chapter 2 organic reaction types_2015

8/18/2019 Chapter 2 Organic Reaction Types_2015

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ORGANIC REACTION

TYPES

CHAPTER 2


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Kinds of Organic Reactions

2

In general, we look at what occurs and try to learnhow it happens.

Common patterns describe the changes.

4 general types:A. Additions – two molecules combine

B. Eliminations – one molecule splits into two

C. Substitutions – parts from two molecules exchange

D. Rearrangements – a molecule undergoes changes in theway its atoms are connected


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A. AdditionTwo reactants add together to form a single productwithout side products.


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B. EliminationSingle reactant splits into 2 products with side product – water or HBr.


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Elimination is the opposite of addition .


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C. SubstitutionTwo reactants exchange parts to give two new products.


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D. RearrangementSingle reactant rearranges the bond and atoms toyield an isomeric product.


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Exercises

8

Classify the following reactions as addition, elimination,substitution or rearrangement.

1)

2)

3)

4)


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How Organic Reactions Occur: Mechanisms

9

In an organic reaction, we see the transformation that hasoccurred. The mechanism describes the steps behind thechanges that we can observe.

Reactions occur in defined steps that lead from reactant to

product. Reaction mechanism – describe in detail everything that

occurs during chemical reaction, which bonds are broken orformed, and in what order, the relative rates of steps

involved. All chemical reactions involve bond-breaking and bond-

making.


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Steps in Mechanisms

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We classify the types of steps in a sequence.

A step involves either the formation or breaking of acovalent bond.

Steps can occur in individually or in combination with other

steps.

When several steps occur at the same time they are said tobe concerted.


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Types of Steps in Reaction Mechanisms

Symmetrical- homolytic Unsymmetrical- heterolytic

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Bond breaking (radical) – 1

bonding electron stays witheach product

Bond-making (radical) – 1bonding electron is donatedby each reactant

Bond-breaking (polar) – 2

bonding electrons stays with1 product.

Bond-making (polar) – 2

bonding electrons aredonated by 1 reactant

Bond formation or breakage can be symmetrical orunsymetrical.


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Indicating Steps in Mechanisms

12

Curved arrows indicate breakingand forming of bonds.

Arrowheads with a “half” head(“fish-hook”) indicate homolyticand homogenic steps (called„radical processes‟) .

Arrowheads with a completehead indicate heterolytic and

heterogenic steps (called „polarprocesses‟)


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Bond breaking forms particles called reaction

intermediates.


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Common Reaction Intermediates

Formed by Breaking a Covalent Bond

14


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Radical Reactions

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Not as common as polar reactions.

Radicals react to complete electron octet of valence shell.

A radical can break a bond in another molecule and abstract a

partner with an electron, giving substitution in the original

molecule.

A radical can add to an alkene to give a new radical, causing an

addition reaction .


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Steps in Radical Substitution

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Three types of steps: Initiation

- Radicals are formed.

- Light supplies the energy to split a molecule.

Propagation

- A radical reacts with molecule to generate another radical.

- Free radical species are constantly generated throughout

the reaction.

Termination

- Combination of any two radicals to form stable product.


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Example: Initiation

formation of Cl radicals form Cl2 and light

Propagation

reaction of chlorine radical with methane to give HCl and •CH3

methyl radical reacts with Cl2 to generate the product and Cl•


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Termination reaction of any two radicals


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Polar Reactions

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Involve species with electron pairs in their orbitals.

More common reaction in organic chemistry.

Occur because of the electrical attraction between positive

and negative centers – most organic compounds areelectrically neutral, bonds in functional group are polar.

Molecules can contain local unsymmetrical electrondistributions due to differences in electronegativities.

This causes a partial negative charge on an atom and acompensating partial positive charge on an adjacent atom.


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The more electronegative atom has the greater electrondensity such as O, F, N, Cl more electronegative than carbon

carbon atom has partial positive charge (δ+).

Metal with lesser electronegativity carbon atom has partialnegative charge (δ-).


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Polarizability

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Polarization is a change in electron distribution as aresponse to change in electronic nature of the surroundings.

Polarizability is the tendency to undergo polarization.

Polar reactions occur between regions of high electron densityand regions of low electron density.

In the halogen family, for example, polarizability increases inthe order F < Cl < Br < I. F atom is the lowest because their electrons are very tightly held;

they are close to the nucleus.

I atom is the highest since their valence electrons are far fromnucleus.

Atoms with unshared pairs are generally more polarizable thanthose with only bonding pairs.


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Generalized Polar Reactions

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Nucleophile: nucleus loving

Negatively polarized

Electron-rich species

Donate pair of electrons toelectron poor atom

Neutral or negatively charged

Example: NH4+ , H2O, OH

, Cl

Electrophile: electron loving

Positively polarized

Electron-poor species

Accepting a pair of electronsfrom electron rich atom

Neutral or positively charged

Example: acids, alkyl halides,carbonyl compounds


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Generalized Polar Reactions

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In general, electrons flow from nucleophile to electrophiles.


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Exercises

Answers:


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An Example of a Polar Reaction: Addition

of HBr to Ethylene

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HBr adds to the part of C-C double bond.

The bond is electron-rich, allowing it to function as a nucleophile.

H-Br is electron deficient at the H since Br is much more

electronegative, making HBr an electrophile.

M h i f Addi i f HB


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Mechanism of Addition of HBr to

Ethylene

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HBr electrophile is attacked by electrons of ethylene

(nucleophile) to form a carbocation intermediate and bromide ion. Bromide adds to the positive center of the carbocation, which is

an electrophile, forming a C-Br bond.

The result is that ethylene and HBr combine to form

bromoethane. All polar reactions occur by combination of an electron-rich site

of a nucleophile and an electron-deficient site of an electrophile.


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U i C d A i P l R ti


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Using Curved Arrows in Polar Reaction

Mechanisms

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Curved arrows are a way to keep track of changes in bondingin polar reaction.

The arrows track “electron movement”.

Electrons always move in pairs.

Charges change during the reaction.

One curved arrow corresponds to one step in a reactionmechanism.

The arrow goes from the nucleophilic reaction site to theelectrophilic reaction site.


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Rules for Using Curved Arrows

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The nucleophilic site can be neutral or negatively charged.


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Rules for Using Curved Arrows

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The electrophilic site can be neutral or positively charged

The octet rule must be followed


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Organic Reaction Types:Nucleophilic Substitutions and Eliminations

Alk l H lid R t ith N l hil


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Alkyl Halides React with Nucleophiles

and Bases

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Alkyl halides are polarized at the carbon-halide bond, makingthe carbon electrophilic.

Nucleophiles will replace the halide in C-X bonds of manyalkyl halides(reaction as Lewis base).

Nucleophiles that are Brønsted bases produce elimination.


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Why this Chapter?

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Nucleophilic substitution, base induced elimination areamong most widely occurring and versatile reaction typesin organic chemistry.

Reactions will be examined closely to see:

- How they occur?- What their characteristics are?

- How they can be used?

Th Di f N l hili


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The Discovery of Nucleophilic

Substitution Reactions

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In 1896, Walden showed that (-)-malic acid could beconverted to (+)-malic acid by a series of chemical steps withachiral 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

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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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Nucleophilic Substitution Reactions

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In this type of reaction, a nucleophile, a species with an

unshared electron pair , reacts with an alkyl halide byreplacing the halogen substituent.

A substitution reaction takes places and the halogensubstituent, called the leaving group, departs as a halide ion.

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

Example:

Nucleophile Alkyl halide(substrate)

Product Halide ion


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Mechanisms of Nucleophilic Substitution

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In a nucleophilic substitution:

But what is the order of bond making and bond breaking?

In theory, there are three possibilities. Bond making and bond breaking occur at the same time

Bond breaking occurs before bond making

Bond making occurs before bond breaking


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Bond Making and Bond Breaking Occur at The Same Time

In this scenario, the mechanism is comprised of one step.

In such a bimolecular reaction, the rate depends upon the

concentration of both reactants. The rate equation is second order.


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Bond Breaking Occurs Before Bond Making

In this scenario, the mechanism has two steps and acarbocation is formed as an intermediate.

Because the first step is rate-determining, the rate depends onthe concentration of RX only.

The rate equation is first order.


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Bond Making Occurs Before Bond Breaking

This mechanism has an inherent problem.

The intermediate generated in the first step has 10 electronsaround carbon, violating the octet rule. Because two other mechanistic possibilities do not violate a

fundamental rule, this last possibility can be disregarded.


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Kinetics of Nucleophilic Substitution

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The study of rates of reactions is called kinetics.

Rate (V) is change in concentration with time.

Rates decrease as concentrations decrease but the rateconstant does not.

Rate units: [concentration]/time such as molL-1/s.

The rate law is a result of the mechanism. 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.


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The SN2 Reaction

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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)


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SN2 Process

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The reaction involves a transition state in which both reactantsare together.

Single step without intermediates when nucleophile react withalkyl halide or tosylate (substrate) from the opposite directionof the leaving group.


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SN2 Transition State

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The transition state of an SN2 reaction has a planararrangement of the carbon atom and the remaining threegroups.


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Stereochemistry of The SN2 Reaction

All SN

2 reactions proceed with backside attack of the nucleophile,

resulting in inversion of configuration at a stereogenic center.

Reactant and Transition State Energy


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Reactant and Transition State Energy

Levels Affect Rate

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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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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)

Characteristics of SN2 Reaction


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Steric Effects on SN2 Reactions

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The carbon atom in (a) bromomethane is readily accessible

resulting 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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The higher the Ea, the slower the reaction rate. Thus, any factor that

increases Ea decreases the reaction rate.

Two Energy Diagrams Depicting The Effect of Steric Hindrance in SN2 Reactions

Steric Effects on SN2 Reactions


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Order of Reactivity in SN2

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The more alkyl groups connected to the reacting carbon, the

slower the reaction.


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Order of Reactivity in SN2

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Methyl and 1° alkyl halides undergo SN2 reactions with ease.

2° Alkyl halides react more slowly.

3° Alkyl halides do not undergo SN2 reactions. This order of reactivity can be explained by steric effects. Steric

hindrance caused by bulky R groups makes nucleophilic attack from

the backside more difficult, slowing the reaction rate.


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The Nucleophile

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Neutral or negatively charged species.

Reaction increases coordination at nucleophile.

Neutral nucleophile acquires positive charge.

Anionic nucleophile becomes neutral.


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Relative Reactivity of Nucleophiles

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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

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A good leaving group reduces the barrier to a reaction.

Stable anions that are weak bases are usually excellent leavinggroups and can delocalize charge.


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Poor Leaving Groups

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If a group is very basic or very small, it is prevents reaction.

Alkyl fluorides, alcohols, ethers, and amines do not typically undergoSN2 reactions.


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The Solvent

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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 interactionswith substrate and permit faster reaction.


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The SN1 Reaction

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Tertiary alkyl halides react rapidly in protic solvents by a mechanism

that involves departure of the leaving group prior to addition of thenucleophile.

Called an SN1 reaction – occurs in two distinct steps while SN2occurs with both events in same step.

If nucleophile is present in reasonable concentration (or it is the

solvent), then ionization is the slowest step.


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Rate-Limiting Step

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The overall rate of a

reaction is controlledby the rate of theslowest step.

The rate depends onthe concentration of

the species and therate constant of thestep.

The highest energytransition state pointon the diagram is thatfor the ratedetermining step(which is not alwaysthe highest barrier).


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SN1 Energy Diagram

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Rate-determining/ rate-limiting step is formation of

carbocation.

First order process


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Stereochemistry of SN1 Reaction

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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

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Carbocation is biased to react on side opposite leaving group.

Suggests reaction occurs with carbocation loosely associatedwith leaving group during nucleophilic addition.

Alternative that SN2 is also occurring is unlikely.


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Effects of Ion Pair Formation

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If leaving group remains associated, then product has more

inversion than retention.

Product is only partially racemic with more inversion thanretention.

Associated carbocation and leaving group is an ion pair.


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Characteristics of the SN1 Reaction

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Substrate

Tertiary alkyl halide is most reactive by this mechanism. Controlled by stability of carbocation.

Hammond postulate, "Any factor that stabilizes a high-energy intermediate stabilizes transition state leading to that

intermediate”.


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Allylic and Benzylic Halides

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Allylic and benzylic intermediates stabilized by delocalization of

charge.

Primary allylic and benzylic are also more reactive in theSN2 mechanism.


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Effect of Leaving Group on SN1

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Critically dependent on leaving group.

Reactivity: the larger halides ions are better leaving groups. In acid, OH of an alcohol is protonated and leaving group is

H2O, which is still less reactive than halide.

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


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Nucleophiles in SN1

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Since nucleophilic addition occurs after formation of

carbocation, reaction rate is not normally affected bynature or concentration of nucleophile.


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Solvent in SN1

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Stabilizing carbocationalso stabilizes associatedtransition state andcontrols rate.

Solvent effects in the SN1reaction are due largelyto stabilization ordestabilization of thetransition state.


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Polar Solvents Promote Ionization

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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


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Exercises


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Biological Substitution Reactions

75

SN1 and SN2 reactions are well known in biological chemistry.

Unlike what happens in the laboratory, substrate in biologicalsubstitutions is often organodiphosphate rather than an alkylhalide.


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Factors in Predicting SN1 vs SN2 Mechanisms

Four factors are relevant in predicting whether a given reaction is

likely to proceed by an SN1 or an SN2 mechanism.

3o > 2oNucleophilicstrength notimportant

Good LGimportant to

form C+

Enhanced bymore polar

solvent

CH3 > 1o

> 2o Needs a strong

nucleophile

Not as important

but enhancesreaction

Enhanced by

less polarsolvent

SN1

SN2

Substrate Nucleophile Leaving Group Solvent

Predicting SN1 vs SN2 Mechanisms:


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N N

The Substrate

The most important is the structure of the alkyl halide (substrate).



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N N

The Nucleophile

The strong nucleophile favors an SN2 mechanism.

The weak nucleophile favors an SN1 mechanism.



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The Leaving Group

A better leaving group increases the rate of both SN1 and SN2

reactions.



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The Solvent

The nature of the solvent is the fourth factor.

Polar protic solvents like H2O and ROH favor SN1

reactions because the ionic intermediates (both

cations and anions) are stabilized by solvation.

Polar aprotic solvents favor SN2 reactions because

nucleophiles are not well solvated, and therefore, are

more nucleophilic.


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Results of SN1 vs SN2 Mechanisms

Kinetics:SN1 rate = k[RX]

SN2 rate = k[RX][Nu:]

Stereochemistry:SN1 both inversion and retention (racemic)

SN2 inversion only

Rearrangements:SN1 rearrangements common

SN2 rearrangements not possible


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Exercises


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Exercises


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Exercise

Eli i ti R ti f Alk l H lid


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Elimination Reactions of Alkyl Halides

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A widely used method for synthesizing alkenes is the elimination of HX

from adjacent atoms of an alkyl halide. When the elements of a hydrogen halide are eliminated from a haloalkane

in this way, the reaction is often called dehydrohalogenation:

A hydrogen atom attached to the carbon atom is called a hydrogen atom.

Since the hydrogen atom that is eliminated in dehydrohalogenation isfrom the b carbon atom, these reactions are often called

eliminations.

Eli i ti R ti f Alk l H lid


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Elimination Reactions of Alkyl Halides

There are two idealized mechanisms for -eliminationreactions, E1 and E2.

E1 mechanism: at one extreme, breaking of the R-Lv

bond to give a carbocation is complete before

reaction with base to break the C-H bond. only R-Lv is involved in the rate-determining step (as in SN1)

E2 mechanism: at the other extreme, breaking of the

R-Lv and C-H bonds is concerted (same time).

both R-Lv and base are involved in the rate-determining step(as in SN2)

Mechanisms of Elimination Reactions:

E1 d E2


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E1 Reaction (Unimolecular Elimination)

X- leaves first to generate a carbocation

E2 Reaction (Bimolecular Elimination)

Concerted transfer of a proton to a base and departure of leaving group

E1 and E2

E2 R ti M h i


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E2 = Elimination, Bimolecular (2nd order). Rate = k [RX] [Nu:-]

E2 reactions occur when a 2° or 3° alkyl halide is treated with astrong base such as OH-, OR-, NH2

-, H-, etc.

E2 Reaction Mechanisms

Elimination Reactions of Alkyl Halides:

Z it ’ R l


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Zaitsev’s Rule

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Elimination is an alternative pathway to substitution.

Opposite of addition.

Generates an alkene.

Can compete with substitution and decrease yield, especiallyfor SN1 processes.

Z it ’ R l f Eli i ti R ti


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Zaitsev’s Rule for Elimination Reactions

91

In the elimination of HX from an alkyl halide, the more highly

substituted alkene product predominates.

The E2 Reaction and the Deuterium

I t Eff t


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Isotope Effect

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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.

G t f Eli i ti E2


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Geometry of Elimination – E2

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Antiperiplanar allows orbital overlap and minimizes steric

interactions.

E2 Stereochemistry


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E2 Stereochemistry

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Overlap of the developing orbital in the transition state

requires periplanar geometry, anti arrangement.

Predicting Product


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Predicting Product

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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.

The E2 Reaction and CyclohexaneFormation


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Formation

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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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Just as SN2 reactions are analogous to E2 reactions, so SN1 reactions

have an analog, E1 reaction. E1 = Elimination, unimolecular (1st order); Rate = k [RX]


Slow step Fast step



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E1 eliminations, like SN1 substitutions, begin with unimolecular

dissociation, but the dissociation is followed by loss of a protonfrom the -carbon (attached to the C+) rather than by substitution.

E1 & SN1 normally occur in competition, whenever an alkyl halide istreated in a protic solvent with a nonbasic, poor nucleophile.

As with E2 reactions, E1 reactions also produce the more highly

substituted alkene (Zaitsev‟s rule). However, unlike E2 reactionswhere no C+ is produced, C+ rearrangements can occur in E1reactions.

Example:


Comparing E1 and E2


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Comparing E1 and E2

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Strong base is needed for E2 but not for E1.

E2 is stereospecifc, E1 is not.

E1 gives Zaitsev orientation.

A Comparison of E1 and E2


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CH3

CH3CH3

Br H

H

H

H

H

Zaitsev

Anti-ZaitsevNaOEt

EtOH /

E2

stereospecific

anti

not

stereospecific

E1EtOH /

ant i

syn

major product

E1 doesn’t require

anti-coplanarity

A Comparison of E1 and E2

Correlation of Structure & Reactivity for

S 1 S 2 E1 E2


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SN1, SN2, E1, E2

Halide

Type SN1 SN2 E1 E2

RCH2X

(primary)

Does not

occur

Highly

favored

Does not

occur

Occurs when

strong bases

are used

R2CHX

(secondary)

Can occur

with benzylic

and allylic

halides

Occurs in

competition

with E2

reaction

Can occur

with benzylic

and allylic

halides

Favored when

strong bases

are used

R3CX

(tertiary)

Favored in

hydroxylic

solvents

Does not

occur

Occurs incompetition

with SN2

reaction

Favored when

bases are

used

Mechanism Review:

Substitution vs Elimination


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Substitution vs Elimination

chapter 2 organic reaction types_2015

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