Limiting Cases: SN1 and SN2 mechanisms
review standard criteria for each mechanism
consider potential energy diagrams to distinguish synchronicity
e.g., SN2 has equal bond-breaking and bond-making (diagonal pathway)
but SN1 has initial bond breaking, followed by bond-making (edge pathway)
Borderline Cases: Solvolysis
solvent as the nucleophile makes kinetic order
indeterminate
(pseudo-first-order because [solvent] is ~ constant)
solvolysis mechanisms are generally distinguishable because for the SN1
mechanism the rate-determining and product-determining steps are not the
same
1) add competitive nucleophiles
if SN2 - rate and products will change
if SN1 - products will change but not rate
2) use different leaving groups and competitive nucleophiles
if SN2 - both rate and product ratio will vary
if SN1 - rates will vary but not the product ratio
The Winstein Ion-Pair Scheme
nucleophile could attack the substrate at any stage of an ionization process
covalent R-X - - -> tight ion pair - - ->
solvent-separated ion pair - - -> free ions (limiting SN1)
(limiting SN2)
if attack by Nu:- is the RDS, observe 2nd-order
if formation of any ion or ion pair is the RDS, observe 1st-order
note that it is possible to have 1st-order kinetics and complete inversion
the overall reaction scheme shifts farther to the right with:
more stable R+
more polar solvent
better leaving group
weaker nucleophile
(all the factors that favor the limiting SN1)
Evidence for Ion Pairs:
the common-ion effect:
the ionization step of an SN1 mechanism could be reversible
apply the steady-state approx. to the cation intermediate
Rate = k1 [RX] { k2 [Nu:-] / ( k-1 [X:-] + k2 [Nu:-] )
(addition of the leaving group ion - common ion - can depress the rate)
(distinguished from the normal salt effect - added salt makes the solvent
more polar - higher ionic strength- and generally increases SN1 rates)
allylic return without a common ion effect:
rearranged allylic chloride appears without a common ion effect
(the rearranged Cl does not come from external Cl - )
racemization and isotopic scrambling rates
Carbocations
nomenclature: generally alkyl cation
Chem Abstracts: alkylium ion
IUPAC: alkenium ion for standard trivalent carbocations (like a protonated
alkene)
alkonium ion for tetravalent or pentavalent "nonclassical" ions
(like a protonated alkane)
protonated alkanes: "magic acid" ( FSO3H / SbF5 / SO2 )
powerful protonating solvent without nucleophile present
observe H/D exchange with methane (CH5+)
observe C-C bond cleavages with higher alkanes
essentially any functional group can be protonated
NMR spectra of many unstable cations observed at low temp
measures of carbocation stability:
solution-phase ionizations ( R-X -----> R+ + X- )
alcohol dehydration equilibria (pKR+)
ROH + H+ <===> R+ + H2O
pKR+ = log([R+]/[ROH]) + HR
HR is an acidity function like Ho but appropriate for the above reaction
structural effects on carbocation stability:
electron-donating groups (inductive/field effects)
alkyl groups (hyperconjugation)
pi bonds (allylic and benzylic systems) (resonance effects)
relatively unstable carbocations:
bridgehead cations (can't be planar)
small ring cations (increased angle strain)
sp2 and sp cations (vacancy in low-energy orbitals)
phenyl cation - empty sp2 orbital, not able to resonance stabilize
vinyl cation - empty p orbital on an sp carbon
Nucleophilicity
The Swain-Scott Equation:
based on SN2 reaction with CH3I, using CH3OH as the reference nucleophile
CH3I + Nu:- ---(kNu)---> CH3-Nu + I-
n = log ( kNu / kMeOH )
can be used to correlate other reactions as an LFER
log ( kNu / kMeOH ) = s n
where s represents the substrate sensitivity to nucleophilicity (rel. to
CH3I = 1)
nucleophilicity vs. basicity:
nucleophilicity - tendency to bond to carbon using a lone pair
basicity - tendency to bond to a proton using a lone pair
nucleophilicity generally parallels basicity - approximation is best when
the series of compounds being compared all use the same atom that acts as
the nucleophile or base
e.g. CH3O- > PhO- > CH3COO- > HSO4-
larger atoms are generally much more nucleophilic
(a polarizability effect and a solvation effect):
e.g. I- > Br- > Cl- > F- and RS- > RO- (for any R)
nucleophilicity is much more susceptible to steric hindrance than basicity
e.g. nucleophilicity often depends on the specific substrate
Hard-Soft Acid-Base Principle:
electrophile/nucleophile (acid/base) reactions are better when matched in
hardness
hard atoms are small, ions have intense charge
(hard acids/electrophiles: H+, Li+, Na+, K+, Mg+2 )
(hard bases/nucleophiles: ROH, RO-, RNH2, NH2-, F-, Cl- )
soft atoms are large, ions have diffuse charge
(soft acids/electrophiles: C-X, Br2, I2, low-valent metals)
(soft bases/nucleophiles: RSH, RS-, R3P, I-, CN- )
hard/hard interactions dominated by electrostatic attraction,
generally involve an early transition state
soft/soft interactions dominated by bond strength,
generally have a late transition state
the C-X bond is generally considered soft, so hard nucleophiles have a greater
tendency to abstract a proton (act as a base), while soft nucleophiles have
a greater tendency to act as a nucleophile (attack carbon)
(affects the competition between substitution and elimination)
the alpha effect:
nucleophiles with an adjacent lone pair are especially good nucleophiles
e.g. peroxides, hydrazine
MO explanation - lone pair repulsions raise HOMO, and are relieved during
rxn
(however, the alpha effect is not seen in the gas phase, suggesting solvation
effects)
solvent effects on nucleophilicity
solvation generally lowers reactivity of a nucleophile
(solvent must be removed at the transition state)
polar, aprotic solvents greatly enhance nucleophilicity over H-bonding solvents
(e.g. DMSO, DMF, CH3CN)
Leaving Group Effects
in general, weaker bases make better leaving groups
HSO4- > ArSO3- > I- > Br- > Cl- > F- > OH- (not a leaving
group)
a range of substituted arene sulfonates are available to fine-tune reactivity
p-CH3- (tosylate) < p-Br- (brosylate) < p-NO2- (nosylate)
CH3SO3- (mesylate) < CF3SO3- (triflate)
both SN1 and SN2 reactions show the same trends, but SN1 is more sensitive
Neighboring Group Participation
involvement of a nearby substituent in a reaction mechanism, usually observed
by effects on the rate (anchimeric assistance) or on the product stereochemistry
Carbocation Rearrangements
carbocations shift a hydride or alkyl group very readily
transition state is a 3-center, 2e- bond (could be an intermediate in some
cases)
for formation of more stable ions or even an equivalent ion, barriers are
very small
e.g. Me3C-C+Me2 shows scrambling of all 5 Me groups at -160· (Ea
< 5 kcal/mole)
even rearrangements through a less stable 2' ion are feasible
e.g. scrambling of Me groups in t-pentyl goes from 3· via 2·
(Ea ~ 10-15 kcal/mole)
1' cations are unlikely intermediates (too high
in energy)
most reactions that might involve 1' cations probably are concerted
(simultaneous shift of the rearranging group as the leaving group leaves)
Nonclassical Ions
2-norbornyl solvolysis
1) exo isomer reacts 350 x faster than endo
(NGP by the sigma bond located behind the leaving group)
2) both exo and endo give only exo products
(the cation can only be attacked from the front)
3) optically active exo gives racemic exo
(either a C or H shift could racemize the cation, or it is symmetrical)
4) optically active endo gives slight excess of inversion
(SN2 competes with NGP when NGP is slow)
5) for exo, loss of optical activity > formation of product
(starting material racemizes by ion pair return)
6) for endo, loss of optical activity = formation of product
(there is no ion-pair return to regenerate endo starting material)
7) 13C NMR of the cation observed in "magic acid" at low temp.
shows 3 absorptions
C-1, C-2, and C-6 are equivalent, C-3, C-5, and C-7 are equivalent, C-4
is unique
8) XPS studies support a single delocalized cation (time scale ~10-15 sec)
e.g. compare tBu cation: 3 neutral C, 1 C at 3.9 eV higher energy
2-norbornyl cation: 5 neutral C, 2 C at 1.5 eV higher energy
Electrophilic Aromatic Substitution
general mechanism includes pi complexes
and a sigma complex:
ArH + E+ ---> {ArH...E+} ---> ArEH+ ---> {ArE...H+} ---> ArE
+ H+
pi complex is a nonspecific donor-acceptor complex
sigma complex includes formation of a new sigma bond and fixes the site
of the reaction
(most commonly, formation of the sigma-complex is the rate-determining step
- it is the only stage of the reaction in which aromatic stabilization is
lost)
Evidence for the Mechanistic Steps of Electrophilic
Aromatic Substitution
1) Formation of a reactive electrophile
a powerful electrophile is needed in order to disrupt aromaticity
NO2+ has been prepared in other ways and also carries out nitration reactions
carbocations from a variety of sources carry out Friedel-Crafts reactions
this step is only rarely the rate-determining step
(if so, the rate is observed to be independent of the aromatic substrate)
2) Formation of a pi-complex between the electrophile and aromatic compound
similar charge-transfer or donor-acceptor complexes are observed spectroscopically
in nonreacting systems
e.g. HCl + benzene:
forms a complex that is non-conducting and doesn't exchange with C6D6
similar complexes with alkenes + halogens or Ag+
pi-complexes usually are not kinetically significant
3) Formation of a sigma-complex
stability of the sigma-complex generally parallels reactivity (formation
is RDS)
sigma-complexes (also called benzenium ions) have been isolated in some
cases
sigma-complexes are electrically conductive, generally
colored intermediates
similar benzenium ions are formed by protonations in magic acid
some sigma-complexes have been trapped by nucleophiles
4) Proton loss (possible isotope effects)
loss of H+ is generally after the RDS, in which case no isotope effect is
observed
if addition of the electrophile is reversible, small isotope effects can
be observed
Substituent Effects on Reactivity and Selectivity
kinetic effects:
activating - substituent increases rate of reaction
deactivating - substituent decreases rate of reaction
effect caused by relative electron density in the aromatic ring
orientation effects:
ortho, para-directing - substituent causes preference for ortho and para
substitution
meta-directing - substituent causes preference for meta substitution
effect caused by the ability of the substituent to stabilize a + charge
in the various resonance forms of the sigma-complex
generally, electron-donating substituents are activating, o,p-directors
(substitution is better at all positions than in benzene, but ortho &
para are especially stable because of direct interaction with the + charge)
generally, electron-withdrawing substituents are deactivating, m-directors
(substitution is worse at all positions than in benzene, but ortho &
para are especially unstable because of direct interaction with the + charge)
the halogens are the major exception - they are deactivating but o,p-directors
(they reduce the overall electron density in the ring, but they can stabilize
the ortho and para positions by resonance)
Partial Rate Factors
defined for a particular reaction, a partial rate factor is the reactivity
of a given position on a monosubstituted benzene relative to one position
of benzene
e.g., for the bromination of toluene, fo = 600, fm = 5.5, fp = 2420
partial rate factors are obtained from product
ratios and relative rates
product ratios: ortho = 1200/3631 = 33%
meta = 11/3631 = 0.3%
para = 2420/3631 = 67%
reactivity (compared to benzene): 3631/6 = 605 x more reactive
partial rate factors provide clear and direct measures of the reactivity
and selectivity effects of a substituent
since partial rate factors are a relative rate, they can be fit to a Hammett
equation
substitution patterns in di- and polysubstituted benzenes can be predicted
Nucleophilic Aromatic Substitution
note that the usual SN1 and SN2 mechanisms are not feasible for an aryl
halide
phenyl cations are very unstable (a vacant sp2 orbital - note there is no
conjugation with the pi system in the ring)
The SNAr Mechanism
addition-elimination mechanism
(conversion from sp2 to sp3 to sp2, analogous to the tetrahedral intermediate)
note that effective substitution can only occur
if attack is at a carbon bearing a leaving group (H: - is a poor leaving group)
the Meisenheimer complex is the anion analog of the sigma-complex
the pentadienyl anion is delocalized and is strongly stabilized by electron-withdrawing
groups ortho and/or para
(typically the reaction requires such activating
groups, such as nitro)
the RDS is the addition step, loss of leaving group is relatively fast
the order of reactivity of the halogens depends
on the ability to stabilize the Meisenheimer complex:
F > Cl > Br > I
pyridine rings and related heterocycles are susceptible to nucleophilic
substitution
The Benzyne Mechanism
elimination-addition mechanism via benzyne intermediate
note that the nucleophile can attach at either
of two positions of the "triple bond"
para starting material could give meta or para
meta starting material could give ortho or meta or para
ortho starting material could give ortho or meta
existing substituents have only slight directing effects:
electron-withdrawal favors the anion closer (nucleophile farther)