfer of a proton to a base and

departure of leaving group

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11.8 The E2 Reaction and the Deuterium Isotope Effect

A proton is transferred to base as leaving group begins to depart

Transition state combines leaving of X and transfer of H

Product alkene forms stereospecifically

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Geometry of Elimination – E2 Antiperiplanar allows orbital overlap and minimizes

steric interactions

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E2 Stereochemistry Overlap of the developing orbital in the transition

state requires periplanar geometry, anti arrangement

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Predicting Product E2 is stereospecific Meso-1,2-dibromo-1,2-diphenylethane with base gives

cis 1,2-diphenyl RR or SS 1,2-dibromo-1,2-diphenylethane gives trans

1,2-diphenyl

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11.9 The E2 Reaction and Cyclohexane Formation Abstracted proton and leaving group should

align trans-diaxial to be anti periplanar (app) in approaching transition state

Equatorial groups are not in proper alignment

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11.10 The E1and E1cB Reactions

Competes with SN1 and E2 at 3° centers V = k [RX], same as SN1

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Comparing E1 and E2 Strong base is needed for E2 but not for E1 E2 is stereospecifc, E1 is not E1 gives Zaitsev orientation

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E1cB Reaction

Takes place through a carbanion intermediate

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11.11 Biological Elimination Reactions All three elimination reactions occur in

biological pathways E1cB very common Typical example occurs during biosynthesis

of fats when 3-hydroxybutyryl thioester is dehydrated to corresponding thioester

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11.12 Summary of Reactivity: SN1, SN1, E1,E1cB, E2 Alkyl halides undergo different reactions in competition,

depending on the reacting molecule and the conditions Based on patterns, we can predict likely outcomes

How to know what mechanism a reaction follows?? SN1? SN2? E1? E2?

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