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CATALYST

Acid-base catalytic reaction


CATALYSTS
 Catalysts increase the rate of a reaction by
decreasing the activation energy of the
reaction.
 Catalysts change the mechanism by which
the process occurs.
CATALYSTS

One way a
catalyst can
speed up a
reaction is by
holding the
reactants
together and
helping bonds to
break.
ENZYMES
 Enzymes are
catalysts in
biological systems.
 The substrate fits
into the active site
of the enzyme much
like a key fits into a
lock.
INFLUENCE OF PH ON REACTION RATE
The hydrolysis of esters is catalysed by both acid and base:

H
OH OH O
H2O acid catalysed
H3C H3C OCH 3 H3C OCH 3
hydrolysis
O CH 3 OH2 OH H

O OH O
H2O base catalysed
H3C H3C OCH 3 H3C + CH3O
hydrolysis
O CH 3 O OH
H
OH
log kobs

7.0
pH
Another example: imine formation:

R NH 2 + H+ R NH 3+
nucleophile inactive

C O + H+ C OH

active

log kobs
H2
R NH 2 + C OH R N C OH
4.5
pH

pH optimum ~ 4.5
H
N C HN C R N C OH2
R R

Slope of plot of log kobs vs. pH is often close to 1:


linearly dependent on [H+] or [OH-]
TWO MECHANISMS FOR ACID CATALYSIS
Specific acid catalysis:
- A proton is transferred to the substrate in a rapid preequilibrium;
subsequently, the protonated substrate reacts further to the
product(s) in the rate determining step:

fast
S + HA SH+ + A
slow
SH+ products

General acid catalysis:


- Proton transfer occurs in a slow, rate determining step;
subsequently, the protonated substrate rapidly reacts to give the
product(s):
slow
S + HA SH+ + A
fast
SH+ products
SPECIFIC ACID/BASE CATALYSIS
Usually found for electronegative elements (O, N), where proton transfer is
fast:

K
E + HA EH+ + A fast

The second step is rate determining and can be mono- or bimolecular:

k1 H2O
EH+ products slow (A1 mechanism)
k2
or EH+ + H2O products slow (A2 mechanism)

Reaction rate:
[H 3O+ ][A - ]
[E][HA] since Ka =
ν = k1[EH + ] = k1K [HA]
[A - ]

k 1K
we can now write: ν= [E][H 3O + ] = k'[E][H 3O + ]
Ka
So the rate is only dependent on the pH, not on [HA] !!
SPECIFIC BASE CATALYSIS

Example: the retro-aldol reaction of I:

x
x

O OH O x
CH 3 base kobs x
2
H3C CH 3 H3C CH 3 x
x
I
[OH-]

kobs is directly proportional to [OH-]. Addition of more base


(in buffer) at constant pH has no effect on kobs;
[OH-] is the only base that occurs in the rate equation.
GENERAL ACID/BASE CATALYSIS
Proton transfer is the rate determining step.
Example: the hydrolysis of ortho esters:

OC2H5 O
H+
H3C OC2H5 + H2O H3C + 2 C2H5OH
OC2H5 OC2H5
III

The reaction is studied in a series of


k(buffer)
buffers (m-NO2-Ph-OH/m-NO2-Ph-O–
): reaction rate increases with
n
increasing buffer concentration, even
if the pH remains constant {k(H3O+)[H3O+] + k(H2O)[H2O]}[III]

[buffer]

n = {k(H2O)·[H2O] + k(H3O+)·[H3O+] + k(m-NO2-Ph-OH)·[m-NO2-Ph-OH]}·[I


NUCLEOPHILICITY

WHAT IS A NUCLEOPHILE ? A BASE ?

WHAT MAKES A GOOD NUCLEOPHILE?


NUCLEOPHILES AND BASES
THE FUNDAMENTAL DISTINCTION

Nucleophilicity kinetic (or rate) parameter

Basicity thermodynamic (or equilibrium)


parameter.

All nucleophiles are bases …...


and all bases are nucleophiles.

A good base is not necessarily


HOWEVER : a good nucleophile, and vice versa.
NUCLEOPHILE VERSUS BASE
Nu1 Nu2 is a better
nucleophile
Nucleophilicity = Kinetic
( FASTER RATE )
Rate = k2[RX][Nu]
Nu2

good nucleophile
increases k2
(I.e., the rate)

Nu1 is a
better base
Basicity = Thermodynamic
( STRONGER BOND )
B:- + H+ B-H
strong base
shifts equilib.
DIFFERENT PLACES ON THE ENERGY PROFILE
DETERMINE NUCLEOPHILICITY AND BASICITY

NUCLEOPHILES
Nucleophilicity is
determined here

activation energy
and rate (kinetics)

faster is better
BASES
Basicity is
determined here

strength of bonds
and position of
equilibrium

lower energy is better


IS THE NUCLEOPHILE IMPORTANT
IN BOTH SN1 AND SN2 REACTIONS ?
NUCLEOPHILES
IMPORTANCE IN SN1 AND SN2 REACTIONS

Nucleophiles are unimportant in an SN1 reaction;


they are not involved in the rate-determining step.

SN1 rate = K1 [RX]

The nature of a nucleophile is only important to


an SN2 reaction.

SN2 rate = K2 [RX][Nu]


WHAT IS A
GOOD NUCLEOPHILE ?

SN2 REACTIONS
WHAT IS THE IDEAL NUCLEOPHILE ?
SN2 REACTIONS
LARGE
..
:Y
.. : STERIC PROBLEMS
no way ! bad

R
SMALL
.. -
: ..
X: good C : Br

R
R
Smaller
is better !
For an SN2 reaction the nucleophile must find
the back lobe of the sp3 hybrid orbital that the
leaving group is bonded to.
EXPECTED “IDEAL” NUCLEOPHILES

cyanide
ROD OR SPEAR - :C N:
SHAPED - + -
:N N N:
azide

These types SMALL


should be
SPHERES .. - .. -
able to find :F:
.. :Cl:
.. etc.
the target !

Generally this idea is correct.


OUR NAÏVE EXPECTATION
We would expect the halides to be good nucleophiles:
ionic radii:
1.36 A 1.81 A 1.95 A 2.16 A
smallest
ion

F- Cl- Br - I-

and we would expect the smallest one (fluoride)


to be the best nucleophile,
….. however, that is not usually the case.
EXPERIMENTAL RESULTS
RELATIVE RATES OF REACTION FOR THE HALIDES
MeOH
CH3-I + NaX CH3-X + NaI
-
Rate = k [CH3I] [X ]
SN2
k
F- 5 x 102 slowest
Cl- 2.3 x 104
Br- 6 x 105
I- 2 x 107 fastest
* MeOH solvates like water but dissolves everything better.
SOLVATION

Solvation reverses our ideas of size.


HEAT OF SOLVATION
ENERGY IS RELEASED WHEN AN ION IS PLACED IN WATER

F- gas phase

- 120 Kcal / mole HEAT OF SOLVATION

F- (g) F- (aq)

O H H O The interaction between

F-
SOLVATED the ion and the solvent
H H is a type of weak bond.
ION
Energy is released when
H H it occurs.
O H H O Solvation lowers the
water solution potential energy of the
nucleophile making it
less reactive.
HALIDE IONS
IONIC
RADIUS 1.36 A 1.81 A 1.95 A 2.16 A

smallest
ion

F- Cl- Br - I-

Heats of
solvation
in H2O - 120 - 90 - 75 - 65
Kcal / mole

-
X(H2O)n
increasing solvation
larger n smaller n

SMALL IONS SOLVATE MORE THAN LARGE IONS


H O CH3 O CH3CH2 O R N
H
WATER
H H AS A SOLVENT
H

H H
H O
+ - O O H H
H O - H
M +
H O X-
H
O H
H+ H O
H
H H O
H
polar OH bonds

Water is a polar molecule.


Negative on the oxygen end, and positive on the hydrogen end.
It can solvate both cations and anions.
SMALL IONS SOLVATE MORE HEAVILY THAN LARGE ONE
strong interaction
F
- with the solvent I
-
BETTER
NUCLEOPHILE
O H
H H O
H H O ...smaller
H
-
H O H H solvent shell
O
H H
H H O
H
- H ...escapes
H O H easily
O O solvent H O
H H …more
shell
potential
energy
“Effective size” is larger.
Heavy solvation lowers the weak interaction
potential energy of the nucleophile. with the solvent
It is difficult for the solvated nucleophile
to escape the solvent shell.
This ion is less reactive.
PROTIC SOLVENTS
H
H O CH3 O CH3CH2 O R N
H
H H H
water methanol ethanol amines

H H
Water is an example of a “protic” H O
solvent.
+ - O O H H
H O - H +
X -
H
Protic solvents are thoseM H O
thatOhave
H
H +
O-H, N-H H O
H
or S-H bonds. H O
H
H
Protic solvents can form hydrogen bonds and can
solvate both cations and anions.
LARGER IONS ARE BETTER NUCLEOPHILES
IN PROTIC SOLVENTS
THREE FACTORS ARE INVOLVED :

In protic solvents the larger ions are solvated less


1 (smaller solvent shell) and they are, therefore,
effectively smaller in size and have more potential
energy.

Since the solvent shell is smaller in a larger ion

2 it can more easily “escape” from the surrounding


solvent molecules during reaction. There is more
potential energy.

3 The larger ions are thought (by some) to be


more “polarizable”.
see the next slide …..
POLARIZABILITY
Polarizability assumes larger ions are able to easily
distort the electons in their valence shell, and that
smaller ions cannot.

C Br
VERY
HYPOTHETICAL

The distortion of large ions is easier because the


orbital clouds are more diffuse.

The nucleophile “flows” into the reactive site.


BASICITY
If everything else is equal, the stronger base is
the better nucleophile.

This principle shows up in a period, where


atoms do not vary appreciably in size, and
solvate to similar extents.

OH- is a better nucleophile than F-


NUCLEOPHILICITY TRENDS
IN PROTIC SOLVENTS
OBSERVED NUCLEOPHILICITY TRENDS
H2O OR OTHER “PROTIC” SOLVENTS

GROUP IV V VI VII

increasing nucleophilicity (ROWS) basicity

CH3- NH2- OH- F- increasing


nucleophilicity
PH2- SH- Cl-
(COLUMNS)
Br-
I-
basicity
more solvation,
larger effective size,
lower potential energy
RELATIVE RATES OF SOME NUCLEOPHILE
MeOH
CH3-I + Nu: CH3-Nu + I-
SN2
Rate = k [CH3I] [X-]

CH3OH 1.0 (solvolysis is faster)


F- 5x 102
CH3COO- 2 x 104 NH3 3.2 x 105
Cl- 2.3 x 102 (CH3)2S 3.5 x 105
C6H5NH2 5 x 105
C6H5SH 5 x 105
C6H5O- 5.6 x 105
N3- 6 x 105
Br- 6 x 105
CH3O- 2 x 106 these are the good
CN- 5 x 106 nucleophiles, but
I- 2 x 107 watch out, some
C6H5S- 8 x 109 are strong bases

CHARGED NEUTRAL
APROTIC SOLVENTS
APROTIC SOLVENTS
- O O
-
O H3C CH3
+ +
CH3 S CH3 H C N CH3 N P N
H3C CH3
CH3 N
dimethylsulfoxide H3C CH3
“DMSO” dimethylformamide
“DMF” hexamethylphosphoramide
O “HMPA”

CH3 C CH3 CH3 C N


acetone acetonitrile APROTIC SOLVENTS
DO NOT HAVE
if scrupulously OH, NH, OR SH BONDS
free of water

They do not form


hydrogen bonds.
APROTIC SOLVENTS SOLVATE CATIONS,
BUT NOT ANIONS (NUCLEOPHILES)

H3C S + CH3 crowded

H3C O CH3
-
S O M+ O S X-
- +
H3C O CH3
The nucleophile is
“free” (unsolvated),
CH3 S CH and therefore is small
3 and not hindered by
a solvent shell.
DIMETHYLSUFOXIDE
space-filling

O
S
H H

density - electrostatic potential plot


DIMETHYLFORMAMIDE

CH3
H3C N C H

+ O
M X-
O
nucleophile is “free”
H C N CH3 (unsolvated)

CH3
OBSERVED NUCLEOPHILICITY
APROTIC SOLVENTS

GROUP IV V VI VII

increasing nucleophilicity (ROWS)

CH3- NH2- OH- F- increasing


nucleophilicity
PH2- SH- Cl-
(COLUMNS)
Br-
I-
decreasing basicity
ionic size
The direction of the red arrow (COLUMNS) represents a
different order than in protic solvents.
WHY NOT ALWAYS USE
APROTIC SOLVENTS FOR SN2 ?
Mostly, it is a matter of expense.

Water, ethanol, methanol and acetone are much


cheaper, especially water.

Water “free” DMSO $47.50 / L


Methanol $14.70 / L DMF $33.75 / L
Ethanol $15.35 / L HMPA $163.40 / L
Acetone $16.60 / L

Cheapest grades available, Aldrich Chemical Co., 2000.


SOLVENTS

WHAT ARE GOOD SOLVENTS FOR SN1 AND SN2 ?


SN1 SOLVENTS = POLAR
SN1 reactions prefer polar-protic solvents that
can solvate the anion and cation formed in the
rate-determining step.

ions

R-X rate-determining
R+ + X-
step solvation of both ions
speeds the ionization

Carbocation
SN2 SOLVENTS = NONPOLAR
OR POLAR-APROTIC
SN2 reactions prefer “non-polar” solvents, or
polar-aprotic solvents that do not solvate the
nucleophile.

.. R
: ..
X:

SMALL, C : Br
UNSOLVATED

R
smaller is better ! R
CF3COOH
POLAR POLAR
APROTIC H2O
SOLVENTS
CF3CH2OH

O- HCOOH
+ SN1
CH3 S CH3
O CH3OH
H C N CH3
CH3CH2OH
CH3
O overall
CH3COOH
CH3 C CH3 polarity
SN2 POLAR
CH3CH2 O CH2CH3
PROTIC
CCl4 SOLVENTS

CH3CH2CH2CH2CH3
NONPOLAR
SOLVENTS NONPOLAR
SOLVENT MIXTURES
SOLVENT MIXTURES ARE VERY COMMON

RX Alkyl halides don’t dissolve in water,


but dissolve in most organic solvents.

NaX Nucleophile salts don’t dissolve in most


organic solvents, but dissolve in water.

Both dissolve in a mixed solvent.


miscible solvents
50% EtOH
CH3CH2CH2CH2 Cl + NaBr
50% H2O
soluble in EtOH soluble in H2O
EXCEPTIONS

NaX Dissolve in polar-aprotic organic solvents:


DMF, DMSO, HMPA.

NaI and NaCN dissolve in acetone,


but NaCl and NaBr do not
THE BOTTOM LINE
SN1
CARBOCATIONS REACT WITH ALL NUCLEOPHILES EQUALLY

The nucleophile is not involved in the rate-determining step.

SN2
BETTER NUCLEOPHILES REACT FASTER GIVING MORE PRODUCT

The nucleophile is involved in the rate-determining step.


HARD-SOFT ACID-BASE THEORY
DEFINITIONS
Arrhenius acids form hydronium ions in
water, and bases form hydroxide ions. This
definition assumes that water is the solvent.
Brønsted and Lowry expanded upon the
Arrhenius definitions, and defined acids as
proton donors and bases as proton acceptors.
They also introduced the concept of conjugate
acid-base pairs.
LEWIS ACIDS & BASES
The Lewis definition further expands the
definitions. A base is an electron-pair donor, and
an acid is an electron-pair acceptor. The two
combine to form an adduct.
A + :B  A-B
LEWIS ACIDS & BASES
This definition includes the “standard” Brønsted-
Lowry acid-base reactions:
H+(aq) + :NH3(aq)  NH4+(aq)

It also includes the reactions of metal ions or


atoms with ligands to form coordination compounds:
Ag+(aq) + 2 :NH3(aq)  Ag(NH3)2+(aq)
LEWIS ACIDS & BASES
In addition, electron-deficient compounds such as
trivalent boron is categorized as a Lewis acid.
B(CH3)3 + :NH3  (CH3)3B←NH3
The HOMO on the Lewis base interacts with the
electron pair in the LUMO of the Lewis acid. The MOs
of the adduct are lower in energy.
LEWIS ACIDS & BASES
The LUMO and
HOMO are called
frontier orbitals. If there
is a net lowering of
energy, the adduct is
stable.
BF3 + NH3
The LUMO of the acid, the HOMO of the
base and the adduct are shown below:
LEWIS ACIDS & BASES
There is the possibility of competing reaction
pathways depending upon which reactants are
present, and the relative energies of possible
products. As a result, a compound such as water
may serve as an acid, a base, an oxidizing agent
(with Group IA and IIA metals) or a reducing
agent (with F2).
LEWIS ACIDS & BASES
A Lewis base has an electron pair in its
highest occupied molecular orbital (HOMO) of
suitable symmetry to interact with the LUMO of
the Lewis acid. The closer the two orbitals are in
energy, the stronger the bond in the adduct.
HARD AND SOFT ACIDS AND BASES
The polarizability of an acid or
base plays a role in its reactivity.
Hard acids and bases are small,
compact, and non-polarizable.
Soft acids and bases are larger,
with a more diffuse distribution of
electrons.
HARD AND SOFT ACIDS AND BASES
In addition to their intrinsic strength,

Hard acids react preferentially with hard bases,


and soft acids react preferentially with soft bases.
HARD AND SOFT ACIDS & BASES
There have been many attempts to
categorize various metal ions and anions to
predict reactivity, solubility, etc.
R.G. Pearson (1963) categorized acids and
bases as either hard or soft (using Kf values).

Hard acids bond in the order: F->Cl->Br->I-


Soft acids bond in the order: I- >Br- >Cl- > F-
HARD AND SOFT ACIDS & BASES
Hard acids tend to bind to hard bases.
Soft acids tend to bind to soft bases.
CHARGE DENSITY – HARD ACIDS
Hard acids typically have a high charge
density. They are often metal ions with a
(higher) positive charge and small ionic size.
Their d orbitals are often unavailable to engage
in π bonding.
CHARGE DENSITY – SOFT ACIDS
Soft acids typically have lower charge
density (lower ionic charge and greater ionic
size). Their d orbitals are available for π
bonding. Soft acids are often 2nd and 3rd row
transition metals with a +1 or +2 charge, and
filled or nearly filled d orbitals.
ACID OR BASE STRENGTH
It is important to realize that hard/soft
considerations have nothing to do with acid or
base strength. An acid or a base may be hard or
soft and also be either weak or strong.
In a competition reaction between two bases
for the same acid, you must consider both the
relative strength of the bases, and the hard/soft
nature of each base and the acid.
D. Energetics of Nucleophile-Electrophile Interactions

qn qe 2(cn ce)2
E  
r E HOM O  E LUM O

qn and qe are charges on nucleophile and electrophile, respectively.

cn and ce are orbital coefficients of nucleophile HOMO and electrophile


LUMO, respectively.

β is the resonance integral.

EHOMO = energy of nucleophile HOMO

ELUMO = energy of electrophile LUMO

Electrostatic term: important for interactions of hard acids with hard bases
65
Orbital interaction term: important for interactions of soft acids with soft bases
Bases (nucleophiles)

Type Species Examples


small halide anions F-, Cl-
H2O, ROH, HO-, RO-,
Hard oxygen nucleophiles ROR, MeCO2-, SO42-,
PO43-
amine nucleophiles RNH2, H2NNH2
larger halide anions Br-
Intermediate nitrogen nucleophiles C6H5NH2, C5H5N, N3-
oxygen nucleophiles NO2-, SO32--
sulfur nucleophiles RSR, RSH, RS-
phosphorus R3P, (RO)3P, R3As
Soft nucleophiles
carbon nucleophiles CN-, CO, R-, C2H4, Ar
others H -, I - 66
Acids (electrophiles)

Type Species Examples


high charge/radius H+, Li+, Mg2+, Ca2+, Al3+,
cations Cr3+, Ti4+, I5+
Hard group II species Be(CH3)2
group III species Al(CH3)3, BF3, B(OR)3
H-bond donors ROH, HOH, RNH2,
RNH3+
moderate charge/radius Fe2+, Cu2+, Zn2+, Pb2+,
Intermediate cations Sn2+, Co2+, Ni2+
carbocations (CH3)3C+, ArH+
low charge/radius Cu+, Ag+, Au+, Hg+, Hg2+,
cations I+, Br+, RO+
Soft carbon electrophiles RL, ArL (L = nucleofuge)
diatomic halogens I2, Br2, ICN 67
radicals O, Cl, Br, I, RO 