Tema 1 QOIII Mod

Tema 1
Catàlisi en reaccions orgàniques
Química Orgànica III Llibres de referència:

Universitat de Barcelona Química Orgánica (5ª ed.)- capítols
23 (23.1-23.7) i 10 (10.13)
Organic Chemistry (8ª ed.) -
chapters 22 (22.1-22.7) and 11 (11.4-
11.5)
Paula Yurkanis Bruice
1
Editorial Pearson
Química Orgànica III – Universitat de Barcelona
Catalitzadors
A catalyst is a substance that increases the rate of a chemical reaction without

itself being consumed or changed in the reaction.
The rate of a chemical reaction depends on the energy barrier of the rate-
determining step that must be overcome in the process of converting reactants
into products.
The height of the “energy hill” is indicated by the free energy of activation (∆G‡).
A catalyst increases the rate of a chemical reaction by

providing a pathway with a lower ∆G‡
2
Catalitzadors
A catalyst can decrease ∆G‡ in one of three ways:
The catalyzed and uncatalyzed reactions have different, but similar,
mechanisms, with the catalyst providing a way to make the reactant more
reactive (the reactant is converted into a less stable species).
3
Catalitzadors
The catalyzed and uncatalyzed reactions have different, but similar, mechanisms,
with the catalyst providing a way to make the transition state more stable
4
Catalitzadors
The catalyst can completely change the mechanism of the reaction, providing
an alternative pathway with a smaller ∆G‡ than the uncatalyzed reaction
5
Catalitzadors
Catalysts are not changed or consumed by a reaction
A catalyst increases the rate of a chemical reaction by providing a pathway with a

lower ∆G‡ - it can do so in one of three ways-
While a catalyst is neither consumed nor changed by a reaction, it must participate
in the reaction to make it go faster – a catalyst may be consumed or changed
during the reaction, but at the end has the same form as at the start of the reaction
Only a small (“catalytic”) amount of catalyst is needed - this is typically 1 -

10% of the number of moles of reactant
Catalysts change the rate constant, not the equilibrium constant
A catalyst does not change the equilibrium constant (∆G°) of the reaction -
the stability of the original reactant and final products is the same for
uncatalyzed and catalyzed reactions
A catalyst does not change the equilibrium constant (∆G°, the amount
of product), only the rate at which the product is formed (∆G‡)
6
Catalitzadors en reaccions orgàniques
How a catalyst can provide a more favorable pathway for a reaction?
A catalyst can increase:

• the susceptibility of an electrophile to nucleophilic attack.
• the reactivity of a nucleophile.
• the leaving propensity of a group by converting it to a weaker base.
• the stability of a transition state.
7
Catàlisi àcida
Acid catalyst - increases the rate of a reaction by donating a proton to a reactant

mechanisms, with the catalyst providing a way to convert the reactant into a
more reactive species (less stable)
Examples:
Addition of water or alcohol to alkene requires protonation by acid - increase the
susceptibility of an electrophile to nucleophilic attack
Substitution or elimination reactions of alcohols require acid to protonate the OH
group - increase the leaving ability of a group by conversion to a weaker base
Acid-catalyzed hydrolysis of an ester
A catalyst must increase the rate of a slow step, because increasing the
rate of a fast step will not increase the rate of the overall reaction
8
Catàlisi àcida
Acid-catalyzed hydrolysis of an ester requires acid for formation and
collapse of the tetrahedral intermediate
9
Catàlisi àcida
How an acid catalyzes the first slow step?
The catalyst increases the electrophilicity of the carbonyl

carbon (makes it more susceptible to nucleophilic addition).
10
Catàlisi àcida
How an acid catalyzes the second slow step?
The catalyst decreases the basicity of the leaving

group (increases its propensity to leave).
pKa CH3OH= 15,7

pKa CH3OH2+= -2,5
11
Catàlisi àcida
There are two types of acid catalysis:
Specific acid catalysis - the proton is fully transferred to the reactant before the
slow step of the reaction - the catalyst provides a way to convert the reactant into
a less stable species
General acid catalysis - the proton is transferred to the reactant during the slow
step of the reaction - the catalyst provides a way to make the transition state more
stable
12
Catàlisi àcida
In specific-acid catalysis, the proton is transferred to the reactant
before the slow step.
A specific-acid catalyst must be a strong enough acid (HCl, H3O+) to protonate

13
the reactant fully before the slow step begins.
Catàlisi àcida
In general-acid catalysis, the proton is transferred to the reactant
during the slow step.
A general-acid catalyst can be a weaker acid because it has only a partially

14
transferred proton in the transition state of the slow step.
Catàlisi bàsica
Base catalyst - increases the rate of a reaction by removing a proton from the
reactant
mechanisms, with the catalyst providing a way to make the transition state
more stable
Examples:
Enediol rearrangement of a monosaccharide - increase the stability of

a transition state
Interconversion of keto and enol tautomers - increase the stability of a
transition state
Dehydration of a hydrate in the presence of hydroxide ion - increase
the stability of a transition state
15
Catàlisi bàsica
In specific-base catalysis, the proton is removed from the reactant
before the slow step of the reaction.
The transition state for the elimination of a hydroxide ion from a negatively charged
tetrahedral intermediate is more stable because a positive charge does not develop on
the electronegative oxygen atom, as it does in the transition state for the elimination of
16
hydroxide ion from a neutral intermediate.
Catàlisi bàsica
In general-acid catalysis, the proton is removed from the reactant during the
slow step of the reaction.
In specific-base catalysis, the base has to be strong enough to remove a proton

from the reactant completely before the slow step begins.
General-base catalysis can proceed with weaker bases, since the proton is only
partially transferred to the base in the transition state of the slow step.
Enzymes catalyze reactions using general-acid and general-base catalysis because

at physiological pH (7.4), the concentration of H+ or OH- (~1 x 10-7 M) is too small
for specific-acid/base catalysis.
17
Catàlisi nucleòfila
Nucleophilic catalyst - increases the rate of a reaction by acting as a nucleophile

and forming a covalent bond with the reactant (nucleophilic catalysis is also known
as covalent catalysis)
The catalyst completely change the mechanism of the reaction, providing an
alternative pathway with a smaller ∆G‡ than the uncatalyzed reaction
Example 1: Nucleophilic substitution reactions
18
Example 1: Nucleophilic substitution reactions
In the uncatalyzed reaction (absence of iodide ion), ethyl chloride is converted to

ethanol in an SN2 reaction:
If iodide ion is present in the reaction mixture, then the reaction takes place by two
successive SN2 reactions:
Iodide ion is a nucleophilic catalyst because it reacts as a nucleophile, forming a

covalent bond with the reactant. The iodide ion consumed in the first reaction is
19
regenerated in the second.
Example 2: Imidazole-catalyzed ester hydrolysis
The uncatalyzed hydrolysis of an ester (absence of imidazole) is very slow

because water is a poor nucleophile, esters are not very electrophilic and
phenoxide is a poor leaving group
20
In the catalyzed reaction:
Imidazole is a better nucleophile than water.

An acyl imidazole hydrolyzes more rapidly than an ester because imidazole is a
better leaving group than a phenolate ion.
21
Catàlisi per ions metàl·lics
Metal ions exert their catalytic effect by coordinating (complexing) with atoms that
have lone-pair electrons. They are Lewis acids.
A metal ion can increase the rate of a reaction in the following ways:
A – by making a reaction center more susceptible to receiving electrons

B – by making a leaving group a weaker base (and better leaving group)
C – by making water a better nucleophile
In A and B, the metal ion exerts the same kind of catalytic effect as a proton
does. However, a metal ion can be a much more effective catalyst than a proton,
because metal ions can have a charge greater that +1. 22
Metal-bound hydroxide ion is a better nucleophile than water.
Complexation of water to a metal decreases the pKa, increasing the tendency of

water to lose a proton - while metal-bound hydroxide is not as good a nucleophile
as hydroxide, it is better than water, and can be generated at reasonable
concentrations at physiological pH
23
Example 1: Cu2+ or Al3+ catalyzed decarboxylation of dimethyloxaloacetate
Complexation of the metal ion with two oxygen atoms of the reactant increases
the rate of decarboxylation by making the carbonyl oxygen more susceptible to
receiving the electrons left behind when CO2 is eliminated:
24
Example 2: Zn2+ catalyzed hydrolysis of methyl trifluoroacetate
Metal-bound hydroxide is a better nucleophile than water.
The metal ion also decreases the basicity of the leaving group.
25
Reaccions intramoleculars
The rate of a chemical reaction depends on the energy barrier (∆G‡) that must be
overcome in the process of converting reactants into products.
It can be determined by the number of molecular collisions with sufficient
energy and with the proper orientation in a given period of time:
What are ways to affect this rate?

Increasing the concentration of the reactant, increases the frequency of the
collisions.
Because a catalyst decreases the energy barrier of the reaction, it increases the
fraction of collisions that occur with sufficient energy to overcome the barrier
Intramolecular reactions: Putting the reacting groups in the same molecule
increases the frequency of the collisions and possibly the probability that
collisions will occur with the proper orientation
26
Relative rates of an intermolecular reaction and intramolecular reactions
27
Relative rates are obtained by dividing the rate constant for each of the reactions by
the rate constant for the slowest reaction in a series.
Because an intramolecular reaction is a first-order reaction and an
intermolecular reaction is a second-order reaction, the relative rates in the table
have units of molarity (M):
The relative rate is also called the effective molarity.
Effective molarity is the [reactant] that would be required in an intermolecular

reaction for it to have the same rate as the intramolecular reaction
The effective molarity is the advantage given to a reaction by having the

reacting groups in the same molecule.
28
The rate of the intramolecular reaction is 1000 times faster than the rate of the
intermolecular reaction.
29
Why five-membered ring formation is faster than six-membered ring formation?
Because the reactant in D

has fewer bonds that are free
to rotate, the groups are more
apt to be in a conformation
than is favorable for a
reaction. Therefore, reaction
D is faster than reaction B.
30
Relative rates of an intermolecular reaction and intramolecular reactions
31
Catàlisi intramolecular
When a catalyst is part of the reacting molecule, the catalysis is called
intramolecular catalysis. “Intramolecular catalysis”, “neighboring group
participation” and “anchimeric assistance” are interchangeable terms
Intramolecular general-acid or general-base catalysis, intramolecular
nucleophilic catalysis, and intramolecular metal-ion catalysis are all possible.
Uncatalyzed reaction:
Two products are formed because there are two nucleophiles

Water and ethanol are not great nucleophiles and chloride is not
a great leaving group
32
Uncatalyzed reaction:
Catalyzed reaction:
Putting a reacting group and a catalyst in the same molecule increases the rate
of the reaction.
If the thio substituent is trans, the compound reacts 70.000 times faster than
the unsubstituted compound. However, if the thio substituent is cis, the 33
compound reacts at about the same rate as the unsubstituted compound.
Intramolecular nucleophilic catalysis:
When the thio substituent is trans to the chloride, the substituent can be an
intramolecular nucleophilic catalyst (it attacks the back side of the carbon to which
the chloro substituent is attached by an SN2 reaction).
Subsequent attack by water or ethanol on the sulfonium ion is rapid because
breaking the three-membered ring releases strain and the positively charged sulfur is
an excellent leaving group. 34
Intramolecular general-base catalysis:
The rate of hydrolysis of phenyl acetate is increased about 150-fold at neutral pH by
putting a carboxylate ion in the ortho position.
35
The ortho-carboxy group is an intramolecular general-base catalyst that increases
the nucleophilicity of water, thereby increasing the rate of formation of the
tetrahedral intermediate.
If there are nitro groups on the benzene ring, the ortho-carboxy substituent acts as
an intramolecular nucleophilic catalyst instead of an intramolecular general-base
catalyst. The carboxy group increases the rate of hydrolysis by converting the ester
to an anhydride, which is more rapidly hydrolyzed than an ester.
36
Catàlisi per metalls de transició
Palladium-catalyzed coupling reactions
Methods that use transition metals to carry out coupling reactions have expanded the
synthetic chemist’s arsenal of reactions that form carbon-carbon bonds.
The Suzuki and Heck Reactions use a palladium catalyst
Both reactions form a new C-C

bond by replacing the halogen of
a vinylic halide or an aryl halide
with a carbon-containing group.
They are substitution reactions.
The palladium atom of the

catalyst is coordinated with
ligands (L2Pd). A common ligand
is triphenylphosphine (PPh3).
37
The Suzuki and Heck Reactions use a palladium catalyst (L2Pd)
Both reactions occur via a catalytic cycle in which the palladium atom participates
in breaking bonds in the reactants and forming the new C-C bond in the product.
The first step of each cycle is the insertion of Pd between the carbon and halogen
to form an organopalladium compound (oxidative addition).
vinylic halide
aryl halide
If the organopalladium compounds has a β-hydrogen on an sp3 carbon, an

elimination reaction will rapidly occur instead of a coupling reaction.
This is the reason why only vinylic and aryl 38

halides are the reactants in these reactions.
The Suzuki and Heck Reactions use a palladium catalyst (L2Pd)
The reactions can be carried out if the reactants have other functional groups.
The reactions are stereospecific: the configuration of the double bond in a vinylic
halide is retained in the product.
The reactions are very efficient, often requiring less than 0.1% of the palladium
catalyst (compared to the reactants) and giving high yields of products (80-98%).
39
Reacció de Suzuki
The Suzuki reaction
It couples the R group of a vinylic or aryl halide with the R’ group of an
organoboron compound in a basic solution in the presence of a Pd catalyst.
The R group of an organoboron compound replaces a halogen in the

vinylic or aryl halide.
40
Reacció de Suzuki
The Suzuki reaction
The R’ group of the organoboron compound can be an alkyl, alkenyl, or aryl group.
41
Reacció de Suzuki
The Suzuki reaction
The R’ group of the organoboron compound can be an alkyl, alkenyl, or aryl group.
- When the reactant is a vinylic halide, the configuration of its double bond is retained
in the product.
- With alkehyl-organoboron compounds, the new double bond in the product is always
trans because an alkenyl-organoboron compound has a trans configuration.
42
Reacció de Suzuki
Mechanism for the Suzuki reaction
The mechanism for the Suzuki
reaction depends on the ligand (L)
and the base. In the case of using 1
PPh3 and hydroxide, the
mechanism for the reaction is:
2
Step 1 - The catalyst (L2Pd) is generated in
situ by two successive dissociations of a
ligand from the more stable precatalyst (L4Pd) 5
Step 2 - Palladium is inserted between
the carbon and the halogen in the vinylic
or aryl halide.
Step 3 - Hydroxide ion displaces the
halide ion.
Step 4 - The R’ group is transferred 3
from boron to Pd as hydroxide ion is
transferred from Pd to boron.
Step 5 - Palladium is eliminated and
a new C-C bond is formed. The
catalyst can now react with another 4
43
molecules of vinylic or aryl halide.
Reacció de Suzuki
Mechanism for the Suzuki reaction
The mechanism for the Suzuki
reaction depends on the ligand (L)
and the base. In the case of using
PPh3 and hydroxide, the
mechanism for the reaction is:
The first step is an oxidative addition

(insertion of a metal between two atoms).
0 +2
L2Pd L2Pd(X)R
The last step is a reductive

elimination (two groups are
eliminated from the metal).
44
Reacció de Suzuki
Preparation of organoboron compounds for Suzuki reactions
An alkyl-organoboron compound is prepared by hydroboration of a terminal alkene.
An alkenyl-organoboron compound is prepared by hydroboration of a terminal alkyne.
Catecholborane is often used as

the boron-containing compound
45
Reacció de Suzuki
Preparation of organoboron compounds for Suzuki reactions
An aryl-organoboron compound is prepared from an organolithium compound and

trimethylborate.
46
Reacció de Heck
The Heck reaction
It couples the R group of a vinylic or aryl halide with an alkene in the presence of
a base (triethylamine) and a Pd catalyst.
- Like the Suzuki reaction, the Heck reaction is a substitution reaction in which
the R group of the vinylic or aryl halide replaces a vinylic hydrogen of an
alkene.
- The new C-C bond joins two sp2 carbons.
- If there is a substituent attached to the alkene (Z), the R group will be trans to
that substituent in the product.
47
Reacció de Heck
The Heck reaction
The new C—C bond joins two sp2 carbons.
48
Reacció de Heck
Mechanism for the Heck reaction
1
8 2
Step 1 - The catalyst (L2Pd) is generated
by two successive dissociations of a
ligand from the precatalyst (L4Pd)
Step 2 - Palladium is inserted
between the carbon and the
halogen (oxidative addition). 7 3
Step 3 - The alkene displaces
one of the ligands (L).
Step 4 - Because carbon is
more electronegative than Pd,
6
R adds to the sp2 carbon of the
alkene (acts as a nucleophile)
and the electrons of the p bond 5 4
add to Pd. This is a concerted
syn addition.
49
Reacció de Heck
Mechanism for the Heck reaction
1
8 2
Step 5 - Rotation around the C-C bond
provides the conformed required for the
next step.
Step 6 - An hydride is transferred
to palladium and the electrons of
the Pd-C bond form the p bond. 7 3
This intramolecular reaction is a
concerted syn elimination with a
hydride being eliminated from a b-
carbon.
Step 7 - A ligand (L) displaces 6
the alkene.
Step 8 - Reductive elimination 5 4
regenerates the catalyst and
forms HBr, which reacts with NEt3
and prevents addition to the
alkene.. 50
Reacció de Heck
The Heck reaction leads to a high yield of a single product only in the
following situations:
- If the the alkene is symmetrical

- If one of the sp2 carbons is sterically hindered to the addition of the
nucleophile. Therefore, internal alkenes are much less reactive than
less sterically terminal alkenes, so internal alkenes are generally not
employed in Heck reactions
- If one of the sp2 carbons is bonded to a group that can withdraw
electons by resonance (C=O, CN)
The electron-withdrawing group makes one carbon more electrophilic.
51
Metàtesi d’olefines
Alkene metathesis (olefin metathesis)
Alkene metathesis is a reaction that breaks the double bond in an alkene and
rejoins the fragments.
When the fragments are joined, each new double bond is formed between
two sp2 carbons that were not previously bonded.
There are two ways the fragments can be joined:
Terminal alkenes give the best yield of a single alkene product because one
of the new alkene products is ethene, which is a gas and it is removed from
52
the mixture as it is formed.
Alkene metathesis requires a transition metal catalyst. Ruthenium catalysts

such as Grubbs catalysts have been found to be the ones most tolerant with
other functional groups.
There are several generations of Grubbs catalysts,

each with different ligands (L).
53
Alkene Metathesis forms E and Z isomers
Two different alkenes can be used as starting materials in alkene metathesis
If the reactant is a diene, ring-closing metathesis can occurs:
54
Mechanism for Alkene Metathesis
Metathesis occurs in two phases.
The first phase creates two metal-containing intermediates. In each intermediate,

the metal is bonded to an sp2 carbon of the starting alkene.
55
Mechanism for Alkene Metathesis (Phase 1)
Step 1 - The Grubbs catalyst and the starting alkene undergo a [2+2] cycloaddition reaction,
which forms two different metallocyclobutane intermediates (the metal can bond to either sp2
carbon of the alkene).
Step 2 – Each of the metallocyclobutane intermediates undergo a ring-opening
reaction, leading to two metal-containing intermediates (I and II).
56
Mechanism for Alkene Metathesis (Phase 2)
In the second phase, each metal-containing intermediate undergoes a [2+2]
cycloaddition reaction with the starting material to form a cyclometallocyclobutane
that undergoes a ring-opening reaction to form the other metal-containing
intermediate and a new alkene and the other metal-containing intermediate.
57
If the alkenes line up the other way, the starting materials are reformed.
Alkyne metathesis
The preferred catalyst for alkyne metathesis is a Schrock catalyst (a catalyst that
contains molybdenum or tungsten).
58

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Tema 1

Catàlisi en reaccions orgàniques

Química Orgànica III Llibres de referència:

A catalyst is a substance that increases the rate of a chemical reaction without

A catalyst increases the rate of a chemical reaction by

A catalyst increases the rate of a chemical reaction by providing a pathway with a

Only a small (“catalytic”) amount of catalyst is needed - this is typically 1 -

Catalysts change the rate constant, not the equilibrium constant

How a catalyst can provide a more favorable pathway for a reaction?

A catalyst can increase:

Acid catalyst - increases the rate of a reaction by donating a proton to a reactant

Acid-catalyzed hydrolysis of an ester

The catalyst increases the electrophilicity of the carbonyl

The catalyst decreases the basicity of the leaving

pKa CH3OH= 15,7

A specific-acid catalyst must be a strong enough acid (HCl, H3O+) to protonate

A general-acid catalyst can be a weaker acid because it has only a partially

Enediol rearrangement of a monosaccharide - increase the stability of

In specific-base catalysis, the base has to be strong enough to remove a proton

Enzymes catalyze reactions using general-acid and general-base catalysis because

Nucleophilic catalyst - increases the rate of a reaction by acting as a nucleophile

Example 1: Nucleophilic substitution reactions

In the uncatalyzed reaction (absence of iodide ion), ethyl chloride is converted to

Iodide ion is a nucleophilic catalyst because it reacts as a nucleophile, forming a

The uncatalyzed hydrolysis of an ester (absence of imidazole) is very slow

In the catalyzed reaction:

Imidazole is a better nucleophile than water.

A – by making a reaction center more susceptible to receiving electrons

Complexation of water to a metal decreases the pKa, increasing the tendency of

Example 1: Cu2+ or Al3+ catalyzed decarboxylation of dimethyloxaloacetate

Example 2: Zn2+ catalyzed hydrolysis of methyl trifluoroacetate

Metal-bound hydroxide is a better nucleophile than water.

What are ways to affect this rate?

The relative rate is also called the effective molarity.

Effective molarity is the [reactant] that would be required in an intermolecular

The effective molarity is the advantage given to a reaction by having the

Because the reactant in D

Two products are formed because there are two nucleophiles

Both reactions form a new C-C

The palladium atom of the

The Suzuki and Heck Reactions use a palladium catalyst (L2Pd)

If the organopalladium compounds has a β-hydrogen on an sp3 carbon, an

This is the reason why only vinylic and aryl 38

The Suzuki and Heck Reactions use a palladium catalyst (L2Pd)

The R group of an organoboron compound replaces a halogen in the

The first step is an oxidative addition

The last step is a reductive

An alkyl-organoboron compound is prepared by hydroboration of a terminal alkene.

An alkenyl-organoboron compound is prepared by hydroboration of a terminal alkyne.

Catecholborane is often used as

An aryl-organoboron compound is prepared from an organolithium compound and

The new C—C bond joins two sp2 carbons.

- If the the alkene is symmetrical

The electron-withdrawing group makes one carbon more electrophilic.

Alkene metathesis requires a transition metal catalyst. Ruthenium catalysts

There are several generations of Grubbs catalysts,

Alkene Metathesis forms E and Z isomers