11. Reactions of Alkyl Halides:Nucleophilic Substitutions
andEliminationsBased on McMurrys Organic Chemistry, 6thedition
Nucleophiles and Leaving Groups:
Alkyl Halides React with Nucleophiles Alkyl halides are
polarized at the carbon-halide bond,making the carbon electrophilic
Nucleophiles will replace the halide in C-X bonds ofmany alkyl
halides(reaction as Lewis base) Nucleophiles that are strong
Brnsted bases canproduce elimination
Reaction Kinetics The study of rates of reactions is called
kinetics The order of a reaction is sum of the exponents of
theconcentrations in the rate law the first example is firstorder,
the second one second order.NaOH + CCH3CH3CH3 Br NaBr + CCH3CH3CH3
OHv = k[C4H9Br]NaOH + NaBr +v = k[CH3Br][NaOH]CH3Br CH3OH
11.4 The SN1 and SN2 Reactions Follow first or second order
reaction kinetics Ingold nomenclature to describe characteristic
step: S=substitution N (subscript) = nucleophilic 1 = substrate in
characteristic step (unimolecular) 2 = both nucleophile and
substrate incharacteristic step (bimolecular)
Stereochemical Modes ofSubstitution Substitution with
inversion: Substitution with retention: Substitution with
racemization: 50% - 50%
SN2 Process The reaction involves a transition state in which
bothreactants are together
Walden Inversion
SN2 Transition State The transition state of an SN2 reaction
has a planararrangement of the carbon atom and the remainingthree
groups
Steric Effects on SN2 ReactionsThe 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
SN2reactions.
Steric Hindrance Raises TransitionState Energy Steric effects
destabilize transition states Severe steric effects can also
destabilize groundstateVery hindered
Order of Reactivity in SN2 The more alkyl groups connected to
the reactingcarbon, the slower the reaction
11.5 Characteristics of the SN2Reaction 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)
The SN1 Reaction Tertiary alkyl halides react rapidly in protic
solventsby a mechanism that involves departure of theleaving group
prior to addition of the nucleophile Called an SN1 reaction occurs
in two distinct stepswhile SN2 occurs with both events in same
step
Stereochemistry of SN1 Reaction The planarintermediateleads to
loss ofchirality A freecarbocation isachiral Product isracemic or
hassome inversion
SN1 in Reality Carbocation is biased to react on sideopposite
leaving group Suggests reaction occurs with carbocationloosely
associated with leaving group duringnucleophilic addition
Effects of Ion Pair Formation If leaving group
remainsassociated, thenproduct has moreinversion than retention
Product is only partiallyracemic with moreinversion than retention
Associated carbocationand leaving group is anion pair
SN1 Energy Diagram Rate-determining step isformation of
carbocationStep through highest energypoint is rate-limiting (k1
inforward direction)k1 k2k-1V = k[RX]
11.9 Characteristics of the SN1Reaction Tertiary alkyl halide
is most reactive bythis mechanism Controlled by stability of
carbocation
Delocalized Carbocations Delocalization of cationic charge
enhances stability Primary allyl is more stable than primary alkyl
Primary benzyl is more stable than allyl
Comparison: Substitution Mechanisms SN1 Two steps with
carbocation intermediate Occurs in 3, allyl, benzyl SN2 Two steps
combine - without intermediate Occurs in primary, secondary
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
Relative Reactivity of Nucleophiles Depends on reaction and
conditions More basic nucleophiles react faster (for
similarstructures. See Table 11-2) Better nucleophiles are lower in
a column of theperiodic table Anions are usually more reactive than
neutrals
The Leaving Group A good leaving group reduces the barrier to
areaction Stable anions that are weak bases are usuallyexcellent
leaving groups and can delocalize charge
Super Leaving Groups
Poor Leaving Groups If a group is very basic or very small, it
is preventsreaction
Effect of Leaving Group on SN1 Critically dependent on leaving
group Reactivity: the larger halides ions are betterleaving groups
In acid, OH of an alcohol is protonated and leavinggroup is H2O,
which is still less reactive than halide p-Toluensulfonate (TosO-)
is excellent leaving group
Allylic and Benzylic Halides Allylic and benzylic intermediates
stabilized bydelocalization of charge (See Figure 11-13) Primary
allylic and benzylic are also more reactivein the SN2
mechanism
The Solvent Solvents that can donate hydrogen bonds (-OH or NH)
slow SN2 reactions by associating with reactants Energy is required
to break interactions betweenreactant and solvent Polar aprotic
solvents (no NH, OH, SH) form weakerinteractions with substrate and
permit faster reaction
Polar Solvents Promote Ionization Polar, protic and unreactive
Lewis base solventsfacilitate formation of R+ Solvent polarity is
measured as dielectricpolarization (P)
Solvent Is Critical in SN1 Stabilizing carbocation also
stabilizesassociated transition state and controls rateSolvation of
a carbocation bywater
Effects of Solvent on Energies Polar solvent stabilizes
transition state andintermediate more than reactant and
product
Polar aprotic solvents Form dipoles that have well localized
negativesides, poorly defined positive sides. Examples: DMSO, HMPA
(shown here)+-++OPN N NCH3CH3CH3CH3CH3CH3
Common polar aprotic
solventsCH3SOCH3OPNNNCH3CH3CH3CH3CH3CH3CHONCH3CH3SO
Odimethylsulfoxide (DMSO)hexamethylphosphoramide
(HMPA)N,N-dimethylformamide (DMF)sulfolane
SN1: Carbocation not very encumbered,but needs to be solvated
in ratedetermining stepPolar protic solvents are good because they
solvate both the leavinggroup and the carbocation in the rate
determining step k1!The rate k2 is somewhat reduced if the
nucleophile is highly solvated,but this doesnt matter since k2 is
inherently fast and not ratedetermining.(slow)
SN2: Things get tight if highly solvatednucleophile tries to
form pentacoordiantetransition statePolar aprotic solvents favored!
There is no carbocation to be solvated.
Nucleophiles in SN1 Since nucleophilic addition occurs
afterformation of carbocation, reaction rate is notaffected
normally affected by nature orconcentration of nucleophile
11.10 Alkyl Halides: Elimination Elimination is an alternative
pathway to substitution Opposite of addition Generates an alkene
Can compete with substitution and decrease yield,especially for SN1
processes
Zaitsevs Rule for EliminationReactions (1875) In the
elimination of HX from an alkyl halide, the morehighly substituted
alkene product predominates
Mechanisms of EliminationReactions 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 anddeparture of leaving group
11.11 The E2 Reaction Mechanism A proton is transferred to base
as leaving groupbegins to depart Transition state combines leaving
of X and transfer ofH Product alkene forms stereospecifically
Geometry of Elimination E2 Antiperiplanar allows orbital
overlap and minimizessteric interactions
E2 Stereochemistry Overlap of the developing orbital in the
transitionstate requires periplanar geometry, anti
arrangementAllows orbital overlap
Predicting Product E2 is stereospecific
Meso-1,2-dibromo-1,2-diphenylethane with basegives cis 1,2-diphenyl
RR or SS 1,2-dibromo-1,2-diphenylethane gives
trans1,2-diphenyl(E)-1bromo-1,2-diphenylethene
11.12 Elimination From Cyclohexanes Abstracted proton and
leaving group should aligntrans-diaxial to be anti periplanar (app)
inapproaching transition state (see Figures 11-19 and11-20)
Equatorial groups are not in proper alignment
11.14 The E1 Reaction Competes with SN1 and E2 at 3 centers V =
k [RX]
Stereochemistry of E1 Reactions E1 is not stereospecific and
there is no requirementfor alignment Product has Zaitsev
orientation because step thatcontrols product is loss of proton
after formation ofcarbocation
Comparing E1 and E2 Strong base is needed for E2 but not for E1
E2 is stereospecifc, E1 is not E1 gives Zaitsev orientation
11.15 Summary of Reactivity: SN1,SN2, E1, E2 Alkyl halides
undergo different reactions incompetition, depending on the
reacting molecule andthe conditions Based on patterns, we can
predict likely outcomes
Special cases, both SN1 and SN2blocked (or exceedingly
slow)BrBrBrCH3CH3CH3CH2BrCarbocation highly unstable, attack from
behind blockedCarbocation highly unstable, attack from behind
blockedCarbocation would be primary, attack frombehind difficult
due to steric blockageCarbocation cant flatten out as required by
sp2hybridization, attack from behind blockedAlso: elimination not
possible, cant place doublebond at bridgehead in small cages
(Bredts rule)
Kinetic Isotope Effect Substitute deuterium for hydrogen at
position Effect on rate is kinetic isotope effect (kH/kD =deuterium
isotope effect) Rate is reduced in E2 reaction Heavier isotope bond
is slower to break Shows C-H bond is broken in or before
rate-limiting step
64 www.ulm.edu/~junk/examkeys/pp230_10_ch11.ppt 31 januari
2010