GREEN CHEMISTRY

Dr. Muhammad Irshad

ORGANIC CHEMISTRY IN
WATER: GREEN AND FAST
Lecture # 7 & 8
Introduction

• Traditionally, water is not a popular solvent for organic

reactions. The limited solubility of many organic substrates

and reagents as well as the fact that a variety of functional
groups is reactive toward water have traditionally contributed
to this lack of popularity of water as a reaction medium.
• Contrarily, the chemistry of all life processes occurs in

aqueous media, and few people will doubt the high quality
and efficiency of these transformations!
Introduction

• Chemical transformations in aqueous solvents are not

new to organic chemists. On the contrary, they have

attracted the attention of scientists for many years: the
first use of water for an organic reaction could be dated
back to Wohler’s synthesis of urea from ammonium
cyanate.
Introduction
• Recently there has been a revival of interest in water as

the reaction medium in organic chemistry. Our increasing

concern for the environment and for safe chemical
procedures are reasons for this change in attitude.
• Interestingly, many organic reactions (and particularly

carbon – carbon bond formation reactions) are

accelerated in water relative to organic solvents. Water
may also have a favorable effect on the stereochemistry
of a variety of organic transformations
Introduction
• Water possesses many unique physical and chemical
properties: a large temperature window in which it remains in
the liquid state, extensive hydrogen bonding, high heat capacity,
large dielectric constant, and optimum oxygen solubility to
maintain aquatic life forms.
• These distinctive properties are the consequence of the unique

structure of water.
• In the many examples of “aqueous reactions”, organic co-

solvents are employed in order to increase the solubility of

organic reactants in water.
Introduction
• In many cases, due to hydrophobic effects, using water as

a solvent not only accelerates reaction rates but also

enhances reaction selectivities, even when the reactants
are sparingly soluble or insoluble in this medium.
• Water soluble compounds such as carbohydrates, can be

used directly without the need for laborious derivatization

and water-soluble catalysts can be reused after
separation from water-insoluble organic products
Organic Reactions in Water

Diels-Alder Reactions
• It is an excellent example of organic reaction water.

• In 1980, Rideout and Breslow reported that both rate enhancement

and excellent selectivity could be achieved for certain Diels-Alder

reactions when they were performed in dilute aqueous solutions.
• The reaction of cyclopentadiene (0.4 mM) with butenone (12.1 and

25.5 mM) in water was studied and progress monitored through UV-
Vis Spectroscopy.
• The reaction was accelerated more than 700-fold in water versus the

aprotic nonpolar organic solvent, 2,2,4-trimethylpentane.

Organic Reactions in Water
Diels-Alder Reactions

• . The rate in methanol, a protic polar organic solvent, was

intermediate but closer to that in the hydrocarbon solution.

• The effects of different additives (lithium chloride, guanidinium

chloride, and cyclodextrins) were also examined.

• Although 4.86 M guanidinium chloride did not significantly affect the

rate, the reaction was accelerated in 4.86 M lithium chloride solution.

Organic Reactions in Water

Diels-Alder Reactions
•

• The cycloaddition of cyclopentadiene with acrylonitrile showed a

small rate increase on changing the solvent from 2,2,4-

trimethylpentane to methanol but was significantly accelerated in
water.
Organic Reactions in Water
Diels-Alder Reactions
• Several factors have been invoked to explain the aqueous rate

acceleration: aggregation of the reactants leading to micellar

catalysis, effects connected with the internal pressure of the solvent,
polarity of the solvent, H-bonding interactions with the solvent, and
hydrophobic interactions
 Organic Reactions in Water
Diels-Alder Reactions (Hydrophobic rate acceleration)
• Breslow proposed that water promotes hydrophobic packing of the two reactants.

• Evidence that a hydrophobic effect was involved came from a series of experiments

that measured the rates of these reactions in the presence of additives known to
increase or decrease the hydrophobic effect .
• A prohydrophobic ('salting-out') agent such as LiCI enhances the hydrophobic effect

by causing free water molecules to collapse around its ions (solvent electrostriction),
thereby making it necessary to disrupt these stable hydration shells before a cavity
can be opened for the solute.
• Antihydrophobic ('salting-in') agents like guanidinium salts decrease the hydrophobic

effect by acting as a bridge between water molecules and nonpolar solutes

 Organic Reactions in Water
Diels-Alder Reactions (Enforced hydrophobic interactions)
• Gibbs energies of activation (kinetically determined activation parameters for a series of

simple Diels-Alder reactions) and Gibbs energies of transfer (thermodynamic parameters

for transfer of reactants and activated complex from alcohol to water-alcohol mixtures and
pure water) give useful information about it.
• A plot of Gibbs energies of transfer for the initial state and activated complex over the

whole mole fraction range from pure I-propanol to pure water reveals that the rate
acceleration in water relative to I-propanol is due mainly to destabilization of the initial state.
• Stabilization of the transition state relative to the initial state was proposed to be a natural

consequence of the reduction of the hydrophobic surface area as the reaction proceeds to
the top of its reaction coordinate. This effect was termed 'enforced hydrophobic interaction'
and is mechanistically distinct from explanations involving hydrophobic packing of
reactants.
 Organic Reactions in Water
Diels-Alder Reactions (Enforced hydrophobic interactions)
 Organic Reactions in Water
Diels-Alder Reactions (Hydrogen-bonding effects)
• Computational work by Jorgensen and co-workers has suggested that the transition

states for this and related Diels-Alder cycloadditions are stabilized by enhanced
hydrogen bonding to water.
• The hydrogen bond between water and the carbonyl was calculated to be stronger

in the transition state because of the enhanced polarization of the carbonyl group.
• compared

• The Gibbs free energies of the initial state and activated complex for the reaction

between CPD and MVK in water (hydrophobic + hydrogen-bonding effects) and

trifluoroethanol (hydrogen-bonding effects only) and found that hydrogen bonding
stabilizes the activated complex more than the initial state
 Organic Reactions in Water
Diels-Alder Reactions (Hydrogen-bonding effects)
 Organic Reactions in Water
Diels-Alder Reactions (Hydrogen-bonding effects)
 Organic Reactions in Water
Diels-Alder Reactions (Structure-facilitated hydrophobic effects)
• In order for the hydrophobic effect to manifest itself at all, both diene and
dienophile must exhibit at least a minimum solubility in water.
• If one or both reaction partners do not meet this minimum solubility requirement,

then no reaction will occur in water. The use of solubilizing additives or solvents
must then be considered, though one runs the risk of losing the hydrophobic
effect in the bargain.
• Fortunately, one can overcome the solubility problem and at the same time

enhance the hydrophobic effect by incorporating a pro hydrophobic functional

group into the substrate structure. The reSUlting 'hybrid' molecule will be
amphiphilic, which could also lead to a rate enhancement if the resulting
preorganization of the reactants in water was productive.
 Organic Reactions in Water
Miscellaneous effects (Preorganizing' additives)
• The effects of cyclodextrin additives on the rates of these aqueous Diels-Alder Reactions

studied. The basis for these experiments was the hypothesis that the activated complex of
diene and dienophile for reactions such as [CPD & Acrylonitrile] and [CPD & MVK] should fit
into the hydrophobic cavity of β-cyclodextrin (cycloheptaamylose) and that this would result in a
rate enhancement.
• Indeed, β -cyclodextrin led to an increase in the rate of the first reaction equal to that observed

with the prohydrophobic salt LiCl.

• A β -cyclodextrin-mediated rate acceleration was also observed for the second reaction but not

for the reaction [9-hydroxymethylanthracene + N-ethylmaleimide] since the diene 9-

hydroxymethylanthracene is too large for the cyclodextrin cavity.
• The fact that all three of these Diels-Alder reactions were decelerated by α-cyclodextrin

(cycloheptaamylose) - whose smaller cavity cannot accommodate even the activated

complexes of the first two reactions - was taken as further support for their hypothesis.
 Organic Reactions in Water
Miscellaneous effects (Lewis-acid catalysis)
• It has long been known that conventional Diels-Alder reactions in aprotic

organic solvents are subject to catalysis by Lewis acids. This is usually

accomplished by complexation of a cationic metal species to a Lewis
basic site on an activating group attached to the dienophile.
• The resulting increase in rate and endo-selectivity can be attributed to

differences in the lowest unoccupied molecular orbital (LUMO) of the

dienophile-Lewis acid complex versus that of the free dienophile.
• If one considers the rate-accelerating effect of hydrogen bonding on the

aqueous Diels-Alder reaction to be the result of a Bronsted acid-base

interaction, then Lewis-acid catalysis in water should be possible.
 Organic Reactions in Water
Miscellaneous effects (Lewis-acid catalysis)
• However, in order to achieve effective Lewis-acid catalysis in water:

(i) the change in free energy upon metal complexation with the substrate
must compensate for the (energetically unfavorable) dehydration events
preceding it;

(ii) Lewis-acid-catalyzed side reactions with water must be minimized; and

(iii) the Lewis acid should dissociate once the Diels-Alder reaction has
occurred to allow catalyst turnover.
 Organic Reactions in Water
Miscellaneous effects (Lewis-acid catalysis)
• The reaction in aqueous CU(N03)2 solution proceeded about 800 times

faster than in water alone and 250000 times faster than in acetonitrile. This
Lewis-acid-catalyzed aqueous Diels-Alder reaction presumably occurs via
a transition state such as 2.50 with bidentate complexation to the metal as
shown.
 Organic Reactions in Water
Miscellaneous effects (Water like reaction Media)
• Reaction of CPD and MVK proceeds about four times faster in formamide

and six times faster in ethylene glycol than it does in methanol.

• The source of these rate accelerations in water-like solvents was
proposed to be due to a 'solvophobic effect' analogous to (though of
smaller magnitude than) the hydrophobic effect seen in water.
• Additional evidence for this idea came from the fact that 'salting-out'

additives such as LiCI also led to a rate increase in 'water-like' solvents.

• Of all the additives tested, only quaternary ammonium salts slowed the

reaction down - presumably by acting as 'pseudo-detergents'.

 Organic Reactions in Water
MICELLAR CATALYSIS
• Micellar catalysis, conducted in the absence of Lewis acid tends to inhibit

the Diels–Alder reaction, relative to the reaction in water. The reason is

that the local reaction medium in the Stern region is less favorable than
bulk water.
• However, by combining Lewis-acid and micellar catalysis, enzyme-like rate

accelerations can be obtained in case the Lewis acid acts as the counter
ion for the micelle.
 Organic Reactions in Water
Diels Alder Reaction
Endo and Exo products
• When a cyclic diene is used in the Diels-Alder reaction, a bridged bicyclic
compound is formed:
• This looks ordinary until we draw the product from a side view which
reveals some nice structures and interesting features of the mechanism
that leads to the formation of two stereoisomers.
 Organic Reactions in Water
Diels Alder Reaction
• The diene and the dienophile can have two alignments. In one of them, the
electron-withdrawing groups of the dienophile are pointing towards/underneath the
diene, and in the second one, these groups are pointing away from the diene.
These two orientations lead to the formation of two products – endo and exo:
 Organic Reactions in Water
Diels Alder Reaction
Endo and Exo products
• In the endo product, the substituents of the dienophile are pointing towards
the larger bridge, while in the exo isomer, they are pointing away from the
larger bridge:
 Organic Reactions in Water
Diels Alder Reaction
Endo and Exo products
• In general, endo is the major product because it is formed when the

electron-withdrawing groups of the dienophile are pointing towards the π

electrons of the diene. This decreases the energy of the transition state
because of a favorable interaction between the non-bonding orbitals of the
diene and the dienophile:
• The exo product, on the other hand, is more stable as the substituent of

the dienophile is pointing away from the larger ring system. Therefore, it is
the thermodynamic product (more stable) and the endo is the kinetic
product (forms faster).
 Organic Reactions in Water
CONCLUSIONS
• Diels – Alder reactions are accelerated in water due to a combination of

enforced hydrophobic interactions and hydrogen bonding, their relative

contributions depending on the nature of the diene and dienophile.
• Lewis-acid catalysis of Diels – Alder reactions involving bidentate

dienophiles in water is possible; also if the beneficial effect of water on the

catalyzed reaction is reduced relative to pure water.
• Micelles, in the absence of Lewis acids, are poor catalysts, but combining

Lewis-acid catalysis and micellar catalysis leads to a rate acceleration that

is enzyme-like.