Pure Appl. Chem., Vol. 72, No. 7, pp. 1365–1372, 2000.

© 2000 IUPAC

Diels–Alder reactions in water*

Sijbren Otto and Jan B. F. N. Engberts

Department of Organic and Molecular Inorganic Chemistry, Stratingh Institute,

University of Groningen, Nijenborgh 4, 9747 AG Groningen, The Netherlands

Abstract: This review illustrates how water, as an environmentally friendly solvent, can have
significant additional benefits when it is used as a solvent for the Diels–Alder reaction. The
mechanism by which the unique properties of water enhance the rate and selectivity are
discussed. Also, possibilities for the achievement of further increases in rate and
enantioselectivity of aqueous Diels–Alder reactions through Lewis-acid and micellar catalysis
are reviewed.

INTRODUCTION

An important part of our efforts towards a more environmentally friendly, green chemistry is aimed at a
reduction of the use of organic solvents. Usually, organic solvents are used in much larger quantities
than the solutes they carry and have a tendency to escape into the environment through evaporation and
leakage. A lot of research is currently devoted to the replacement of organic solvents by a less
environmentally hazardous one. Nature’s own solvent, water, is ideally suited for this purpose owing to
its non-toxic character. Its enormous abundance on this planet makes water a cheap and readily accessible
alternative.
The increased focus on water in synthetic organic chemistry during the past few decades has
resulted in a large number of reactions that can now be performed successfully in an aqueous medium.
Among these reactions are allylation reactions, the aldol condensation, the Michael addition, the Mannich
reaction, indium-mediated allylation and Grignard-type additions and the benzoin condensation [1].
Surprisingly, also notoriously solvent-insensitive reactions such as the Claisen rearrangement and the
1,3-dipolar cycloaddition can benefit dramatically from an aqueous medium. Perhaps the most striking
and unexpected example of a reaction that benefits from the use of an aqueous solvent system is the
Diels–Alder reaction. Herein we will summarize how the unique properties of water, as expressed in
strong hydrogen bonding interactions and hydrophobic interactions, enhance the rate and selectivity of
this important organic transformation. The synthetic merits of these effects will be briefly highlighted.
Finally, the considerable potential of catalysis of Diels–Alder reactions in water by micellar aggregates
and Lewis acids will be briefly discussed.

SPECIAL EFFECTS OF WATER ON DIELS–ALDER REACTIONS

For a long time water was not a popular solvent for the Diels–Alder reaction. Before 1980 its use had
been reported only incidentally. Diels and Alder themselves performed the reaction between furan and
maleic acid in an aqueous medium in 1931 [2], an experiment which was repeated by Woodward and
Baer in 1948 [3]. These authors noticed a change in endo–exo selectivity when comparing the reaction
in water with that in ether. Also, in two patents the Diels–Alder reaction is mentioned in connection with
water [4]. In 1973 Eggelte, de Koning, and Huisman studied the reaction of maleic acid with furan in
several solvents [5]. These authors noticed, for the first time, a beneficial rate effect of water on the
Diels–Alder reaction. Still, it was not until the work of Breslow et al. that it became common knowledge
that water was a unique medium for Diels–Alder reactions [6].
*Pure Appl. Chem. Vol. 72, No. 7, 2000. A special topic issue on green chemistry.

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1366 S. OTTO AND J. B. F. N. ENGBERTS

In general, the use of an aqueous medium increases the rate of Diels–Alder reactions significantly
as compared to all organic solvents. In extreme cases accelerations can exceed a factor of 10 000 [7]. In
addition, aqueous solvents tend to enhance the selectivity of the reaction. More specifically, the gener-
ally observed preference for the formation of the endo cycloadduct is even more pronounced in water.
Also, the regioselectivity and diastereofacial selectivity tends to increase in aqueous media.

The effect of water on the rate of Diels–Alder reactions

Breslow and Rideout [6] interpreted the acceleration of Diels–Alder reactions in water in terms of a
hydrophobic effect. Alternatively, in the literature the acceleration is sometimes attributed to micellar
catalysis [8]. However, since water accelerates Diels–Alder reactions also when the reactants are
distributed homogeneously throughout the solution, this explanation lacks generality. Kinetic
measurements on the intramolecular Diels–Alder reaction of 1 (entry 1 in Table 1) support this suggestion.
In this reaction diene and dienophile are already associated, and still water is capable of accelerating
this process by a factor of 153 compared to the reaction in n-hexane [9].
Studies of solvent effects on the Diels–Alder reaction led to useful insight into the origin of the
special rate effect of water. Most studies have focused on type A Diels–Alder reactions [10]. A multipa-
rameter analysis by Gajewski revealed the importance of the cohesive energy density (ced, not to be
confused with the internal pressure [11]) of the solvent, together with the hydrogen-bond donating
capacity [12]. The ced essentially quantifies solvophobicity, underlining the importance of hydropho-
bic interactions in rationalizing the effect of water on Diels–Alder reactions. This special type of hydro-
phobic interactions is best referred to as “enforced hydrophobic interactions” [13]. The term “enforced”
is used to stress the fact that the association of the nonpolar reagents is driven by the reaction and only
enhanced by water. Other solvent effect studies by a large number of authors further demonstrated that
reactivity is primarily determined by two solvent parameters: the hydrogen-bond donating capacity and
the solvophobicity [14]. This pattern strongly suggests that in water, a hydrogen-bond donating solvent
par excellence, the Diels–Alder reaction benefits not only from enforced hydrophobic interactions but
also from hydrogen-bonding interactions. The small size of water molecules allows efficient interaction
with hydrogen-bond acceptors by forming more hydrogen bonds than protic organic solvents.
The importance of hydrogen bonding interactions is apparent from the results of detailed kinetic
studies on a number of carefully selected Diels–Alder reactions. In entry 2 of Table 1 the reactions of
cyclopentadiene with a carbonyl- (3) and a sulfonyl- (6) activated dienophile are compared [7a]. Due to
the insulating effect of the sulfur atom in 6, the reactivity of this compound is much less affected by
hydrogen bonding than the reactivity of 3. This decreased sensitivity of 6 to hydrogen bonding shows
up in a much less pronounced water-induced acceleration as compared to that for 3. Further support
comes from a Diels–Alder reaction where the reactants lack hydrogen-bond accepting sites (entry 3)
[15]. The acceleration of the reaction of 8a with 4 by water is modest, as can be expected in the absence
of activation by hydrogen bonds. However, upon introduction of a hydrogen-bond accepting substitu-
ent (8b) the aqueous acceleration is significantly enhanced. Finally, the reaction between cyclohexadiene
and nitrosobenzene has been studied (entry 4) [16]. This reaction is classified by Desimoni as a type C
Diels–Alder reaction, indicating that it is insensitive to specific interactions with the solvent, such as
hydrogen bonding [10]. Consequently, the aqueous rate enhancement is modest, underlining the impor-
tance of hydrogen bonding interactions for Diels–Alder reactions that experience large beneficial ef-
fects from water.
Further insights into the peculiar features of the Diels–Alder reaction in water have been obtained
from the Gibbs energies of transfer from 1-propanol to water of the starting materials and product for
the Diels–Alder reaction between methyl vinyl ketone and ethyl vinyl ketone with cyclopentadiene [9].
When combined with the Gibbs energies of activation, these data allow a direct comparison of the
chemical potentials of the initial states, the transition states, and the product of this reaction in these two
solvents. In water the initial state is significantly destabilized relative to 1-propanol. Hydrophobic hy-

© 2000 IUPAC, Pure and Applied Chemistry 72, 1365–1372

 Diels–Alder reactions in water 1367

Table 1. Relative rate constants of some selected Diels–Alder reactions in water compared to organic solvents of
different hydrogen-bond donor capacities.

a
Aprotic EtOH HFP H2O
1 O N

O N O 1 1.90 - 153
HO 2C (hexane)
O 1 CO 2H 2
2 O
+
O 1 4.79 100 290
3 4 5 (CH3CN)
S O O
O + 1 2.49 22.6 71.0
O 6 4 S 7 (CH3CN)

3 R
+ Br a 1 1.69 - 8.95
N R (CH3CN)

4 8a,b Br aR=H N b - 1 - 102

b R = OCOCH3 9a,b
4
N O + N 1 1.14 5.49 44.3
(toluene)
10 11 12 O
5 n+
a X=NO2 e X=OCH3 X
X O ML b X=Cl - +
f X=CH2SO3 Na
c X=H + - 4
13a-g N d X=CH3 g X=CH2N (CH3)3 Br O
M=CoII,NiII,CuII,ZnII N 14a-g

a
1,1,1,3,3,3-hexafluoropropanol

dration of the initial state is clearly unfavorable compared to solvation in 1-propanol. This also applies
to the product state. The transition state, however, has nearly equal chemical potentials in water and in
1-propanol. Apparently, in aqueous solution the hydrocarbon parts of the activated complex have com-
pletely lost their nonpolar character. Recent work on Diels–Alder reactions of a series of
N-alkylmaleimides with different dienes has confirmed this [17]. Addition of methylene units or methyl
groups to the diene results in a destabilization of the initial state of the Diels–Alder reaction with
N-alkylmaleimides in water as compared to 1-propanol. Nevertheless, the transition states in water and
1-propanol have comparable chemical potentials. On the basis of computer simulations Jorgensen et al.
arrived at approximately the same conclusions [18]. Recently, Furlani and Gao, following a similar
approach, estimated the Gibbs energy of hydration of the Diels–Alder reaction of cyclopentadiene with
isoprene and methyl vinyl ketone in water [19]. Surprisingly, the authors observed that, relative to the
initial state, water stabilized the transition state of the former process more than the latter (19 kJ/mole
versus 15 kJ/mole). This trend opposes the experimental data collected in Table 1, which seem to indi-
cate that the aqueous acceleration diminishes when the hydrogen-bonding interactions become impos-
sible.
Finally, the activation parameters for Diels–Alder reactions in water and in a number of organic
solvents have been obtained. For the reaction of methyl vinyl ketone with cyclopentadiene the accelera-
tion on going from 1,4-dioxane to water is mainly enthalpic in origin [20]. Comparing water with
1-propanol the enthalpy and entropy of activation contribute about equally [13a]. When the rate of the
reaction in water is compared to that in methanol, the entropy term dominates the rate enhancement

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1368 S. OTTO AND J. B. F. N. ENGBERTS

[21]. One may conclude that hydrogen-bonding interactions mainly affect the enthalpy of activation. In
contrast, under the typical reaction conditions, the hydrophobic part of the acceleration in water is most
likely mainly an entropy effect. Note that the Diels–Alder reaction in water benefits from both a re-
duced enthalpy of activation as well as a reduced entropy of activation. This pattern is rather unusual
and can be interpreted as another indication for the simultaneous operation of two mechanisms of
activation.
In summary, a wealth of experimental data as well as a number of sophisticated computer simula-
tions unequivocally indicate that two important effects underlie the acceleration of Diels–Alder reac-
tions in aqueous media: hydrogen bonding and enforced hydrophobic interactions. In terms of transi-
tion state theory: hydrophobic hydration raises the initial state more than the transition state and hydro-
gen-bonding interactions stabilize the transition state more than the initial state. The highly polarizable
activated complex plays a key role in both of these effects.

The effect of water on the selectivity of Diels–Alder reactions

Three years after the report on the large effects of water on the rate of the Diels–Alder reaction, Breslow
et al. demonstrated that also the endo–exo selectivity of this reaction benefits markedly from employing
aqueous media [22]. Based on the influence of salting-in and salting-out agents, Breslow pinpoints
hydrophobic effects as the most important contributor to the enhanced endo–exo selectivity. Hydrophobic
effects are assumed to stabilize the more compact endo transition state more than the extended exo
transition state. This difference in compactness of both states is evident from the well-known smaller
activation volume for the endo cycloaddition [23].
In addition, the high polarity of water is assumed to strengthen the preference for endo cycloadduct.
Actually, the solvent sensitivity of the endo–exo product ratio was already recognized by Berson et al.,
who based an empirical solvent polarity parameter on the endo–exo ratio of the reaction between me-
thyl acrylate and cyclopentadiene [24].
Studies of solvent effects on the endo–exo selectivity of Diels–Alder reactions have revealed the
importance of hydrogen-bonding interactions besides the already mentioned solvophobic interactions
and polarity effects [25]. Further evidence for the significance of the former interactions comes from
computer simulations [26] and the analogy with Lewis-acid catalysis which is known to enhance dra-
matically the endo–exo selectivity.
In conclusion, the special influence of water on the endo–exo selectivity seems to be a result of
the fact that this solvent combines in it three characteristics that all favor formation of the endo adduct:
(1) water is a strong hydrogen-bond donor, (2) water is polar, and (3) water induces hydrophobic inter-
actions.
Water is also reported to increase the diastereofacial- and regioselectivity of Diels–Alder reac-
tions [14a,c,27]. Mechanistic investigations have been carried out on the reaction between cyclopentadiene
and (1R,2S,5R)-menthyl acrylate, which has been shown to be dominated by the hydrogen-bond donor
characteristics of the solvent together with its polarity [14].

Synthetic applications
Grieco was the first to demonstrate that the astonishing rate and selectivity enhancements of Diels–
Alder reactions in water can be exploited successfully in organic synthesis [28]. He extensively studied
the reactivity of dienes containing hydrophilic carboxylate, or ammonium groups, as well as hetero
Diels–Alder reactions of iminium ions. These processes can be successfully employed in natural product
synthesis.
The extensive work of Lubineau and coworkers further demonstrates the merits of water with
respect to the rates and selectivities of the Diels–Alder reaction [1a,21,27a,29]. Since 1985 the Lubineau
group has published a large number of articles dealing mainly with dienes that were rendered water

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 Diels–Alder reactions in water 1369

soluble through the temporary introduction of a sugar moiety. The efficiency of Diels–Alder reactions
between these compounds and standard dienophiles is still significantly enhanced in aqueous solutions,
despite the presence of the hydrophilic sugar group in the diene. The sugar moiety can be removed after
completion of the Diels–Alder reaction. Lubineau et al. also studied the hetero Diels–Alder reactions of
glyoxylic acid and its sodium salt in some detail. Also these reactions were shown to benefit consider-
ably from the use of water as a solvent.
Waldmann et al. studied the possible influence of a-amino-acid derivatives as chiral auxiliaries
on the diastereoselectivity of several Diels–Alder reactions in aqueous media [30]. In contrast to the
advantageous influence of the medium on rate and endo–exo selectivity, Waldmann did not observe an
increase in diastereofacial selectivity.
Many other authors successfully employed aqueous Diels–Alder reactions in natural product syn-
thesis [31]. Interestingly, also photochemical [4+2] cycloadditions benefit from aqueous media [32].
The rate of the addition of singlet oxygen to an aromatic compound, for example, is significantly en-
hanced by water. Recently, the scaling up of water-based Diels–Alder reactions has been studied [33].

Lewis-acid catalysis of Diels–Alder reactions in water

There is a considerable potential for even further enhancing rates and selectivities of Diels–Alder reactions
in water through the use of catalysts. In organic solvents Lewis-acid catalysis of Diels–Alder reactions
is well established [34]. Unfortunately, extension of the use of Lewis-acid catalysts into aqueous media
is hampered by the strong interactions between water and the catalyst as well as the Lewis-basic acceptor
sites in the Diels–Alder reactants. However, once these difficulties are overcome, extreme rate
enhancements are anticipated. The first example of such a Lewis-acid catalyzed Diels–Alder reaction
has recently been published [35]. Efficient interactions between catalyst and substrate are achieved
through bidentate coordination of the 3-phenyl-1-(2-pyridyl)-2-propen-1-one dienophile (13) to the
aqua transition metal ion catalysts (entry 5 in Table 1). When comparing the rate of the catalyzed
reaction in water with the uncatalyzed reaction in acetonitrile, accelerations amount up to 5 orders of
magnitude. Also, the endo–exo ratio increases significantly in the presence of a Lewis-acid catalyst.
Interestingly, upon introduction of chiral a-amino acid-derived ligands enantioselectivity is in-
duced [36]. For instance, in the presence of commercially available Na-methyltryptophan the Cu2+-
catalyzed reaction of 13c with cyclopentadiene gives the Diels–Alder adduct 14c in 74% enantiomeric
excess. This is the first example of enantioselectivity in a Lewis-acid catalyzed organic reaction in
water. Most significantly, water turned out to enhance the enantioselectivity as compared to organic
solvents. Mechanistic studies led to the conclusion that enantioselectivity in this reaction is a result of
arene–arene interactions between the aromatic ring of the a-amino acid ligand and the pyridine ring of
the dienophile, shielding one face of the dienophile from approach of the diene. It is not unlikely that
water strengthens these arene–arene interactions, at least partly as a result of hydrophobic interactions.
Since arene–arene interactions are held responsible for the enantioselectivity in many other reactions
involving chiral catalysts, water seems to hold considerable potential as a solvent for enantioselective
catalysis.

Micellar catalysis of Diels–Alder reactions [37]

In view of the hydrophobic character of most Diels–Alder reactants strong binding of these compounds
to micellar aggregates is expected. In theory, the resulting concentration of the reactants in the micellar
microenvironment is anticipated to promote the Diels–Alder reaction. Surprisingly, in practice, micelles
are usually inhibiting Diels–Alder reactions, rather than promoting them [15,16,20,22,38]. Most likely,
this is a result of the fact that in the cases studied so far the purely hydrocarbon diene prefers the interior
of the micelles, whereas the more polar dienophile resides on average in the headgroup region of the
aggregates. This spatial separation results in a modest inhibition of the reaction.

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1370 S. OTTO AND J. B. F. N. ENGBERTS

To date there is only one example of efficient micellar catalysis of a Diels–Alder reaction [39]. As
compared to the uncatalyzed reaction in acetonitrile, micelles of copper didodecylsulfate turned out to
be capable of inducing million-fold accelerations of the Diels–Alder reaction between 13 and
cyclopentadiene. This large effect is mainly a result of the efficient interaction between the catalytically
active copper ions and the dienophile. Both species are present in the headgroup region of the micelles
in high local concentrations.

EPILOGUE
In this review we have highlighted that the use of water as a solvent for the Diels–Alder reaction is not
merely an environmentally friendly alternative, but has considerable additional advantages in the form
of significant water-induced increases in rates and selectivities. Possibilities exist for further rate
enhancements and even for enantioselective catalysis by using (chiral) Lewis-acid catalysts in an aqueous
medium. Despite these obvious benefits water is still not always the solvent of choice for the Diels–
Alder reaction. The poor water solubility of many Diels–Alder reactants and the difficulties in achieving
efficient interaction between Lewis-acid catalyst and substrate are major obstacles. The use of micelles
and low concentrations of cosolvents might provide ways around these obstacles eventually transforming
the Diels–Alder reaction into a clean and green process.

REFERENCES
1. (a) A. Lubineau, J. Auge, Y. Queneau. Synthesis 741 (1994). (b) C. Li. Chem. Rev. 93, 2023
(1993). (c) J. B. F. N. Engberts, B. L. Feringa, E. Keller, S. Otto. Recl. Trav. Chim., Pays-Bas 115,
457 (1996). (d) C. Li, T.-H. Chan. Organic Reactions in Aqueous Media. Wiley, New York (1997).
(e) P. A. Grieco. Organic Synthesis in Water. Blacky Academic and Professional, London (1998).
2. O. Diels and K. Alder. Ann. 490, 243 (1931).
3. R. B. Woodward and H. Baer. J. Am. Chem. Soc. 70, 1161 (1948).
4. (a) H. Hopff and C. W. Rautenstrauch. U.S. Patent 2,262,002 (1942). (b) L. C. Lane and C. H. J.
Parker. U.S. Patent 2,444,263 (1948).
5. T. A. Eggelte, H. De Koning, H. O. Huisman. Tetrahedron 29, 2491 (1973).
6. R. Breslow and D. Rideout. J. Am. Chem. Soc. 102, 7816 (1980).
7. (a) S. Otto, W. Blokzijl, J. B. F. N. Engberts. J. Org. Chem. 59, 5372 (1994). (b) J. B. F. N.
Engberts. Pure Appl. Chem. 67, 823 (1995).
8. A likely explanation for some reactions: (a) P. A. Grieco, P. Garner, H. Zhen-Min. Tetrahedron
Lett. 24, 1897 (1983). But unlikely for others: (b) D. D. Sternbach and D. M. Rossana. J. Am.
Chem. Soc., 104, 5853 (1982). (c) T. Dunams, W. Hoekstra, M. Pentaleri, D. Liotta. Tetrahedron
Lett. 29, 3745 (1988). (d) C. K. Pai and M. B. Smith. J. Org. Chem. 60, 3731 (1995).
9. W. Blokzijl. Ph.D. Thesis, University of Groningen (1991).
10. Diels–Alder reactions of type A are governed by LUMOsolvent-HOMOsolute interactions. See:
G. Desimoni, G. Faita, P. P. Righetti, L. Toma. Tetrahedron 46, 7951 (1990).
11. (a) P. A. Grieco, J. J. Nunnes, M. D. Gaul. J. Am. Chem. Soc. 112, 4549 (1990). (b) A. Lubineau
and Y. Queneau. J. Org. Chem. 52, 1001 (1987). (c) A. Kumar. J. Org. Chem. 59, 230 (1994).
12. J. J. Gajewski. J. Org. Chem. 57, 5500 (1992).
13. (a) W. Blokzijl, M. J. Blandamer, J. B. F. N. Engberts. J. Am. Chem. Soc. 113, 4241 (1991).
(b) W. Blokzijl and J. B. F. N. Engberts, J. Am. Chem. Soc. 114, 5440 (1992).
14. See: (a) C. Cativiela, J. I. García, J. A. Mayoral, A. J. Royo, X. Assfeld, M. F. Ruiz-Lopez. J. Phys.
Org. Chem. 5, 230 (1992). (b) X. Assfeld, M. F. Ruiz-López, J. I. García, J. A. Mayoral, L.
Salvatella. J. Chem. Soc., Chem. Commun. 1371 (1995). (c) C. Cativiela, J. I. Garcia, J. Gil, R.

© 2000 IUPAC, Pure and Applied Chemistry 72, 1365–1372

 Diels–Alder reactions in water 1371

M. Martinez, J. A. Mayoral, L. Salvatella, J. S. Urieta, A. M. Mainar, M. H. Abraham. J. Chem.

Soc., Perkin Trans.2 653 (1997) and references therein.
15. G. K. Van der Wel, J. W. Wijnen, J. B. F. N. Engberts. J. Org. Chem. 61, 9001 (1996).
16. J. W. Wijnen and J. B. F. N. Engberts. Liebigs Ann. / Recueil 1085 (1997).
17. A. Meijer, S. Otto, J. B. F. N. Engberts. J. Org. Chem. 63, 8989 (1998).
18. (a) J. F. Blake and W. L. Jorgensen. J. Am. Chem. Soc. 113, 7430 (1991). (b) J. F. Blake,
L. Dongchul, W. L. Jorgensen. J. Org. Chem. 59, 803 (1994).
19. T. R. Furlani and J. Gao. J. Org. Chem. 61, 5492 (1996).
20. I. Hunt and C. D. Johnson. J. Chem. Soc., Perkin Trans. 2 1051 (1991).
21. A. Lubineau, H. Bienaymé, Y. Queneau, M. Scherrmann. New J. Chem. 18, 279 (1994).
22. (a) R. Breslow, U. Maitra, D. Rideout. Tetrahedron Lett. 24, 1901 (1983). (b) R. Breslow and
U. Maitra. Tetrahedron Lett. 25, 1239 (1984)
23. T. Asano and W. J. LeNoble. Chem. Rev. 78, 407 (1978).
24. J. A. Berson, Z. Hamlet, W. A. Mueller. J. Am. Chem. Soc. 84, 297 (1962).
25. C. Cativiela, J. I. García, J. A. Mayoral, L. Salvatella. J. Chem. Soc., Perkin Trans. 2, 847 (1994).
26. I. Schlachter, Y. Mattay, J. Suer, U. Howeler, G. Wurthwein, E. Wurthwein. Tetrahedron 53, 119
(1997).
27 (a) A. Lubineau, J. Auge, N. Lubin. J. Chem. Soc., Perkin Trans. 1 3011 (1990). (b) S. Arseniyadis,
R. Rodriquez, D. V. Yashunsky, J. Camera, G. Ourisson. Tetrahedron Lett. 35, 4843 (1994).
28. (a) P. A. Grieco, P. Garner, H. Zhen-Min. Tetrahedron Lett. 24, 1897 (1983). (b) P. A. Grieco, K.
Yoshida, P. Garner. J. Org. Chem. 48, 3137 (1983). (c) P. A. Grieco, K. Yoshida, H. Zhen-Min.
Tetrahedron Lett. 25, 5715 (1984) (d) K. Yoshida, P. A. Grieco. Chem. Lett. 155 (1985).
(e) P. A. Grieco, P. Galatsis, R. F. Spohn. Tetrahedron 42, 2847 (1986). (e) K. Yoshida and
P. A. Grieco. J. Org. Chem 49, 5257 (1984). (f) P. A. Grieco and M. D. Kaufman J. Org. Chem.
64, 6041 (1999) and references therein.
29. (a) A. Lubineau and Y. Queneau. Tetrahedron Lett. 26, 2653 (1985). (b) A. Lubineau and Y.
Queneau. Tetrahedron 45, 6697 (1989). (c) A. Lubineau, H. Bienayme, Y. Queneau. Carbohydrate
Res. 270, 163 (1995). (d) A. Lubineau, E. Grand, M.-C. Scherrmann. Carbohydrate Res. 297,
169 (1997). (e) A. Lubineau, J. Auge, N. Lubin. Tetrahedron Lett. 32, 7529 (1991). (f) A. Lubineau,
J. Augé, E. Grand, N. Lubin. Tetrahedron 34, 10265 (1994).
30. H. Waldmann and M. Dräger. Liebigs Ann. 681 (1990).
31. (a) M. Naruse, S. Aoyagi, C. Kibayashi. Tetrahedron Lett 35, 595 (1994). (b) M. Naruse, S.
Aoyagi, C. Kibayashi. J. Org. Chem. 59, 1358 (1994). (c) M. Naruse, S. Aoyagi, C. Kibayashi. J.
Chem. Soc., Perkin Trans. 1 1113 (1996). (d) D. R. Williams, R. D. Gaston, I. B. Horton.
Tetrahedron Lett. 26, 1391 (1985). (e) L. Van Royen, R. Mijngheer, P. J. De Clercq. Tetrahedron
41, 4667 (1985). (f) A. K. Saskena, V. M. Girijavallabhan, Y. Chen, E. Jao, R. E. Pike, J. A. Desai,
D. Rane, A. K. Ganguly. Heterocycles 35, 129 (1993).
32. B. Cazin, J. Aubry, J. Rigaudy. J. Chem. Soc., Chem. Commun. 952 (1986).
33. (a) G. Chen. Diss. Abstr. Int. 57, 6934-B (1997). (b) W. Siegel and A. Kramer. Eur. Pat. Appl. EP
98-122148 981125.
34. (a) H. B. Kagan and O. Riant. Chem. Rev. 92, 1007 (1992). (b) U. Pindur, G. Lutz, C. Otto. Chem.
Rev. 93, 741 (1993).
35. (a) S. Otto, J. B. F. N. Engberts. Tetrahedron Lett. 36, 2645 (1995). (b) S. Otto, F. Bertoncin, J. B.
F. N. Engberts. J. Am. Chem. Soc. 118, 7702 (1996).
36. (a) S. Otto, G. Boccaletti, J. B. F. N. Engberts. J. Am. Chem. Soc. 120, 4238 (1998). (b) S. Otto
and J. B. F. N. Engberts. J. Am. Chem. Soc. 121, 6798 (1999).
37. A review on this topic is forthcoming: S. Otto and J. B. F. N. Engberts Reactions and Synthesis in

© 2000 IUPAC, Pure and Applied Chemistry 72, 1365–1372

1372 S. OTTO AND J. B. F. N. ENGBERTS

Surfactant Systems, J. Texter (Ed.), Marcel Dekker, New York, to be published.

38. (a) N. K. Sangwan and H.-J. Schneider. J. Chem. Soc., Perkin Trans. II 1223 (1989). (b) D. D.
Sternbach and D. M. Rossana. J. Am. Chem. Soc. 104, 5853 (1982). (c) J. W. Wijnen and
J. B. F. N. Engberts. J. Org. Chem. 62, 2039 (1997).
39. S. Otto, J. C. T. Kwak, J. B. F. N. Engberts. J. Am. Chem. Soc. 120, 9517 (1998).

© 2000 IUPAC, Pure and Applied Chemistry 72, 1365–1372

 Published on Web 12/20/2003

Multicomponent Reactions Are Accelerated in Water

Michael C. Pirrung* and Koushik Das Sarma
Department of Chemistry, LeVine Science Research Center, Duke UniVersity, Durham, North Carolina, 27708
Received September 18, 2003; E-mail: michael.pirrung@duke.edu

The use of water as a solvent for organic transformations offers Scheme 1. Multicomponent Reactions Accelerated in Water
several “green chemistry” benefits.1 In many reactions, such as the
Diels-Alder cycloaddition,2 significant rate enhancements are
observed in water compared to organic solvents. This acceleration
has been attributed to many factors, including the hydrophobic
effect,3 enhanced hydrogen bonding in the transition state,4 and the
high cohesive energy density of water (550.2 cal‚mL-1 at 25 °C).5
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The Diels-Alder reaction is also known for its negative activation

volume, owing to a transition state that is more compact than
reactants. Reactions with negative activation volumes are acceler-
ated at high pressure and, with nonpolar reactants, in water.6
The multicomponent reactions important in combinatorial chem-
istry7 are predicted to exhibit negative activation volumes owing
to the condensation of several molecules into a single reactive
intermediate and product. Promotion of the Passerini8 and the Ugi9
reactions at high pressure provides further support for this idea and
suggests they could be accelerated in water. Although aqueous/
organic solvent mixtures have been used in multicomponent
reactions, they are not expected to show the same rate effects as
for pure water as solvent. The influence of water on the rates of
the Ugi or Passerini reactions has not been earlier examined.10 In
organic solvent, the Passerini reaction is first order in each reactant
and is believed to involve preequilibrium formation of an isonitrile- Table 1. Passerini Reaction (eq 1) under Various Reaction
Conditions
carbonyl adduct followed by protonation of this tetrahedral
intermediate by the acid.11 The rate-determining step follows, either time temp conversion yield rate
the nucleophilic addition of the carboxylate to the nitrilium ion or solvent (h) (°C) (%) (%) (M-2 s-1)b
the subsequent rearrangement reaction. As described below, not CH2Cl2 18 25 50 45 0.01
only does the use of water as solvent permit multicomponent H2O 3.5 25 100 95 0.18
2.5 M aq LiCl 0.3 25 100 95 ND
reactions to be conducted rapidly, the products are often insoluble, 1.0 M aq LiCl 0.8 25 100 95 2.86
facilitating their ready isolation. This method permits rapid 1.0 M aq glucose 0.8 25 100 95 ND
syntheses of compound libraries. 0.5 M aq glucose 2 25 100 94 1.29
As a prototype, the Passerini reaction in eq 1 (see Scheme 1) H2O 2 4 100 93 0.20
H2O 5 50 100 91 0.10
was studied under various conditions summarized in Table 1. In
CH2Cl2 this reaction gives fair conversion and yield. When a ND - not determined. b Percent standard deviations were 3-6%.
performed in water, the reaction is complete in 3.5 h (95% isolated)
and becomes heterogeneous because the product is poorly soluble. The broader applicability of the accelerating effect of water on
Determination of the rates of product formation by gas chroma- multicomponent reactions is supported by a nearly 50-fold ac-
tography (after extraction into organic solvent) showed that water celeration for the Ugi reaction in eq 2. Likewise, the creation of
provides ∼18-fold acceleration over CH2Cl2. To address questions strained β-lactam rings by Ugi reaction with β-keto-acids is
concerning the basis of the rate acceleration (vide infra), this unknown in organic solvents, as exemplified by the complete failure
reaction was examined in MeOH (no reaction) and formamide (15% of the reaction in eq 3 in MeOH, THF, or CH2Cl2. This reaction
conversion, 24 h). Because the hydrophobic effect is increased by proceeds well in water, however (72 h, 65% yield).
ionic or nonionic solutes,6 the effects of LiCl and glucose were Evaluation of the effects of water on multicomponent reactions
examined. At high LiCl concentration, the reaction was so fast that known to be accelerated by high pressure also seemed germane to
quality rate data could not be obtained; therefore, a lower this work. The Passerini reaction shown in eq 4 was reported8 to
concentration was used to demonstrate an additional 16-fold require 16.5 h at 3 kbar in 3-methyl-2-butanone as solvent (39%
acceleration over pure water. Likewise, a high glucose concentration isolated yield). Of course, performing a reaction in water is much
provided a very rapid rate, and lower glucose concentration showed more convenient than performing it at high pressure. In pure water
7-fold acceleration over pure water. While solute effects have earlier (36 h, mechanical shaking, 44% conversion), the product can be
been used to examine the acceleration of reactions in water, obtained in comparable yield using only 5 equiv of ketone. In 2.5
temperature effects have not often been studied. At 4 °C, the rate M aqueous LiCl, the isolated yield is 65%. The Ugi reaction shown
increases 11%, and at 50 °C, the rate decreases 44%. in eq 5 was reported9 to require 14 d at a pressure of 9 kbar in
444 9 J. AM. CHEM. SOC. 2004, 126, 444-445 10.1021/ja038583a CCC: $27.50 © 2004 American Chemical Society

Chart 1. Building Blocks for Multicomponent Reactions
Scheme 2. Synthesis of a β-Lactam Library by Ugi Reaction
CH2Cl2 (61% isolated yield). In pure water at STP, the product is
isolated in 55% yield in only 72 h, and in 2.5 M aqueous LiCl the
yield is 75%.
This method for the acceleration of multicomponent reactions
was applied to the parallel synthesis of 32 Passerini reaction
products from building blocks 1, 2, and 3 (Chart 1). The acid was
used in 10% excess, with the aldehyde and isonitrile in equimolar
amounts. These reactions are complete in 3-6 h at 25 °C. For solid
products, isolation simply involved filtration and washing with 10%
aqueous NaHCO3. For the few liquid products, isolation was by
extraction, filtration through NaHCO3/Celite and Na2SO4/SiO2, and
evaporation. Yields were 72-93% (av 87%), and crude HPLC
purities were 72-100% (av 87%). Likewise, preparation of Ugi
reaction products by parallel synthesis was performed in water.
Amines 4 were used with building blocks 1, 2 (except 2{4}), and
3 to give a 48-compound library. These reactions were complete
in 3 h at 25 °C, and products were isolated by extraction. The crude
HPLC purities were 83-99% (av 95%), and yields were 78-95%
(av 86%). These results are summarized in Tables S1 and S2.
Use of β-amino acids in the Ugi reaction (Scheme 2) produces
β-lactams.12 A library of 32 β-lactams was created by Ugi reaction
in water using building blocks 2, 3, and 5 and isolated by extraction.
The HPLC purity of the crude reaction products was 70-99% (av
89%), and the yields of these products were 71-89% (av 84%).
These results are summarized in Table S3.
Identification of specific factors contributing to acceleration in
water of the multistep reactions studied here is even more
challenging than with concerted reactions such as the Diels-Alder
reaction. Direct mechanistic involvement of water in bond-making
COMMUNICATIONS
is a tempting alternative to hydrophobic and cohesive energy density
effects or hydrogen bonding in the transition state. Significantly
slower rates in the protic, hydrogen-bonding solvent methanol
suggest that water plays no direct role in these reactions. Formamide
has a lower cohesive energy density (376.4 cal‚mL-1) than water
but a higher dielectric constant. The reaction in eq 1 is much slower
in formamide, suggesting that cohesive energy density is more
important than dielectric constant and refuting the hypothesis that
stabilization of charged intermediates in water contributes to rate
acceleration.
Distinguishing between hydrophobic and cohesive energy density
effects on rates can be difficult because hydrophobic effects scale
with the solvent-accessible surface area in the transition state and
cohesive energy density effects scale with the volume of the
transition state. These parameters are obviously correlated. The
cohesive energy density of water decreases with temperature [554.3
at 4 °C (+0.75% vs rt); 542.2 at 50 °C (-1.45% vs rt)], which
may explain the inverse temperature dependence. The much slower
reaction in formamide suggests a steep dependence of the rate on
cohesive energy density. Alternatively, when the rate is sensitive
to hydrophobic effects, inverse temperature dependence may result
from a large heat capacity of activation.14
The utility of two multicomponent reactions has been signifi-
cantly expanded by conducting them in water. They can exhibit
rate accelerations compared to those in organic solvents of nearly
300-fold, and the insolubility of the Passerini products in water
makes isolation trivial. The crude reaction products show purity
adequate for initial biological testing.
Acknowledgment. Financial support from NIH AI48521 is
gratefully acknowledged.
Supporting Information Available: Tables of yields and purities
for each library (PDF). This material is available free of charge via the
Internet at http://pubs.acs.org.
References
(1) Breslow, R. In Green Chemistry; Anastas, P. T., Williamson, T. C., Eds.;
Oxford Press: New York, 1998, Chapter 13. DeSimone, J. M. Science
2002, 297, 799-803.
(2) Otto, S.; Engberts, J. B. F. N. Pure Appl. Chem. 2000, 72, 1365-1372.
(3) Breslow, R. Acc. Chem. Res. 1991, 24, 159-164. Otto, S.; Engberts, J.
B. F. N. Org. Biomol. Chem. 2003, 1, 2809-20.
(4) Chandrasekhar, J.; Shariffskul, S.; Jorgensen, W. L. J. Phys. Chem. B
2002, 106, 8078-85.
(5) Lubineau, A.; Augé, J. Top. Curr. Chem. 1999, 206, 2-39. Lubineau,
A.; Augé, J.; Queneau, Y. Synthesis 1994, 742-60.
(6) Lubineau, A. J. Org. Chem. 1986, 51, 2142-2144.
(7) Ugi, I.; Heck, S. Comb. Chem. High Throughput Screen. 2001, 4, 1-34.
(8) Jenner, G. Tetrahedron Lett. 2002, 43, 1235-1238.
(9) Yamada, T.; Yanagi, T.; Omote, Y.; Miyazawa, T.; Kuwata, S.; Sugiura,
M.; Matsumoto, K. J. Chem. Soc., Chem. Commun. 1990, 1640-1.
(10) The Ugi and Passerini reactions have been conducted in water using sugar
reactants (de Nooy, A. E. J.; Masci, G.; Crescenzi, V. Macromolecules
1999, 32, 1318-20), but this work did not compare the rates to reactions
in organic solvent.
(11) Baker, R. H.; Stanonis, D. J. Am. Chem. Soc. 1951, 73, 699-702.
(12) Gedey, S.; van der Eycken, J.; Fülöp, F. Org. Lett. 2002, 4, 1967-1969.
(13) Dack, M. R. J. Chem. Soc. ReV. 1975, 4, 211-229.
(14) Kohnstam, G. AdV. Phys. Org. Chem. 1967, 5, 121-172.
JA038583A
J. AM. CHEM. SOC. 9 VOL. 126, NO. 2, 2004 445
 Angewandte
Chemie

Organic Chemistry

“On Water”: Unique Reactivity of Organic

Compounds in Aqueous Suspension**

Sridhar Narayan, John Muldoon, M. G. Finn,

Valery V. Fokin, Hartmuth C. Kolb, and
K. Barry Sharpless*

Water is a desirable solvent for chemical reactions for reasons

of cost, safety, and environmental concerns, and the study of
organic reactions in aqueous solvents has an intriguing
history.[1] Most notably, certain pericyclic reactions such as

[*] Dr. S. Narayan, Dr. J. Muldoon, Prof. M. G. Finn, Prof. V. V. Fokin,

Prof. H. C. Kolb, Prof. K. B. Sharpless
Department of Chemistry and
the Skaggs Institute of Chemical Biology
The Scripps Research Institute
10550 North Torrey Pines Road
La Jolla, CA 92037 (USA)
Fax: (+ 1) 619-554-6738
E-mail: sharples@scripps.edu
[**] We thank Dr. Vladislav Litosh for carrying out preliminary work.
Support from the National Institutes of Health, National Institute of
General Medical Sciences (GM 28384), the National Science
Foundation (CHE9985553), the Skaggs Institute for Chemical
Biology, and the W. M. Keck Foundation is gratefully acknowledged.
S.N. thanks the Skaggs Institute for a postdoctoral fellowship. We
also thank Dr. Suresh Suri, Edwards Air Force Base, California, for a
generous gift of quadricyclane. We urge our fellow chemists to float
their problematic reactions on water and to send observations of
success or failure to us at onwater@scripps.edu for public
dissemination with attribution.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.

Angew. Chem. Int. Ed. 2005, 44, 3275 –3279 DOI: 10.1002/anie.200462883
2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim 3275
Communications
Diels–Alder cycloadditions[2] and Claisen rearrangements[3] stirring the reactant(s) with water to generate an aqueous
of hydrophobic compounds have been found to be acceler- suspension. Nonpolar liquids that separate from water into a
ated in dilute aqueous solution. Yet, either organic co- clear organic phase are ideal candidates for these reactions.
solvents and/or substrate modifications are almost always Solid reactants can also be utilized, provided one reaction
employed in preparative-scale reactions performed in partner is a liquid and adequate mixing is ensured. Vigorous
water,[1] as it is assumed that solubility is required for efficient stirring promotes the reaction, most likely by increasing the
reaction. Not only do these strategies detract from the area of surface contact between the organic and aqueous
simplicity and advantages sought from the use of water in phases. The observed rate acceleration does not depend on
the first place, but, as we report here, the venerable the amount of water used, as long as sufficient water is present
assumption “corpora non agunt nisi soluta” (substances do for clear phase separation to occur.[10] The product is isolated
not interact unless dissolved) can be distinctly counterpro- simply by phase separation or filtration. In cases where clear
ductive. phase separation does not occur, such as in small-scale
In recent years, we have focused on modular synthetic reactions, liquid–liquid extraction may be necessary.
techniques that rely on a few nearly perfect reaction types.[4] Seeking insight into the origin of rate acceleration in the
In the course of this work, we have noticed that many such DMAD–quadricyclane cycloaddition, the reaction between 1
reactions often proceed optimally in pure water,[5] and and 2 was carried out under a variety of conditions and the
particularly when the organic reactants are insoluble in the time to completion was monitored (Table 2). Under homo-
aqueous phase.[6] We present here several examples that
illustrate a remarkable phenomenon: substantial rate accel- Table 2: Reaction of quadricyclane (1) with dimethyl azodicarboxylate in
eration when insoluble reactants are stirred in aqueous various solvents.[a]
suspension, denoted here as “on water” conditions. Even
when the rate acceleration is negligible, the use of water as the
only supporting medium has other advantages including ease
of product isolation and above all, safety, thanks to its high
heat capacity[7] and unique redox stability. Solvent Conc. [m][b] Time to completion
In connection with our studies on the reactivity of strained toluene 2 > 120 h
olefins, we explored the preparation of 1,2-diazetidines from EtOAc 2 > 120 h
quadricyclane (1) by the 2s + 2s + 2p cycloaddition with CH3CN 2 84 h
azodicarboxylates, discovered by Lemal and co-workers.[8] CH2Cl2 2 72 h
DMSO 2 36 h
The typical reaction conditions involve heating 1 with
MeOH 2 18 h
dimethyl azodicarboxylate (DMAD, 2) in toluene or benzene neat 4.53 48 h
at 80 8C for 24 h or longer.[8, 9] In contrast, when a mixture of on D2O 4.53 45 min
DMAD and quadricyclane is vigorously stirred “on water”, on C6F14 4.53 36 h
the reaction is complete within a few minutes at ambient on H2O 4.53 10 min
temperature. The corresponding neat (solvent-free) reaction MeOH/H2O (3:1, homogeneous) 2 4h
of these two liquids takes nearly two days to reach comple- MeOH/H2O (1:1, heterogeneous) 4.53 10 min
MeOH/H2O (1:3, heterogeneous) 4.53 10 min
tion, which shows that the rate acceleration is not the sole
consequence of an increase in the effective concentration of [a] Compound 3 was the only product observed in each case. [b] Con-
reagents (Table 1). centrations of the neat and heterogeneous reactions are calculated from
the measured density of a 1:1 mixture of 1 and 2. DMSO = dimethyl-
As the cycloaddition of DMAD with quadricyclane
sulfoxide.
demonstrates, the “on water” method consists simply of

genous conditions, polar protic solvents accelerate the

Table 1: Reaction of quadricyclane (1) with dimethyl azodicarboxylate reaction, with observed reaction rates in the following
(2). order: MeOH/H2O (3:1) > MeOH > DMSO > CH3CN 
CH2Cl2 > EtOAc  toluene.[11] This trend suggests that hydro-
gen bonding, charge stabilization, and dipolar effects may
each be important for rate acceleration.[12] While water
contributes to such properties in homogeneous mixtures,
Solvent Conc. [m] T [8C] t Yield [%][a] heterogeneity was crucial for observing large rate accelera-
tions. Thus, the presence or absence of methanol in a
neat 4.53[b] 0 2h 0[c]
heterogeneous reaction made little difference, but the rate
neat 4.53[b] 23 48 h 85
toluene 1 80 24 h 74
slowed considerably when enough methanol was used to
on H2O 4.53[d] 0 1.5 h 93 make the reaction homogeneous. However, heterogeneity in
on H2O 4.53[d] 23 10 min 82 itself is not responsible for rate acceleration as the reaction
“on” perfluorohexane was only slightly faster than the neat
[a] Yields are of isolated pure products. [b] Calculated from the measured
density of a 1:1 mixture of 1 and 2. [c] No product discernible after 2 h. reaction. Interestingly, a significant solvent isotope effect was
[d] The maximum effective concentration “on water” is assumed to be also observed: the reaction slowed noticeably when D2O was
the same as that of the neat reaction. used in place of water.

3276
2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim www.angewandte.org Angew. Chem. Int. Ed. 2005, 44, 3275 –3279

Acceleration of reactions “on water” is evident even when
a nonpolar solvent comprises a part or most of the organic
phase as shown in Table 3. Thus, the reaction of quadricyclane
(1) with diethyl azodicarboxylate (DEAD, 4), carried out
simply by stirring a toluene solution of DEAD with 1 “on
water”, proceeds at a considerably higher rate than when the
reaction is carried out in toluene alone.
Table 3: Cycloaddition of quadricyclane (1) performed with DEAD
(commercial reagent in toluene) “on water”.[a]
t [h] Conversion [%][b]
toluene[c] toluene on H2O[d]
3 4 42
6 8 56
17 18 69
[a] Isolated yield after 24 h at 23 8C: toluene, 24 %; toluene “on water”,
72 %. [b] Determined by 1H NMR spectroscopy using acetophenone as
internal standard. [c] Commercial DEAD in toluene used (49 %, 2.86 m).
[d] As [c], except for the presence of an equal volume of water to toluene.
We have found that the high reactivity of azodicarbox-
ylates “on water” is not limited to their cycloaddition
reactions: the ene reactions of these compounds respond
similarly to conditions of aqueous suspension relative to
organic solution. Leblanc et al. have used the ene reaction of
bis(trichloroethyl) azodicarboxylate (7) to achieve the allylic
amination of olefins under thermal conditions.[13] In nonpolar
solvents such as benzene, prolonged heating at 80 8C was
reportedly required to attain useful levels of reactivity with
simple olefins such as cyclohexene (6). In the absence of
solvent, the reaction of liquid 6 and solid 7 was found to
proceed at 50 8C, but still required 36 h for completion as well
as the presence of excess cyclohexene. In contrast, the
reaction performed “on water” was complete within eight
hours at 50 8C and afforded the product in 91 % yield (see
Table 4). The neat reaction between 6 and 7 not only
appeared to be slower, but the reaction mixture was also
considerably harder to mix uniformly. In contrast, when
heated to 50 8C “on water” the reaction mixture initially
formed a molten organic phase, which gave way to the
Table 4: Ene reaction of cyclohexene (6) with bis(trichloroethyl) azodi-
carboxylate (7) “on water”.
Solvent T [8C] t [h] Yield [%]
benzene 80 24 70[a]
neat 50 36[b] 62
on H2O 50 8 91
[a] Data from Ref. [13]. [b] Additional 6 added after 24 h.
Angew. Chem. Int. Ed. 2005, 44, 3275 –3279 www.angewandte.org
Angewandte
Chemie
product as a white precipitate. In practical terms, reactions of
solid components in aqueous suspension are more reprodu-
cible and convenient than in the absence of solvent, as water
provides for efficient “mixing” of the reactants without the
dilution cost of a true solvent. Furthermore, the effective
melting point of solid reaction mixtures is noticeably lowered
in the presence of water, such that a fused organic phase is
often formed.
The notion of the special nature of water as a solvent for
organic reactions began with examples of Diels–Alder
reactions more than fifty years ago.[14] The first quantitative
data were reported by Rideout and Breslow, who showed that
Diels–Alder reactions between nonpolar compounds pro-
ceeded at much higher rates in water (dilute homogeneous
solution) than in organic solvents.[15] Rate accelerations as
high as 200-fold were noted in certain cases. Breslow et al.
also noted the high endo selectivity of certain Diels–Alder
reactions carried out in water, under both homogeneous and
heterogeneous conditions.[16] Although rate acceleration and
selectivity were ascribed primarily to hydrophobic effects, it
has since been appreciated that hydrogen bonding plays an
important role.[17] Ironically, much of the careful quantitative
work on the process does not directly apply to synthetic
chemistry, as the experiments reported by Breslow, Engberts,
and others were conducted at low concentrations (mm or less)
to maintain homogeneity in water, while preparative reac-
tions usually require much higher concentrations. In a rare
example of a heterogeneous process, Grieco et al. reported
the Diels–Alder reaction of an acyclic diene bearing a
carboxylic acid group to occur in aqueous suspension faster
than in organic solution.[18] The best results were obtained in
the reactions of diene carboxylate salts with various dien-
ophiles in water, and the rate accelerations due to water were
ascribed to micellar catalysis.[19] As some of these reactions
were carried out under conditions similar to ours, we
evaluated the effectiveness of the “on water” protocol for
Diels–Alder reactions.
We performed the cycloaddition of the water-insoluble
trans, trans-2,4-hexadienyl acetate (9) and N-propylmaleimide
(10) under various conditions (Table 5). As before, a protic
solvent (methanol) was better than nonprotic solvents, and
Table 5: Comparison of water versus organic solvents for a typical Diels–
Alder reaction.
Solvent Conc. [m] Time to completion [h] Yield [%]
toluene 1 144 79
CH3CN 1 > 144 43[a]
MeOH 1 48 82
neat 3.69[b] 10 82
H2O 3.69[b] 8 81
[a] Yield after chromatographic purification. Other yields are of crude
products, which were > 95 % pure by 1H NMR spectroscopy. [b] Calcu-
lated from the measured density of a 1:1 mixture of 9 and 10.

2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim 3277
Communications
the reaction in aqueous suspension showed substantial rate
acceleration over homogeneous solution. Consistent with the
results of Grieco et al.[18] and in contrast to the reaction of 1 +
2 described above, the neat Diels–Alder addition of 9 to 10
(both liquids) was approximately as fast as in water suspen-
sion.[20]
Claisen rearrangements are another significant class of
reactions for which the accelerating effect of water is well-
recognized.[21] The initial discovery appears to have been
made during mechanistic studies of the chorismate–prephen-
ate rearrangement, a key step in the biosynthesis of shikimic
acid.[22] Brandes, Grieco, and Gajewski then performed a
kinetic study on the rearrangement of an allyl vinyl ether
substrate with an attached carboxylate functionality.[23] The
rate of rearrangement of the carboxylate salt in water was
found to be about two orders of magnitude higher than that of
the methyl ester in nonpolar solvents.[24] These findings were
exploited further by Grieco et al., who used the accelerating
influence of water to promote difficult rearrangements.[25]
In contrast to the aliphatic Claisen rearrangements, the
effect of water on the analogous aromatic Claisen rearrange-
ment is little known.[26] We have made preliminary measure-
ments on naphthyl ether 12, which undergoes rearrangement
at an appreciable rate even at room temperature. Table 6
Table 6: Comparison of solvents for an aromatic Claisen rearrangement
(0.28–0.46 m), performed at room temperature.[a]
Solvent Yield [%][b]
toluene 16
DMF 21
CH3CN 27
MeOH 56[c]
neat 73
on H2O 100
[a] Conversion was monitored by 1H NMR analysis of aliquots. [b] Except
in the case of MeOH, no other products were detected by 1H NMR
spectroscopy. [c] 14 % of 4-chloro-1-naphthol was also observed.
shows the effect of various solvents on this process. After five
days at 23 8C, the sample of 12 in aqueous suspension had
completely rearranged to 13, while the rearrangement was
considerably slower in organic solvents. The neat reaction was
again closest in rate to water and required one further day to
reach completion. As with Diels–Alder reactions, the “on
water” protocol provides the best set of conditions in terms of
efficiency, convenience, and safety, even when rate acceler-
ations are not large.
Non-pericyclic reactions such as the opening of epoxides
and aziridines with heteroatom nucleophiles also derive
unique benefits from the “on water” environment. Hydrogen
bonding is crucial for the activation of such electrophiles,
making these ring-opening processes autocatalytic and diffi-
3278
2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
cult to control under neat conditions. Instead, protic solvents
such as alcohols and especially alcohol/water mixtures
provide good homogeneous media for these transforma-
tions.[4] Here too, we find that water alone is the medium of
choice. The reactions are completed in shorter times than in
other protic solvents, and the pure product often precipitates,
to be isolated by simple filtration.
The reaction of cyclohexadiene monoepoxide (14) with N-
(3-chlorophenyl)piperazine (15) is illustrative (Table 7).
Table 7: Application of the “on water” method to the nucleophilic
opening of an epoxide.
Solvent Conc. [m] t [h] Yield [%]
toluene 1 120 < 10[a]
neat 3.88[b] 72 76
EtOH 1 60 89
on H2O 3.88[b] 12 88
[a] Determined by 1H NMR spectroscopic analysis of the crude reaction
mixture. [b] Calculated from the measured density of a 1:1 mixture of 14
and 15.
When heated at 50 8C, the reaction “on water” was completed
overnight, while the reactions in solution in ethanol or
without solvent required approximately three days to reach
completion. In toluene, less than 10 % conversion occurred
after five days at the same temperature. Thus, taking into
account the concentrations of the reagents, the rates of
reactions “on water” and in ethanol appeared to be approx-
imately the same, and greater than that for the reaction
performed in the absence of solvent.
Thus, a variety of reactions can be efficiently carried out in
aqueous suspension, with the most dramatic effects observed
for the addition of azodicarboxylates to unsaturated hydro-
carbons. To the best of our knowledge, these examples
represent some of the largest rate accelerations due to water
observed under preparative conditions, that is, at molar
concentrations. A central theme in the field of aqueous
organic chemistry has been the need to promote solubility in
these reactions. Clearly, solubility is not essential.
Although the reactivity phenomenon described here has
immediate practical implications, its origins are presently
unclear; nevertheless, a few preliminary remarks are in order.
For example, it is possible that reactions “on water” actually
proceed through small amounts of dissolved solutes. Rate
acceleration in homogeneous aqueous solution has been
attributed to a variety of effects such as hydrophobic
aggregation,[2, 15] cohesive energy density,[27] or ground-state
destabilization.[28, 29] Breslow et al. have invoked solution-
phase hydrophobic effects to explain the high endo selectivity
of certain Diels–Alder reactions in aqueous suspension and
solution.[2a, 16] Engberts and co-workers made a fundamental
point by providing evidence that, in cycloaddition reactions,
hydrophobic destabilization will have a considerably greater
www.angewandte.org Angew. Chem. Int. Ed. 2005, 44, 3275 –3279

impact on the ground state than on the transition state.[29, 30]
The importance of hydrogen bonding in the acceleration of
Diels–Alder reactions in aqueous solution is supported by
both experimental[31] and theoretical[32] studies.
However, it seems that many of the reactions described
above are simply too fast for the acceleration to be solely due
to solution-phase phenomena. In this regard, the observed
requirement for heterogeneity and the finding that the rates
of reactions “on water” often exceed those of the same
reactions performed in the absence of solvent demand
attention. Perhaps the unique properties of molecules at the
macroscopic phase boundary between water and insoluble
hydrophobic oils play a role.[33] The same principles that
contribute to solution-phase effects may be amplified at such
phase boundaries, but other factors, such as the redistribution
of surface species driven by surface-tension energetics,[34] may
also be relevant. We plan to keep exploring the “on water”
phenomenon both for practical applications and mechanistic
understanding.
Received: December 10, 2004
Published online: April 21, 2005
.
Keywords: click chemistry · cycloaddition · interfaces ·
rearrangement · water chemistry
[1] a) Organic Synthesis in Water (Ed.: P. A. Grieco), Blackie,
London, 1998; b) C.-J. Li, Chem. Rev. 1993, 93, 2023; c) U. M.
Lindstrom, Chem. Rev. 2002, 102, 2751.
[2] a) R. Breslow, Acc. Chem. Res. 1991, 24, 159; b) “Structure and
Reactivity in Aqueous Solution”, R. Breslow, ACS Symp. Ser.
1994, 568, 291.
[3] J. J. Gajewski, Acc. Chem. Res. 1997, 30, 219.
[4] H. C. Kolb, M. G. Finn, K. B. Sharpless, Angew. Chem. 2001, 113,
2056; Angew. Chem. Int. Ed. 2001, 40, 2004.
[5] V. V. Fokin, K. B. Sharpless, Angew. Chem. 2001, 113, 3563;
Angew. Chem. Int. Ed. 2001, 40, 3455.
[6] Z. M. Wang, K. B. Sharpless, J. Org. Chem. 1994, 59, 8302; Z. P.
Demko, K. B. Sharpless, J. Org. Chem. 2001, 66, 7945.
[7] At 4.18 J cm 3 K, water has an unusually high heat capacity for a
liquid; see: NIST Chemistry WebBook (Eds.: P. J. Linstrom,
W. G. Mallard), NIST Standard Reference Database Number 69,
March 2003, National Institute of Standards and Technology,
Gaithersburg MD, 20899 (http://webbook.nist.gov).
[8] N. Rieber, J. Alberts, J. A. Lipsky, D. M. Lemal, J. Am. Chem.
Soc. 1969, 91, 5668.
[9] R. Platz, W. Fuchs, N. Rieber, U.-R. Samuel, J. Jung (BASF AG),
DE 2615878, 1977 [Chem. Abstr. 1978, 88, 37 803].
[10] The amount of water used can be chosen to best balance/control
the exothermicity of the reaction, as the resulting increase in
total reaction volume does not constitute dilution of the reaction
zone.
[11] For an example of solvent effect on the cycloaddition of
quadricyclane with azodicarbonyl compounds, see: M. E.
Landis, J. C. Mitchell, J. Org. Chem. 1979, 44, 2288.
[12] A. Rodgman, G. F. Wright, J. Org. Chem. 1953, 18, 465. For the
only reported example, to our knowledge, of the accelerating
influence of water on the reactions of azodicarboxylates, see:
L. E. Gast, E. W. Bell, H. M. Teeter, J. Am. Oil Chem. Soc. 1956,
33, 278.
[13] Y. Leblanc, R. Zamboni, M. A. Bernstein, J. Org. Chem. 1991,
56, 1971; For Lewis acid mediated ene reactions of azodicarbox-
Angew. Chem. Int. Ed. 2005, 44, 3275 –3279 www.angewandte.org
Angewandte
Chemie
ylates at 60 8C, see: M. A. Brimble, C. H. Heathcock, J. Org.
Chem. 1993, 58, 5261.
[14] R. B. Woodward, H. Baer, J. Am. Chem. Soc. 1948, 70, 1161; H.
Hopff, C. W. Rautenstrauch, US 2262002, 1939 [Chem. Abstr.
1942, 36, 10 469].
[15] D. C. Rideout, R. Breslow, J. Am. Chem. Soc. 1980, 102, 7816.
[16] R. Breslow, U. Maitra, D. Rideout, Tetrahedron Lett. 1983, 24,
1901.
[17] For an excellent recent review of the role of hydrophobic effects
on reactivity, see: S. Otto, J. B. F. N. Engberts, Org. Biomol.
Chem. 2003, 1, 2809.
[18] P. A. Grieco, P. Garner, Z. He, Tetrahedron Lett. 1983, 24, 1897.
[19] P. A. Grieco, K. Yoshida, P. Garner, J. Org. Chem. 1983, 48, 3137;
However, see: R. Breslow, U. Maitra, Tetrahedron Lett. 1984, 25,
1239, and Ref. [28b].
[20] As both starting materials and the product are oils, the neat
reaction is not prone to physical “mixing” issues, which can arise
when one of the reactants is a solid. Even when mixing is not an
issue, we have encountered a few cases where the reactions “on
water” are two- to threefold faster than the corresponding neat
reaction, although the example shown here is typical.
[21] J. J. Gajewski in Organic Synthesis in Water (Ed.: P. A. Grieco),
Blackie, London, 1998, p. 82.
[22] a) S. D. Copley, J. R. Knowles, J. Am. Chem. Soc. 1987, 109,
5008; b) R. M. Coates, B. D. Rogers, S. J. Hobbs, D. R. Peck,
D. P. Curran, J. Am. Chem. Soc. 1987, 109, 1160; c) J. J. Gajewski,
J. Jurayj, D. R. Kimbrough, M. E. Gande, B. Ganem, B. K.
Carpenter, J. Am. Chem. Soc. 1987, 109, 1170; d) B. Ganem,
Angew. Chem. 1996, 108, 1015; Angew. Chem. Int. Ed. Engl.
1996, 35, 937.
[23] E. Brandes, P. A. Grieco, J. J. Gajewski, J. Org. Chem. 1989, 54,
515.
[24] Grieco subsequently reported that the rearrangement of the
same methyl ester in aqueous suspension was qualitatively
comparable in rate and efficiency to that of the carboxylate salt
in homogeneous solution. See Ref. [25].
[25] P. A. Grieco, E. B. Brandes, S. McCann, J. D. Clark, J. Org.
Chem. 1989, 54, 5849.
[26] a) W. N. White, E. F. Wolfarth, J. Org. Chem. 1970, 35, 2196; b) J.
An, L. Bagnell, T. Cablewski, C. R. Strauss, R. W. Trainor, J.
Org. Chem. 1997, 62, 2505.
[27] a) G. Desimoni, G. Faita, P. P. Righetti, L. Toma, Tetrahedron
1990, 46, 7951; b) J. J. Gajewski, J. Org. Chem. 1992, 57, 5500;
“Structure and Reactivity in Aqueous Solution: Characterization
of Chemical and Biological Systems”, J. J. Gajewski, N. L.
Brichford, ACS Symp. Ser. 1994, 568, 229.
[28] a) W. Blokzijl, J. B. F. N. Engberts, Angew. Chem. 1993, 105,
1610; Angew. Chem. Int. Ed. Engl. 1993, 32, 1545; b) “Structure
and Reactivity in Aqueous Solution”, W. Blokzijl, J. B. F. N.
Engberts, ACS Symp. Ser. 1994, 568, 303.
[29] A. Meijer, S. Otto, J. B. F. N. Engberts, J. Org. Chem. 1998, 63,
8989.
[30] W. Blokzijl, J. B. F. N. Engberts, J. Am. Chem. Soc. 1992, 114,
5440.
[31] a) S. Otto, W. Blokzijl, J. B. F. N. Engberts, J. Org. Chem. 1994,
59, 5372; b) G. K. van der Wel, J. W. Wijnen, J. B. F. N. Engberts,
J. Org. Chem. 1996, 61, 9001.
[32] J. Chandrasekhar, S. Shariffskul, W. L. Jorgensen, J. Phys. Chem.
B 2002, 106, 8078.
[33] a) R. U. Lemieux, Acc. Chem. Res. 1996, 29, 373; b) D. N. Shin,
J. W. Wijnen, J. Engberts, A. Wakisaka, J. Phys. Chem. B 2001,
105, 6759; c) D. N. Shin, J. W. Wijnen, J. Engberts, A. Wakisaka,
J. Phys. Chem. B 2002, 106, 6014; d) S. K. Pal, J. Peon, A. H.
Zewail, Proc. Natl. Acad. Sci. USA 2002, 99, 1763; e) L. R. Pratt,
A. Pohorille, Chem. Rev. 2002, 102, 2671.
[34] J. T. Koberstein, J. Polym. Sci. Part B 2004, 42, 2942.

2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim 3279
 View Article Online / Journal Homepage / Table of Contents for this issue

TUTORIAL REVIEW www.rsc.org/csr | Chemical Society Reviews

Organic chemistry in water

Chao-Jun Li*ab and Liang Chenb
Received 24th October 2005
First published as an Advance Article on the web 21st November 2005
DOI: 10.1039/b507207g

Water has emerged as a versatile solvent for organic chemistry in recent years. Water as a solvent
is not only inexpensive and environmentally benign, but also gives completely new reactivity. The
types of organic reactions in water are broad including pericyclic reactions, reactions of carbanion
equivalent, reactions of carbocation equivalent, reactions of radicals and carbenes, transition-
metal catalysis, oxidations-reductions, which we discuss in this tutorial review. Aqueous organic
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reactions have broad applications such as synthesis of biological compounds from carbohydrates
and chemical modification of biomolecules.

1. Introduction oxygen gas in water, an important property in the early

Life, the most complex form of organic compounds on Earth,
requires the construction of chemical bonds in an aqueous
environment. Following nature’s lead, we should think of
water as a versatile solvent for organic chemistry. Since it was
reported that Diels–Alder reactions could be greatly acceler-
ated by using water as a solvent instead of organic solvents,1
there has been considerable attention directed toward the
development of organic reactions in water. Besides Diels–
Alder reactions, other examples cover almost all of the most
useful organic reactions, even reactions involving water-
sensitive compounds.2 It is obvious that water is the most
inexpensive and environmentally benign solvent. 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. Furthermore, the low solubility of
development of life in an anaerobic environment, can facilitate
air-sensitive transition-metal catalysis in open air. The use of
water as a solvent also implies the elimination of tedious
protection–deprotection processes for certain acidic-hydrogen-
containing functional groups, which contributes to the overall
synthetic efficiency. Water soluble compounds such as
carbohydrates, can be used directly without the need for
laborious derivatization and water-soluble catalysts can be re-
used after separation from water-insoluble organic products.
Aqueous organic chemistry is also essential for the emerging
field of chemical biology which uses chemical tools to study
biological systems. Although aqueous organic chemistry has
broad applications and a bright future, current organic
chemistry textbooks do not touch on this subject. In order to
compensate for this omission in organic chemistry textbooks,
this introductory review will provide non-specialists with some
insight into this field.

a
Department of Chemistry, McGill University, 801 Sherbrooke Street 2. Pericyclic reactions
West, Montreal, Quebec H3A 2K6, Canada
b
Department of Chemistry, Tulane University, New Orleans, Pericyclic reactions are important processes in organic synth-
Louisiana 70118, USA esis for constructing cyclic structures and for controlling

Chao-Jun Li received his PhD at Liang Chen was born in 1977

McGill University (1992). He
spent 1992–94 as a NSERC
Postdoctoral Fellow at Stanford
University and became assistant
professor (1994), associate pro-
fessor (1998), and full professor
(2000) at Tulane University
(US). In 2003, he became a Pro-
fessor and Canada Research
Chair (Tier I) in Organic/Green
Chemistry at McGill University
in Canada. His widely recognized
researches include the develop-
Chao-Jun Li ment of Grignard-type reactions
in water, transition-metal
catalysis in air and water, Alkyne-Aldehyde-Amine coupling (A3-
coupling), Asymmetric Alkyne-Aldehyde-Amine coupling (AA3-
coupling), and Cross-Dehydrogenative-Coupling (CDC) reactions.
in Fujian, China. He received
his Bachelor degree from
Nanjing University, China.
Thereafter, he spent two years
working with Professor Xiao-
rong Wang at the State Key
Laboratory of Pollution
Control & Resource Reuse
in Nanjing, China. In 2005,
he obtained his PhD under
the supervision of Professor
C.-J. Li at Tulane University,
New Orleans, for the develop-
Liang Chen ment of water-compatible
catalytic reactions of sp-C–H
bonds. Currently, he is a postdoctoral fellow with
Professor Yandulov at Stanford University, focusing on
catalytic fluorinations.

68 | Chem. Soc. Rev., 2006, 35, 68–82 This journal is ß The Royal Society of Chemistry 2006
 View Article Online

stereochemistry. Since Breslow’s discovery that Diels–Alder

reactions proceed faster (as high as 700-fold) and have a higher
endo/exo selectivity in water than in organic solvents, extensive
experimental and theoretical studies have been carried out on
this topic. The small size and high polarity of a water molecule,
as well as a three-dimensional hydrogen bonded network
system of bulk water, provide some unique properties which
include a large cohesive energy density, a high surface tension,
and a hydrophobic effect. These unique properties are believed
to be responsible for the rate and selectivity enhancements of
pericyclic reactions and the ‘‘on-water’’ effect. The hydrogen
bonding between water and organic molecules is also believed
to play an important role in the rate accelerations of some
organic reactions in water.
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It is worth mentioning that, in many cases, both water-

soluble and water-insoluble reactants can be accelerated in
water and, sometimes, larger rate increases are found
with water-insoluble substrates (denoted by Sharpless and
co-workers as the ‘‘on-water effect’’).3 For instance, the Diels–
Alder reaction (Scheme 1) of the water-insoluble trans, trans-
2,4-hexadienyl acetate (1) and N-propylmaleimide (2) showed
substantial rate acceleration in aqueous suspension over
homogeneous solution. The reaction rate is faster in a protic
solvent such as methanol than in nonprotic solvents such as
acetonitrile and toluene.3 It suggests that hydrogen bonding
and hydrophobic effects may both be important for the
observed rate acceleration.
Claisen rearrangements, which have negative volume
changes of activation as compared to the Diels–Alder
reactions, are also accelerated in water. The rearrangement
of naphthyl ether (4) to 5 in aqueous suspension is completed
within five days at room temperature, whereas it is much
slower in organic solvents (Scheme 2). The neat reaction is also
slower than the aqueous reaction.3
Beside Diels–Alder cycloadditions and Claisen rearrange-
ments, other pericyclic reactions also show rate enhancements
in water. For instance, 2s + 2s + 2p cycloaddition (Scheme 3)
Scheme 2 Rate acceleration of Claisen rearrangements by water
solvent. (Reprinted with permission from ref. 3. Copyright 2005,
Wiley-VCH.)
of quadricyclane (6) with azodicarboxylates (7) at room
temperature occurs much faster by using water as a solvent
than organic solvents.3 The unusual reactivity described here is
possibly due to the greater impact of the hydrophobic effect on
the ground state than the transition state.
The rate accelerations of pericyclic reactions in aqueous
solution have been applied to the total synthesis of a variety of
biologically active compounds. Total synthesis of gambogin
(14), a biologically active compound against the Hela and
HEL cell lines, includes two key steps of a Claisen rearrange-
ment and a Claisen/Diels–Alder cascade reaction (Scheme 4).
The Claisen/Diels–Alder cascade reaction from 10 to 11
showed dramatic rate accelerations in aqueous solutions
(Table 1). The great rate enhancement of Claisen rearrange-
ment from 12 to 13 is also observed in aqueous solutions
(Table 2).4
Various experiments indicate that the hydrogen-bonding
contributes, to a certain degree, to the rate enhancements of
pericyclic reactions in water as well as the hydrophobic effect.5
For example, the rate of the cycloaddition reactions of

Scheme 1 Rate acceleration of Diels–Alder reactions by water Scheme 3 Rate acceleration of 2s + 2s + 2p cycloadditions by water
solvent. (Reprinted with permission from ref. 3. Copyright 2005, solvent. (Reprinted with permission from ref. 3. Copyright 2005,
Wiley-VCH.) Wiley-VCH.)

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Scheme 4 Solvent effects for total synthesis of gambogin. (Reprinted with permission from ref. 4. Copyright 2005, Wiley-VCH.)

pyridazinium-dicyanomethanide 1,3-dipole (15) with the dipo-
larophile ethyl vinyl ketone (16) is enhanced by gradually
increasing the mole fraction of water in the organic solvents
(from 0 to 1) of acetonitrile, acetone, methanol, ethanol, and
tert-butyl alcohol at 37 uC (Scheme 5). In each case,
exponential rate enhancements are triggered as the mole
fraction of water surpasses ca. 0.9. When methanol replaces
water, no triggering effect is observed. These results suggest
that hydrogen-bonding and hydrophobic effects dominate the
rate enhancements. The theoretical calculation of the transi-
tion state structure strongly supports this conclusion.5
Beside the rate enhancement, the enhancement of endo/exo
selectivity of aqueous reactions is observed not only in non-
catalyzed Diels–Alder reactions but also in Lewis acid catalyzed-
reactions. For instance, compared to organic solvents, the
enantioselectivity of copper-catalyzed Diels–Alder reaction of

Table 1 Rate acceleration of the Claisen/Diels–Alder cascade reac- Table 2 Rate acceleration of the Claisen rearrangement from 12 to 13
tion from 10 to 11 by aqueous solutions by aqueous solutions
Solvent T/uC t/h Conversion [%] Solvent T/uC t/h Conversion [%]

MeOH 65 4 0 MeOH 50 4.5 50

Trifluoroethanol 65 4 0 Trifluoroethanol (TFE) 25 4 0
EtOH 65 4 0 EtOH 25 4 0
MeOH/H2O (1 : 1) 65 4 100 MeOH/H2O (1 : 1) 50 2.5 100
TFE/H2O (1 : 1) 65 4 100 TFE/H2O (1 : 1) 25 75 100
EtOH/H2O (1 : 1) 65 4 100 EtOH/H2O (1 : 1) 25 72 100

70 | Chem. Soc. Rev., 2006, 35, 68–82 This journal is ß The Royal Society of Chemistry 2006

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Scheme 5 Triggering effect for the introduction of water to organic
solvents in cycloaddition reactions.
Scheme 6 The enhancement of selectivity for Diels–Alder reaction by
water.
3-phenyl-1-(2-pyridyl)-2-propen-1-one (18) with cyclopenta-
diene (19) is greatly enhanced by the use of water as the
solvent (Scheme 6).6
In agreement with experiments, density functional theory
studies show that the computed endo preference is enhanced to
2.4 kcal mol21 in an aqueous solution. The endo/exo selectivity
partly arises from hydrogen bonding, and partly from the
bulk-phase effects, which includes enforced hydrophobic
interactions and anti-hydrophobic co-solvent effects.7
3. Reactions of carbanion equivalent
The metal-mediated carbanion based reaction is one of the
most important methods used to form carbon–carbon bonds.
Traditionally, many metal-mediated carbanion based reactions
involving organomagnesium and organolithium reagents are
often very hard to handle because these reactions require strict
exclusion of moisture and oxygen and often require low
temperature (e.g. 278 uC) conditions. Recently, they have been
modified to work successfully in water by using metals such as
indium, tin and zinc as the metal mediators for reactions of
carbonyl compounds and imines with allyl halides.42
Miyaura reported a rhodium-catalyzed addition of aryl or
alkenylboronic acids to a,b-unsaturated carbonyl compounds
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View Article Online
(Scheme 7)8 and 1,2-addition to aldehydes in aqueous organic
mixtures.9 Related asymmetric conjugate additions have been
(most noticeably) reported by Hayashi and co-workers.10
The Rh(I) [Rh(COD)2Cl or Rh(COD)2BF4]-catalyzed
Grignard-type phenylation of carbonyl compounds from
trimethylphenylstannane with aldehydes 21 occurs smoothly
in water and under an atmosphere of air.11 When methyl
groups of organotin compounds are replaced by halogens, the
reaction requires the addition of a base, which will generate
PhSn(OH)nX32n species in situ and enhance its reactivity
(Scheme 8A).12 Barbier-Grignard type carbonyl alkylation can
be carried out in water as well. In the presence of Zn/CuI and a
catalytic amount of InCl, the Barbier–Grignard type reaction
of various aldehydes 24 with alkyl iodides 25 yields the desired
alcohol products 26 in water (Scheme 8B).13 It is important to
note that the aldehyde bearing hydroxyl group does not have
to be protected prior to the reaction in water.
Although metal-mediated Barbier-type allylation reactions
are highly regio- and stereoselective, a-adduct products are
seldom to be obtained (Scheme 9A). With water as a solvent,
regioselective allylation (a-adduct versus c-adduct) becomes
possible. In the presence of 2 mL of water solvent, reaction of
1 mmol of aldehyde 27 with 1.2 mmol allyl bromide (28) gives
100% of c-adduct 29 in high yield; while in the presence of
6 equiv. of water solvent, 99% of a-adduct 30 is obtained
(Scheme 9B).14 Here, water is not only a good solvent for the
allylation reaction, but also is necessary for the formation of
an oxonium ion intermediate which furnishes a-adduct
products. Too much water solvent is believed to completely
suppress the formation of the oxonium intermediate.
Conjugate addition of unsaturated carbonyl compounds
with arylmetallic reagents also proceeds well in water. In the
presence of a Rh(I) catalyst, the reaction of phenyl tin chloride
32 with conjugated enone 31 successfully gives the desired
Scheme 7 Addition of boronic acid derivative to aldehydes in
aqueous conditions.
Scheme 8 Barbier–Grignard type reaction in water.
Chem. Soc. Rev., 2006, 35, 68–82 | 71
Published on 21 November 2005. Downloaded on 10/9/2020 1:53:32 PM.
Scheme 9 Water-induced selective allylation. (Reprinted with permission from ref. 14. Copyright 2003, American Chemical Society.)
addition product 33 in high yield in water under basic
conditions (Scheme 10).12
4. Reactions of carbocation equivalent
In organic reactions, carbocations are often initiated by the
coordination/reaction of protonic and Lewis acids. A variety
of Lewis and protonic acids-catalyzed reactions of carbocation
equivalent have been developed and many have been applied
in industry. However, these reactions generally are moisture
sensitive and even a small amount of water stops the reactions
because most acids react with water instead of the substrates.
Recently, various kinds of protonic and various Lewis acids
have been found to retain catalytic activities in aqueous media.
Particularly, many of them are not only compatible with
water, but also activated by water. Rare earth metal salts such
as Sc(OTf)3 and Yb(OTf)3 can be used for aqueous organic
reactions. For example, Yb(OTf)3 is found to be highly
effective for catalyzing the Mukaiyama aldol reaction of
benzaldehyde (34) with silyl enol ether 35 in aqueous solution
which is much less effective in dry organic solvents
Scheme 10 Conjugate addition of unsaturated carbonyl compounds
with arylmetallic reagents in water.
72 | Chem. Soc. Rev., 2006, 35, 68–82
View Article Online
(Scheme 11).15 The enhancement of the reaction rate by water
is very likely due to the change of the acid catalyst’s structure
and activity caused by water, or to the regeneration of the
active catalyst from the corresponding intermediate which is
faster in water than in dry organic solvents.
Most catalytic asymmetric reactions of carbocation are
conducted at low reaction temperatures (e.g., 278 uC) in
aprotic anhydrous solvents such as dry toluene, dichloro-
methane, and propionitrile. Recently, Cu(II) together with a
chiral ligand has been found to be effective for asymmetric
aldol reactions in an aqueous solution. In the presence of a
catalytic amount of Cu(OTf)2 and bis(oxazoline) ligand 37, the
reaction of benzaldehyde (38) with silyl enol ether 39 furnishes
the desired aldol product 40 in a high yield with good
enantioselectivity (Scheme 12). In contrast, dry organic
solvents such as dry ethanol and dry dichloromethane, give
much lower yields and selectivities.15 The possible reason for
the higher enantioselectivity in water is that water rapidly
hydrolyzes the silyl cation equivalent, which is generated
during the aldol reactions and is responsible for the decrease of
Scheme 11 The enhancement of the reaction rate for Mukaiyama
aldol reaction by water.
This journal is ß The Royal Society of Chemistry 2006

Scheme 12 Lewis acid-catalyzed asymmetric reaction in aqueous
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solution.
enantioselectivity by catalyzing aldol reactions to give racemic
products.
One of the major drawbacks of using water as a solvent is
the low solubility of most organic substrates in water. It could
be overcome by the use of surfactants, which solubilize organic
substances in water. While the reaction of benzaldehyde (41)
with silyl enol ether 42 gives almost no desired aldol product
43 in the presence of a catalytic amount of Sc(OTf)3 in water, a
high yield of the corresponding aldol adduct is obtained when
the reaction is carried out in the presence of a catalytic amount
of Sc(OTf)3 and sodium dodecyl sulfate (SDS, a surfactant) in
water (Scheme 13).15 Recently, a new type of catalyst, ‘‘Lewis
acid-surfactant combined catalyst (LASC)’’ has been deve-
loped. It acts both as a Lewis acid to catalyze the reaction and
as a surfactant to solubilize organic substrates in water.
Scandium tris(dodecyl sulfate) (Sc(DS)3) is a good example
because it is very effective for catalyzing the reaction of
benzaldehyde (41) with silyl enol ether 42 in water
(Scheme 13).15
Boron compounds have also been developed as catalysts for
the reaction of carbocation equivalents in water. In the
presence of a catalytic amount of a boron source, SDS and
benzoic acid, the reaction of benzaldehyde (44) with silyl enol
ether (45) gives a highly diastereoselective aldol adduct (46) in
water at ambient temperature (Scheme 14).16 In contrast,
traditional boron aldol reactions are performed at a lower
temperature and need strictly anhydrous conditions. It is
Scheme 13 LASC-catalyzed organic reaction in water.
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Scheme 14 Boron compound-catalyzed organic reactions in water.
(Reprinted with permission from ref. 16. Copyright 2001, Wiely-VCH.)
important to note that the use of water as a solvent is essential
in this reaction. Almost no corresponding products are
obtained in organic solvents, such as ethyl ether and
dichloromethane, and a very low yield of product is obtained
under the neat condition (Scheme 14).
Dehydration is a very common reaction in organic
chemistry. It is difficult to carry out in water because water
molecules generated during the reaction must be removed to
shift equilibrium toward the side of the dehydrated product.
With a surfactant-type acid catalyst, dehydration has been
successfully developed in water. Emulsion droplets are formed
in water in the presence of a surfactant-type catalyst and
organic substrates. The emulsion droplets have a hydrophobic
interior which would concentrate acid catalysts onto the
surface of droplets and enhance the reaction rate toward the
side of the dehydrated product. On the other hand, water
molecules generated during the reaction are removed from
droplets due to the hydrophobic nature of their interior, which
shift the equilibrium toward the desired side (Scheme 15).
A representative example of dehydration in water is protonic
acid-catalyzed dehydrative esterification. Dodecylbenzene-
sulfonic acid (DBSA), which acts as a protonic acid–
surfactant–combined catalyst (BASC), is very effective for
catalyzing esterification of acids with alcohols in water
(Scheme 16A).17 Beside the esterification, etherification
(Scheme 16B) and thioetherification (Scheme 16C) also
proceed smoothly in water by the catalyst DBSA.
Dithioacetals are very useful in organic synthesis as power-
ful protective groups for carbonyl compounds. The DBSA-
catalyzed system is also applicable to dithioacetalization in
water which yields dithioacetal products (Scheme 17). The
reaction proceeds very well not only for ketones but also for
aldehydes.17
The use of water as a solvent is the key to obtaining high
yield and selectivity for the asymmetric Mannich-type reac-
tion. With the combination of catalyst ZnF2 and a chiral
diamine 61, the reaction of hydrazono ester 62 and silyl enol
ether 63 gives the corresponding product (R)-64 in a high
yield with a high enantioselectivity in an aqueous solution.
However, in dry organic solvents, such as tetrahydrofuran, no
product is obtained in this reaction. This asymmetric
reaction can be used for a four-step enantioselective
synthesis of HPA-12 (65), the first compound of a specific
inhibitor for sphingomyelin synthesis in mammalian cells
(Scheme 18).18
Chem. Soc. Rev., 2006, 35, 68–82 | 73

Scheme 15 Dehydration in water with a surfactant-type catalyst.
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Scheme 16 Esterification, etherification and thioetherification in water.
5. Reactions of radicals and carbenes
Water is the solvent of choice for reactions of radicals and
carbenes since strong O–H bonds (enthalpy 436 kJ mol21) are
not easily attacked. Recently, water has been examined as a
solvent for these reactions. Significant solvent effects have
been reported in atom-transfer radical cyclizations. For
example, treatment of allyl iodoacetate 66 in water with
triethylborane, a radical initiator, provides the corresponding
lactone product 67 in 78% yield. In contrast, in organic
solvents such as hexane, benzene, methanol, tetrahydrofuran
(THF), DMSO, etc., the reaction is sluggish, and yields no or
little lactone product (Scheme 19).19
Scheme 17 Dithioacetalization in water.
74 | Chem. Soc. Rev., 2006, 35, 68–82
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The radical cyclization which forms medium- and large-ring
lactones also proceeds much more efficiently in water than in
organic solvents. The reaction of a-iodo ester 68 with
triethylborane in water gives nine-membered lactone 69 in
69% yield. In contrast, in organic solvents such as hexane,
benzene, and methanol, the atom-transfer radical cyclization
provides no or little lactone (Scheme 20A).19 Similarly, the
eighteen-membered lactone is formed by radical cyclization
much more efficiently (70% yield) in water than in benzene
(14% yield, Scheme 20B). Ab initio calculations suggest that
both the large dielectric constant of water and the high
cohesive energy density of water are responsible for the
acceleration of the cyclization.19
The radical reaction of organic halides in water proceeds
smoothly to give the corresponding reduced products. For
instance, reactions of various organic halides 72 with
phosphinic acid (hypophosphorous acid) in aqueous ethanol
in the presence of a radical initiator azo-bis-isobutryonitrile
(AIBN) and a base NaHCO3 give the reduced products 73 in
high yields (Scheme 21).20
Similarly, D3PO2 is excellent for radical deuteration of
organic halides (Scheme 22). The reduction of organic halides
74 with D3PO2 in D2O provides labelled compounds 75 which
can be assayed in vivo.20
Water is also a choice of solvent for free-radical polymeri-
zation. The high heat capacity of water allows effective
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Scheme 18 Asymmetric Mannich-type reaction in water and its application for total synthesis of HPA-12.

Scheme 19 Atom-transfer radical cyclization in water. (Reprinted

with permission from ref. 19. Copyright 2000, American Chemical
Society.)

transfer of the heat from polymerization. Compared to organic

solvents, the high polarity of water distinguishes remarkably
the miscibility of many monomers from polymers. Today,
aqueous free-radical polymerization is applied in industries.21
Reactions of carbenes take place in water too. An example is
that water-soluble ruthenium alkylidenes 76 bearing cationi-
cally functionalized phosphine ligands are stable and initiate
olefin metathesis reactions in water. In the presence of 76, Scheme 20 Medium- and large-ring formation by radical cyclization
monomer 77 is quantitatively polymerized in aqueous envir- in water. (Reprinted with permission from ref. 19. Copyright 2000,
onments (Scheme 23).22 American Chemical Society.)

6. Transition-metal catalysis
The use of late transition metals for catalyzing reactions is of
growing importance in modern organic chemistry.23
Conventionally, organometallic chemistry and transition-
metal catalysis are carried out under an inert gas atmosphere
and the exclusion of moisture has been essential.24 The reason
could be that water as a ligand often occupies metals’
coordination sites. On the other hand, metal–carbon bonds
are easily attacked by water either via proton transfer Scheme 21 Simple radical reduction in water.

This journal is ß The Royal Society of Chemistry 2006 Chem. Soc. Rev., 2006, 35, 68–82 | 75

Scheme 22 Isotope labelling via an aqueous radical reaction.
(electrophilic reaction) or via the oxygen (nucleophilic reac-
tion). However, recent studies have shown that in water such
catalyses are both facilitated and can be operated in open air.25
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Hydration of nitriles 79 to generate the corresponding
amides 80 has wide application, such as as intermediates for
organic synthesis and as raw materials for plastics, detergents
and lubricants etc. Hydration of nitriles traditionally is carried
out with acids or bases such as H2SO4 and NaOH. However,
many functional groups such as carbon–carbon double bonds
cannot survive this process. In addition, hydrolysis of amide
products usually occurs to produce carboxylic acid by-
products, especially in acidic conditions. Carefully controlled
conditions with one equivalent of water with respect to starting
material nitriles are necessary for the traditional hydration of
nitriles to amides. However, with the easily prepared,
inexpensive, and supported ruthenium hydroxide catalyst
Ru(OH)x/Al2O3, the hydration of various nitriles gives
quantitatively the corresponding amide products in water.26
Various functional groups such as carbon–carbon double
bonds tolerate this hydration process. For example, the
hydration of acrylonitrile (81), which is important for industry,
provides acrylamide (82) quantitatively (Scheme 24). No side
reactions, such as hydration of carbon–carbon double bonds
and polymerization of acrylonitriles, occur. The water solvent
also provides a way to recycle the transition metal catalyst.
The Ru(OH)x/Al2O3 catalyst is easily separated from the
reaction mixture by filtration. After separation of the catalyst,
the catalyst can be reused at least twice with no considerable
loss of activity.
Scheme 23 Ruthenium carbene-catalyzed aqueous polymerization. (Reprinted with permission from ref. 22. Copyright 2000, American Chemical
Society.)
76 | Chem. Soc. Rev., 2006, 35, 68–82
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Scheme 24 Ru-catalyzed hydration of nitriles to amides in water.
Rhodium-catalyzed addition of arylboronic acids to
activated olefins (i.e. olefins with electron-withdrawing
groups) has been significantly studied. However, a common
requirement of this process is the activation of olefins with
electron-withdrawing groups. The reaction substrates are
expanded from activated olefins to general un-activated ones
by switching organic solvents to water. With a combination of
rhodium catalyst and water-soluble phosphine ligand TPPDS,
a variety of un-activated styrenyl olefins 83 are reacted with
arylboronic acids 84 in water to produce ‘‘Heck-type’’
products 85, while the reaction of vinyl heteroaromatic
compounds 86 with arylboronic acids 87 gives addition–
hydrolysis products 88 (Scheme 25).27 Notably, in each case,
either no reaction or only sluggish reaction is observed in
organic solvents with water-soluble sulfonated ligands or with
triphenylphosphines.
Palladium catalyzed C–N bond formation can be carried out
in water too. With a combination of a phosphine ligand 89 and
a palladium catalyst, un-reactive aryl chlorides 90 are reacted
with amines 91 in water smoothly to afford the corresponding
amination products 92 (Scheme 26).28
Compared to other late transition metals, gold has not been
extensively explored as a catalyst. However, recent studies
show gold has unique catalytic properties in several organic
reactions. Gold-catalyzed organic reactions can be carried out
in water too. A representative example is that the gold-
catalyzed three-component reaction of aldehydes 93, amines 94
and terminal alkynes 95 efficiently affords propargyl amine
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Scheme 25 Rh-catalyzed reaction of un-activated olefins with arylboronic acids in water.
Scheme 26 Pd-catalyzed C–N bond formations in water.
products 96 in water (Scheme 27).29 Transition metal-catalyzed
asymmetric organic reactions are also possible with the use of
water as a solvent. With Cu(I) as a catalyst and chiral pybox
(100) as a ligand, the addition of terminal alkynes 97 to imines
98 in water at room temperature affords the corresponding
propargyl amine products 99 with a good yield and enantio-
selectivity (Scheme 27).30
7. Oxidations–reductions
Oxidation reactions have often been conducted using stoichio-
metric amounts of heavy metal reagents (e.g. potassium
permanganate, V2O5) or moisture-sensitive oxidants
(e.g. oxalyl chloride, N,N9-dicyclohexylcarbodiimide (DCC)).
Recently, new oxidative reactions have been developed in
aqueous media by water-compatible oxidants, such as O2
and H2O2.
Using clean, safe, and inexpensive molecular oxygen as a
sole oxidant, a variety of 2-naphthols and substituted phenols
can be converted to the corresponding biaryl compounds by
ruthenium catalyst Ru(OH)x/Al2O3 in moderate to excellent
yields in water. Thus, in the presence of 5 mol% of Ru(OH)x/
Al2O3 and 1 atm O2, the oxidative coupling of 2-naphthol
(101) in water quantitatively produces 1,19-binaphthalene-
2,29-diol (BINOL) (102), which is a very important building
block and ligand. It is important to note, Ru(OH)x/Al2O3
catalyst can be reused without the loss of any catalytic activity
even after the seventh recycling run (Scheme 28).31
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Catalytic oxidation of alcohols can be achieved in water
by molecular oxygen by using a novel amphiphilic resin-
dispersion of palladium nanoparticles (ARP-Pd). In the
presence of the nano-palladium catalyst, primary alcohols
give the corresponding aldehydes products, and secondary
alcohols give the corresponding ketones in water (Scheme 29).
ARP-Pd can be reused with negligible loss of catalytic activity
after several runs.32
Aqueous oxidative polymerization provides a convenient
way for product separation. Using molecular oxygen as an
oxidant and K3[Fe(CN)6] as a catalyst, the oxidative poly-
merization of 2,6-dimethylphenol (DMP) 111 in aqueous
NaOH solution gives poly(2,6-dimethyl-1,4-phenyleneoxide)
(PPO) 112, an important plastic in engineering
(Scheme 30).33 The DMP monomer is dissolved in aqueous
NaOH solution, while the PPO polymer product is
insoluble in it. The precipitated product is separated
from the reaction mixture by simple distillation after the
reaction and the aqueous solution can be reused for the
polymerization.
Hydrogen peroxide, another water-compatible oxidant, is
also often used in aqueous oxidative reactions. In the presence
of polyoxometalate, Na12[WZnZn2(H2O)2(ZnW9O34)2], which
is easily prepared in one step in water from simple salts,
various alcohols are converted into the corresponding alde-
hyde or ketone products in water by hydrogen peroxide. The
in situ prepared catalyst polyoxometalate could be recycled in
water.34
Chem. Soc. Rev., 2006, 35, 68–82 | 77
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Scheme 27 Gold- and copper-catalyzed reactions in water.

When lithium borohydride (LiBH4) is modified to the more

Scheme 28 Oxidative coupling of 2-naphthol in water.
Water is rarely used as the solvent in a reduction reaction
because most reducing agents are incompatible in water.
However, water-compatible sodium/lithium borohydride is
frequently used in water to reduce ketones or aldehydes.
hydrophobic reducing agent lithium pentafluorophenyl bor-
ohydride (LiC6F5BH3), a hydrophobically directed selective
reduction of ketones is observed in water. As an example,
quaternized, b-keto diamines (113) are reduced by LiC6F5BH3
to 114 almost exclusively in water. In contrast, the use of
methanol as a solvent gives equal amounts of products 114 and
115 (Scheme 31).35
A new water-soluble ruthenium complex of b-cyclodextrin-
modified amino alcohols 116 serves as a supramolecular
catalyst in the selective reduction of ketones. In the presence of
NaCOOH, this Ru-base catalyst reduces conjugated (117) and
non-activated unconjugated ketones (118) to the correspond-
ing alcohols with good yields and enantioselectivities in water
(Scheme 32).36

Scheme 29 Catalytic oxidative reaction of alcohols in water.

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 View Article Online

Scheme 30 Polymerization of DMP in water.

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Scheme 31 Hydrophobically directed selective reduction of ketones. (Reprinted with permission from ref. 35. Copyright 2003, American Chemical
Society.)

8. Synthetic applications
Because of its unique properties, aqueous organic chemistry
has found wide applications in organic synthesis, life science
and chemical biology.
8.1. Carbohydrate chemistry
One of the most important advantages of aqueous organic
reactions in organic synthesis is that water-soluble hydroxyl-
containing molecules can be used directly without the need of
tedious protection–deprotection processes. Thus, the most
important application for carrying out organic reactions in
water is carbohydrate chemistry where the protection–
deprotection processes are involved most extensively.
C-Glycosides have wide applications used as a variety of
building blocks for total synthesis of natural products and as
potential enzyme inhibitors. Traditionally, C-Glycosidic
ketones are prepared from a protected sugar by addition of a
suitable nucleophile in anhydrous conditions. A new protocol
using water as a solvent eliminates tedious protection–
deprotection processes, and thus it greatly increases the overall
yields. With commercially available D-glucose (121) and
pentane-2,4-dione (122) as starting substrates, b-C-glycosidic
ketone 123 is obtained in one step with almost a quantitative
yield in aqueous NaHCO3 solution (Scheme 33). In a sharp
contrast, in organic solvents the b-C-glycosidic ketone 123 is
prepared from benzylated D-glucose, a protected sugar, in
seven steps in an overall low yield.37
Polyhydroxylated N-heterocycles, or azasugars, which show
broad biological activities, are among the most attractive

Scheme 32 Enantioselective reduction of ketones in water.

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Scheme 33 One-step synthesis of b-C-glycosidic ketone in water.
synthetic targets. The most commonly employed methods for
the synthesis of azasugars have involved starting from
commercially available carbohydrates because their structures
are similar to those of sugars. However, their asymmetric
synthesis usually requires lengthy procedures and produces
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low yields. With the use of water as a solvent for all the steps,
an extremely efficient asymmetric synthesis of a pyrrolidine
azasugar has been developed in only four steps, without any
protection–deprotection process, and in 60% overall yield. At
first, a modified Sharpless asymmetric dihydroxylation of
achiral and cheap 1,6-dibromodiene 124 gives the chiral bis-
electrophilic diol 125 in a good yield and enantioselectivity
(70% yield, 97% ee). Notably, it has unique and useful
reactivity in water (Scheme 34) because of the instability of
124 and 125 in organic solvents. The following selective
hydrolysis of 125 affords triol 126 in 98% yield. Then, with
dinuclear peroxotungstate K2[W2O3(O2)4(H2O)2] as a catalyst
and H2O2 as an oxidant, a novel water-compatible epoxidation
of 126 affords the desired epoxy alcohol 127 in 99% yield
(92% ds). Finally, following the nucleophilic displacement of
the bromide by ammonia, an intramolecular ring opening of
the epoxide gives azasugar 128 in 88% yield. The overall yield
of 128 is thus 60%.38
8.2. Chemical modification of biomolecules
Aqueous organic chemistry is essential for the emerging field
of chemical biology, which uses chemical tools to study
biology. Since life constructs chemical bonds in aqueous
Scheme 34 Total synthesis of azasugar in water. (Reprinted with permission from ref. 38. Copyright 2005, The Royal Society of Chemistry.)
80 | Chem. Soc. Rev., 2006, 35, 68–82
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environments, selective chemical reactions designed to modify
biomolecules are now recognized as powerful tools in chemical
biology. They provide insight into cellular processes and
inspire new strategies for protein engineering. To achieve this
goal, the participating functional groups must have a narrow
distribution of reactivity and must be inert toward biological
molecules. In addition, the selective chemical reactions must
occur at room temperature and in aqueous physiological
environments.
Azides and alkynes are highly energetic functional groups
and nearly inert to biomolecules. The Huisgen cycloaddition of
azides 129 and alkynes 130 is irreversible and thermodynami-
cally more favorable by approximately 30–35 kcal mol21.
However, the reaction requires elevated temperature. A
copper(I)-catalyzed version, recently developed by Sharpless
and co-workers, occurs readily at physiological temperatures
and in aqueous solutions (Scheme 35A). This reaction enables
the selective modification of various biological molecules such
as virus particles, nucleic acids, and proteins. An example is
the cowpea mosaic virus (CPMV) which has 60 identical copies
of a two-protein unit around a single-stranded RNA genome.
In the presence of Cu(I) catalyst, the virus CPMV (132),
decorated with azides, is efficiently coupled with the dye-
alkyne 133 (Scheme 35B).39
The modified Staudinger reaction is another chemoselective
reaction designed to modify biomolecules. The Staudinger
reaction occurs between phosphines and azides to produce aza-
ylides. In the presence of water, the phosphines and azides
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Scheme 35 Chemical modification of CPMV by azide-alkyne [3 + 2] cycloaddition.
react efficiently at room temperature to produce amines and
phosphine oxides (Scheme 36A). Both phosphines and azides
are nearly inert to biological molecules. Therefore, the classical
Scheme 36 Classical and modified Staudinger reactions. (Reprinted
with permission from ref. 40. Copyright 2000, American Association
for the Advancement of Science.)
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Staudinger reaction is a good candidate for the chemical
modification of bio-molecules.
However, the aza-ylides are not stable in water which limits
their application for constructing a new and useful covalent
bond under physiological conditions. Using an electrophilic
trap, Bertozzi and co-workers developed an aqueous
Staudinger reaction that would ultimately produce a stable
amide bond (Scheme 36B). With this modified Staudinger
reaction, the water-soluble biotinylated phosphine 145 couples
with azides installed within cell surfaces to produce stable cell-
surface adducts 146 (Scheme 37).40
9. Conclusion and outlook
Extraordinary attention has been paid to organic reactions
in water in the past decade and research and development
in this area is still increasing exponentially.41 This review
provides an introductory overview of this field. The types of
organic reactions in water are now as diverse as those in
organic solvents. It is worthy of note that completely new
reactivities of reactions have been discovered in water.
The wide application of aqueous organic reactions also
provides a driving force for the future development of
this area.
Acknowledgements
We are grateful to NSERC, NSF and NSF-EPA Joint
Program for a Sustainable Environment for support of our
research. L.C. thanks a Cancer Research Fellowship by the
Chem. Soc. Rev., 2006, 35, 68–82 | 81
Published on 21 November 2005. Downloaded on 10/9/2020 1:53:32 PM.
Scheme 37 Reaction of biotinylated phosphine with cell surface azido sialic acid. (Reprinted with permission from ref. 40. Copyright 2000,
American Association for the Advancement of Science.)
Tulane University Cancer Center. C.J.L. is a Canada Research
Chair (Tier I) at McGill University.
References
1 R. Breslow, Acc. Chem. Res., 2004, 37, 471.
2 L. Chen and C.-J. Li, Org. Lett., 2004, 6, 3151; C. J. Li, Chem.
Rev., 1993, 93, 2023.
3 S. Narayan, J. Muldoon, M. G. Finn, V. V. Fokin, H. C. Kolb and
K. Barry Sharpless, Angew. Chem., Int. Ed., 2005, 44, 3275.
4 K. C. Nicolaou, H. Xu and M. Wartmann, Angew. Chem., Int. Ed.,
2005, 44, 756.
5 R. N. Butler, W. J. Cunningham, A. G. Coyne and L. A. Burke,
J. Am. Chem. Soc., 2004, 126, 11923.
6 S. Otto, G. Boccaletti and J. B. F. N. Engberts, J. Am. Chem. Soc.,
1999, 121, 6798.
7 S. Kong and J. D. Evanseck, J. Am. Chem. Soc., 2000, 122, 10418.
8 M. Sakai, H. Hayashi and N. Miyaura, Organometallics, 1997, 16,
4229.
9 M. Sakai, M. Ueda and N. Miyaura, Angew. Chem., Int. Ed., 1998,
37, 3274.
10 T. Hayashi, Synlett, 2001, 879.
11 C.-J. Li and Y. Meng, J. Am. Chem. Soc., 2000, 122, 9538.
12 T. S. Huang, Y. Meng, S. Venkatraman, D. Wang and C.-J. Li,
J. Am. Chem. Soc., 2001, 123, 7451.
13 C. C. K. Keh, C. M. Wei and C.-J. Li, J. Am. Chem. Soc., 2003,
125, 4062.
14 K.-T. Tan, S.-S. Chng, H.-S. Cheng and T.-P. Loh, J. Am. Chem.
Soc., 2003, 125, 2958.
15 S. Kobayashi and K. Manabe, Acc. Chem. Res., 2002, 35, 209.
16 Y. Mori, K. Manabe and S. Kobayashi, Angew. Chem., Int. Ed.,
2001, 40, 2816.
17 K. Manabe, S. Iimura, X.-M. Sun and S. Kobayashi, J. Am. Chem.
Soc., 2002, 124, 11971.
18 S. Kobayashi, T. Hamada and K. Manabe, J. Am. Chem. Soc.,
2002, 124, 5640.
19 H. Yorimitsu, T. Nakamura, H. Shinokubo, K. Oshima, K. Omoto
and H. Fujimoto, J. Am. Chem. Soc., 2000, 122, 11041.
82 | Chem. Soc. Rev., 2006, 35, 68–82
View Article Online
20 H. Yorimitsu, H. Shinokubo and K. Oshima, Bull. Chem. Soc.
Jpn., 2001, 74, 225.
21 S. Mecking, A. Held and F. M. Bauers, Angew. Chem., Int. Ed.,
2002, 41, 544.
22 D. M. Lynn, B. Mohr, R. H. Grubbs, L. M. Henling and
M. W. Day, J. Am. Chem. Soc., 2000, 122, 6601.
23 R. H. Crabtree, The Organometallic Chemistry of Transition
Metals, 2nd Edn, Wiley Interscience; New York, 1988.
24 B. Cornils, W. A. Herrmann, R. Schlogl, Eds., Catalysis from A to
Z: A Concise Encyclopedia, John Wiley & Sons, 2000.
25 C.-J. Li, Acc. Chem. Res., 2002, 35, 533.
26 K. Yamaguchi, M. Matsushita and N. Mizuno, Angew. Chem., Int.
Ed., 2004, 43, 1576.
27 M. Lautens, A. Roy, K. Fukuoka, K. Fagnou and B. Martin-
Matute, J. Am. Chem. Soc., 2001, 123, 5358.
28 X. H. Huang, K. W. Anderson, D. Zim, L. Jiang, A. Klapars and
S. L. Buchwald, J. Am. Chem. Soc., 2003, 125, 6653.
29 C. M. Wei and C.-J. Li, J. Am. Chem. Soc., 2003, 125, 9584.
30 C. M. Wei and C.-J. Li, J. Am. Chem. Soc., 2002, 124, 5638.
31 M. Matsushita, K. Kamata, K. Yamaguchi and N. Mizuno, J. Am.
Chem. Soc., 2005, 127, 6632.
32 Y. Uozumi and R. Nakao, Angew. Chem., Int. Ed., 2003, 42, 194.
33 K. Saito, T. Tago, T. Masuyama and H. Nishide, Angew. Chem.,
Int. Ed., 2004, 43, 730.
34 D. Sloboda-Rozner, P. L. Alsters and R. Neumann, J. Am. Chem.
Soc., 2003, 125, 5280.
35 M. R. Biscoe and R. Breslow, J. Am. Chem. Soc., 2003, 125, 12718.
36 A. Schlatter, M. K.Kundu and W.-D. Woggon, Angew. Chem., Int.
Ed., 2004, 43, 6731.
37 F. Rodrigues, Y. Canac and A. Lubineau, Chem. Commun., 2000,
2049 and references therein.
38 U. M. Lindstrom, R. Ding and O. Hidestal, Chem. Commun., 2005,
1773.
39 Q. Wang, T. R. Chan, R. Hilgraf, V. V. Fokin, K. B. Sharpless and
M. G. Finn, J. Am. Chem. Soc., 2003, 125, 3192.
40 E. Saxon and C. R. Bertozzi, Science, 2000, 287, 2007.
41 For recent leading reviews, please see: C.-J. Li, Chem. Rev., 2005,
105, 3095; U. M. Lindstrom, Chem. Rev., 2002, 102, 2751.
42 C.-J. Li, Tetrahedron, 1996, 52, 5643.
This journal is ß The Royal Society of Chemistry 2006
 Angewandte
Chemie

DOI: 10.1002/anie.200705347
Organic Synthesis

Highly Efficient Organic Reactions “on Water”, “in Water”, and

Both**
Nelly Shapiro and Arkadi Vigalok*

Water is the most abundant and environmentally friendly (Scheme 1).[11] As both the starting materials and products are
solvent in nature. Yet, its application in organic synthesis is insoluble in water, they can be easily separated from the
currently limited.[1] As most organic compounds have low aqueous phase at the end of the reaction. The bubbling of gas
solubility in water, much effort has been invested in the
development of organic microenvironments in the aqueous
phase, for example, in micellar catalysis.[2, 3] Recently, reac-
tions of water-insoluble organic compounds that take place in
aqueous suspensions (“on water”) have received a great deal
of attention because of their high efficiency and straightfor-
Scheme 1. Aldehyde oxidation “on water”.
ward synthetic protocols.[4] Nevertheless, such reactions are
still rare and lack generality. Herein we report a general
procedure toward a common aerobic oxidation of aldehydes through the liquid phase was not required, thus making the
that takes place “on water” and its use in the consecutive use of a condenser or other reactant traps unnecessary. The
three-component Passerini reaction both “on water” and “in reactions proceeded smoothly both on a small scale (1 mmol)
water”. and on a relatively large laboratory scale (50 mmol). Table 1
The oxidation of aldehydes by oxygen or oxygen/nitrogen
mixtures is a well-known reaction.[5] Organic chemistry
Table 1: Aldehyde oxidation “on water”.[a]
textbooks pay very little attention to the use of air in the
synthesis of carboxylic acids from aldehydes. Notably, air is Entry Aldehyde Oxidation Yield [%]
conditions
the ultimate “green” oxidant, more so than hydrogen
peroxide, which is considered “green” for synthetic oxidation 1 cyclo-C6H11CHO (1 a) A 87
processes. In industry, aldehyde oxidation reactions are 2 1a B 87
usually performed in bulk liquid aldehyde or organic solvents, 3 1a C 66
4 nC7H15CHO (1 b) A 50
with the stream of gas passing through the liquid phase.[6]
5 1b B 60
Various additives are often introduced into the system,[7] but 6 2-ethyl hexanal (1 c) A 86
the role of these is still unclear.[8] As the solubility of nonpolar 7 1c B 88
gases, such as molecular oxygen, is generally low in any 8 1c C 75[b]
solvent,[9] we hypothesized that the solvent is unnecessary or 9 benzaldehyde (1 d) A 83
even detrimental to the oxidation process. An aldehyde 10 1d B 81
11 1d C 53
oxidation taking place in thin layers of aldehyde, which
12 nC4H9CHO (1 e) A 11
increases the surface of interaction between the reagents, has
also been reported, however, the yields were poor.[10] Alter- [a] See the Experimental Section for detailed reaction conditions. [b] 90 %
yield after 2 h with O2.
natively, such an increase in surface interaction can be
achieved by mixing the aldehyde with water in the presence
of oxygen. Indeed, we found that hydrophobic aliphatic
(branched and linear) and aromatic aldehydes undergo facile shows typical results of the oxidation of liquid aldehydes “on
oxidation upon simply stirring their aqueous emulsions in air water”. The reaction was especially straightforward for the
to give the corresponding carboxylic acids in high yields preparation of solid carboxylic acids, such as benzoic acid,
which precipitated from the reaction mixture and could be
[*] N. Shapiro, Dr. A. Vigalok isolated by simple filtration. Importantly, very low amounts of
School of Chemistry, The Sackler Faculty of Exact Sciences by-products (mainly the corresponding formate) were
Tel Aviv University, Tel Aviv 69978 (Israel) observed in the “on water” reaction compared with the
Fax: (+ 972) 3-640-6205 same reaction performed in bulk aldehyde. No oxidation was
E-mail: avigal@post.tau.ac.il
observed under the same conditions when the reaction was
[**] This work was supported by the Israel Science Foundation and The
carried out in methanol or dichloromethane instead of water.
Porter School of Environmental Studies at Tel Aviv University. N.S. is
the recipient of Gutwirth Foundation and Rieger Foundation Moreover, the addition of THF (5 %) also completely
Fellowships, as well as the Israel Ministry of Science, Culture, and inhibited the reaction.
Sport Fellowship for the Advancement of Women in Science. The highly efficient conversion of aldehydes into carbox-
Supporting information for this article is available on the WWW ylic acids described above inspired us to explore the
under http://www.angewandte.org or from the author. possibility of coupling this reaction with a known “on

Angew. Chem. Int. Ed. 2008, 47, 2849 –2852  2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim 2849
Communications
water” accelerated process. Recently, Pirrung et al. reported slight heating (40 8C) to give the Passerini reaction products.
elegant multicomponent Passerini- and Ugi-type reactions On the other hand, more water soluble aldehydes gave
that were accelerated by using water as a solvent.[4a, 12, 13] This mixtures of the Passerini products with another product—the
finding led us to explore the possibility of using an aldehyde a-hydroxyamide (Scheme 2). The ratio between the products
as the source of both carbonyl and ester functions in the roughly followed the solubility properties of the aldehyde
Passerini reaction (Scheme 2).[14] In this three-component (Table 2). Both propionic aldehyde and acetaldehyde, which
are fully miscible with water, formed gemi-
nal diols in 100 % yield in aqueous solu-
tions.[17] a-Hydroxyamides were the only
products obtained for these two aldehydes
(Table 2, entries 15 and 16, 17 and 18,
respectively). Although water-miscible
aldehydes do not readily oxidize under
these conditions, the lack of a carboxylic
Scheme 2. Tandem aldehyde oxidation/Passerini reaction “on water”. acid moiety was not responsible for the
absence of the three-component Passerini
products with such aldehydes. The reaction
reaction, only two components would be added to the between acetaldehyde, isocyanide, and acetic acid resulted in
reaction mixture, with the third one generated in situ from the formation of the a-hydroxyamide as the only product,
one of the reagents. As many aldehydes and carboxylic acids which suggests that the reaction “in water” only gives this
show considerable solubility in water, it was important to compound. In contrast, the reaction between octanoic
establish to what extent the reactions proceed “in water” aldehyde, isocyanide, and acetic acid gave only the Passerini
rather than “on water”.[15] To this end, we studied the reaction product. It is likely that the formation of a gem-diol
of various aldehydes with water-insoluble isocyanides, which significantly decreases the concentration of the water-soluble
gave the Passerini products in the oxidation/three-component aldehyde in the reaction. In addition, water competes
reaction sequence, (Table 2). As isocyanides slowly hydrolyze favorably with the carboxylate in the nucleophilic addition
upon stirring with water, a slight excess of the aldehyde was to the carbonyl carbon atom when the reaction takes place “in
used.[16] Interestingly, the reactions between the highly hydro- water”.
phobic aldehydes and the isocyanides “on water” and in air In all cases, water-insoluble aldehydes gave the three-
were complete after 3–4 hours at room temperature or upon component Passerini products in high yields, while partially
soluble aldehydes gave mixtures of both products, thus
indicating the competition between the “in water” and “on
Table 2: Aldehyde oxidation/Passerini reaction “on water” and “in
water”.[a]
water” reactions. Also, more hydrophobic pentyl isocyanide
(4) reacted significantly faster than ethyl isocyanoacetate (3)
Entry Aldehyde Isonitrile Product ratio [%] and gave significant amounts of the Passerini product, even
RCHO R1CH2NC 5 7 6 8
with partially water soluble aldehydes (Table 2, entries 11 and
1 1a 3 80 0 – – 14,). In support of the heterogeneous nature of the reaction
2 1a 4 – – 81 (90)[b,d] 0 mixture, the product distribution showed some dependence
3 1b 3 90 0 – –
on the stirring rates (Table 2, compare entries 11 and 12).[18]
4 1b 3 84[c] 0 – –
5 1b 4 – – 90 (71)[d] 0 Importantly, almost no reaction was observed when the
6 1d 3 30[e] 0 – – reactions were performed in methanol or dichloromethane
7 1d 4 – – 57[e] 0 under the same conditions. Furthermore, the reaction “in
8 1e 3 12 37 – – water” was significantly slower than the reaction “on water”
9 1e 4 – – 37 11 even when the reactants were partially water soluble.[19]
10 R = iPr, 1 f 3 5[d] 74[d] – – We further investigated the mechanism of the “on water”
11 R = iPr, 1 f 4 – – 35 (30)[d] 42 (34)[d]
oxidation–Passerini reaction sequence by using isotope label-
12 R = iPr, 1 f 4 – – 28[f ] 60[f ]
13 R = nPr, 1 g 3 2 51 – – ing experiments. When 1-octanal (1 b) was stirred with H218O
14 R = nPr, 1 g 4 – – 36 44 (2 mL) under oxygen for 5 hours, about 60 % of the 1-
15 R = Et, 1 h 3 0 58 – – octanoic acid (2 b) obtained had one labeled oxygen atom
16 R = Et, 1 h 4 – – 7(4)[d] 32 (30)[d] incorporated in the structure (Table 3, entry 1). As no 18O
17 R = Me, 1 i 3[g] 0 72 – – incorporation was observed when nonlabeled 1-octanoic acid
18 R = Me, 1 i 4[g] – – 0 59
was stirred with H218O, the incorporation of this isotope
[a] Conditions: The mixture of the aldehyde and isocyanide in a 3:1 ratio occurs prior to the formation of the carboxylic acid. Two
was stirred at 1100 rpm for 3 h at 40 8C. The organic products were possible pathways may account for this labeling: either rapid
extracted with CH2Cl2, the solvent was evaporated, and the mixture aldehyde/gem-diol equilibration[20] on the water surface or an
analyzed by 1H NMR spectroscopy. [b] After 4 h. [c] The reaction was
exchange reaction in one of the peroxo or radical species that
performed at room temperature. [d] Yield of isolated product. [e] Benzoic
acid precipitates during the reaction, which results in lower yields. [f ] The are postulated in the oxidation of aldehydes by molecular
reaction was stirred at 300 rpm. [g] An aldehyde/isocyanide ratio of 10:1 oxygen (Scheme 3).[5] Interestingly, when the Passerini reac-
was used. tion (Scheme 2) was performed in H218O, the incorporation of

2850 www.angewandte.org  2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Angew. Chem. Int. Ed. 2008, 47, 2849 –2852
 Angewandte
Chemie

Table 3: 18O Isotope distribution in aldehyde oxidation–Passerini reac- purification system. The use of standard deionized water gave
tions “on H218O”.[a] comparable results. The reagents were purchased from Sigma–
Aldrich and used as received. In several cases, the aldehydes were
Entry Reaction on “H218O” 18
O Isotope distribution in product
purified by distillation, however, the reactivity of the distilled
1 1b 2b compounds was found to be identical to that of the commercially
O2, 5 h 1 (2 G 16O): 3 (16O + 18
O) available chemicals. The reactions were performed in test tubes with
2 1 b (3 equiv) + 3 5b the Radleys Carousel Workstation. Alternatively, the reactions could
air, 3 h 1 (2 G 16O): 7 (16O + 18
O): 20 (2 G 18O) be performed in disposable 20 mL scintillation vials. Complete
3 1 b (3 equiv) + 4 6b product characterization is reported in the Supporting Information.
air, 3 h 1 (2 G 16O): 2 (16O + 18
O): 3 (2 G 18O) Conditions for aldehyde oxidation: Method A: A suspension of
4 1b + 2b + 3 5b aldehyde (100 mL, ca. 0.6–1 mmol) in pure water (3 mL) was added to
air, 3 h 1 (2 G 16O): 8 (16O + 18
O) a 50 mL glass tube equipped with a magnetic stirrer bar and stirred at
5 1b + 2b + 4 6b room temperature at 1100 rpm for 12 h in the presence of air. The
air, 3 h 1 (2 G 16O): 6 (16O + 18
O) product was quantitatively extracted with CH2Cl2 and isolated after
solvent evaporation. When CDCl3 was used instead of CH2Cl2
[a] All reactions were performed under standard conditions for the
without solvent evaporation, the 1H NMR analysis of the reaction
aldehyde oxidation and Passerini reactions.
mixture showed a product distribution identical to that obtained
under standard work-up conditions, thus indicating that no
volatile organic compounds are formed. Method B: A suspen-
sion of aldehyde (100 mL, ca. 0.6–1 mmol) in pure water (3 mL)
was added to a 50 mL round-bottomed flask and stirred at room
temperature for 2 h in pure molecular oxygen at 1 atm. The
product was quantitatively extracted with CH2Cl2 and isolated
after solvent evaporation. Method C: A suspension of aldehyde
(5 mL) in pure water (50 mL) was added to a 500 mL round-
bottomed flask and stirred at room temperature for 12 h in the
presence of air. The product was quantitatively extracted with
CH2Cl2 and isolated after solvent evaporation. Generally, most
of the product could be collected by simple phase separation of
the reaction mixture. The organic solvents were used to ensure
quantitative mass balance of organic compounds.
Scheme 3. General mechanism for aerobic oxidation of aldehydes (see Conditions for the Passerini reaction: Unless reported
Ref. [5]). otherwise, a suspension of aldehyde (0.51 mmol) and isocyanide
(0.17 mmol, 3:1 ratio) in water (3 mL) was stirred for 3 h at 40 8C
in the presence of air in a 50 mL glass reactor. Generally, 2 equiv
one (minor product) and two (major product) labeled oxygen of the aldehyde was sufficient to achieve high yields of the Passerini
atoms into the final products was observed (Table 3, entries 2 product, however, small amounts of hydrolyzed isocyanide were
and 3; 5 b and 6 b, respectively). obtained in some cases. For 1 i, 10 equiv of aldehyde was used. The
The reaction with nonlabeled 1-octanal (1 b), 1-octanoic organic products were extracted with CH2Cl2, the solvent was
acid (2 b), and ethyl isocyanoacetate (3) or pentyl isocyanide evaporated and the mixture analyzed by 1H NMR spectroscopy. No
(4) in H218O, gave the Passerini product with one incorporated by-products were observed in the reactions of aldehydes with
18 isocyanides. Small amounts of recovered starting materials and
O as the major product (Table 3, entries 4 and 5; 5 b and 6 b,
hydrolysis of the isocyanide were also observed.
respectively). For comparison, the Passerini reaction products
showed no incorporation of 18O upon stirring “on H218O” in Received: November 21, 2007
the presence of acid. The less reactive ethyl isocyanoacetate Revised: January 20, 2008
(3) gave more 18O incorporation in the Passerini reaction Published online: March 3, 2008

product compared to the reaction with pentyl isocyanide (4).
In conclusion, we have reported a general approach for
“on water” oxidation of aldehydes by using air or molecular
oxygen as the oxidant. This method can be extended to
perform consecutive organic reactions “on water” with
hydrophobic organic compounds, such as the multicomponent
Passerini reaction. The reported reactivity significantly
advances the use of water as a medium for organic reactions.
We are currently investigating the interaction modes between
water and organic substrates as well as the scope of the “on
water” oxidation of aldehydes in triggering other organic
transformations.
Experimental Section
General experimental procedures: All reactions were performed in
ultrapure water (W 18 MOhm, < 10 ppb total organic content), which
was obtained by using the Barnstead EASYpure II UF water
.
Keywords: aldehydes · green chemistry · oxidation ·
Passerini reaction · water
[1] For general references, see: a) Organic Synthesis in Water (Ed.:
P. A. Grieco), Springer, New York, 1997; b) Clean Solvents:
Alternative Media for Chemical Reactions and Processing: ACS
Symp. Ser. 2002, 819 (Eds.: M. A. Abraham, L. Moens);
c) Organic Reactions in Water (Ed.: U. M. Lindstroem), Black-
well, Oxford, UK, 2007; d) H. C. Hailes, Org. Process Res. Dev.
2007, 11, 114.
[2] a) P. Scrimin in Supramolecular Control of Structure and
Reactivity (Ed.: A. Hamilton), Wiley, Chichester, UK, 1996,
p. 101; b) M. N. Khan, Micellar Catalysis, CRC Press, Boca
Raton, USA, 2006.
[3] For examples of homogeneous aqueous chemistry, see: a) W.
Blokzijl, J. B. F. N. Engberts, J. Am. Chem. Soc. 1992, 114, 5440;
b) I. Vilotijevic, T. F. Jamison, Science 2007, 317, 1189; c) see

Angew. Chem. Int. Ed. 2008, 47, 2849 –2852  2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim www.angewandte.org 2851
Communications
also: J. B. F. N. Engberts, M. J. Blandamer, Chem. Commun.
2001, 1701, and references therein.
[4] a) M. C. Pirrung, K. Das Sarma, J. Am. Chem. Soc. 2004, 126,
444; b) S. Narayan, J. Muldoon, M. G. Finn, V. V. Fokin, H. C.
Kolb, K. B. Sharpless, Angew. Chem. 2005, 117, 3339; Angew.
Chem. Int. Ed. 2005, 44, 3275; c) B. K. Price, J. M. Tour, J. Am.
Chem. Soc. 2006, 128, 12899; d) A. El-Batta, C. Jiang, W. Zhao,
R. Anness, A. L. Cooksy, M. Bergdahl, J. Org. Chem. 2007, 72,
5244; e) D. Gonzalez-Cruz, D. Tejedo, P. de Armas, F. Garcia-
Tellado, Chem. Eur. J. 2007, 13, 4823; key earlier work: f) D. C.
Rideout, R. Breslow, J. Am. Chem. Soc. 1980, 102, 7816; g) A.
Lubineau, J. Org. Chem. 1986, 51, 2142.
[5] a) J. R. McNesby, C. A. Heller, Chem. Rev. 1954, 54, 325; b) S. S.
Maslov, E. A. Blyumberg, Russian Chem. Rev. 1976, 45, 155;
c) L. Sajus, I. S. De Roch in Comprehensive Chemical Kinetics,
Vol. 16 (Eds.: C. H. Bamford, C. F. H. Tipper), 1980, p. 89.
[6] F. Koch in Applied Homogeneous Catalysis with Organometallic
Compounds, 2nd ed. (Eds.: B. Cornils, W. A. Herrmann), Wiley-
VCH, Weinheim, 2002, p. 427.
[7] For detailed analysis of additives effect on aldehyde oxidation,
see: a) C. Lehtinen, G. Brunow, Org. Process Res. Dev. 2000, 4,
544; b) C. Lehtinen, V. Nevalainen, G. Brunow, Tetrahedron
2001, 57, 4741.
[8] D. R. Larkin, J. Org. Chem. 1990, 55, 1563.
[9] R. Battino, T. R. Rettich, T. Tominaga, J. Phys. Chem. Ref. Data
1983, 12, 163.
[10] K. Buechner, H. Tummes, DE 1154454, 1963.
[11] As the aldehyde oxidation reactions can be influenced by even
trace amounts of metal (see for example: F. Loeker, W. Leitner,
2852 www.angewandte.org  2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2000, 6, 2011), the reactions were performed under
strict metal-free conditions.
[12] M. C. Pirrung, K. Das Sarma, Tetrahedron 2005, 61, 11456.
[13] For additional references, see: a) A. R. Extance, D. W. M.
Benzies, J. J. Morrish, QSAR Comb. Sci. 2006, 25, 484; b) I.
Kanizsai, Z. Szakonyi, R. Sillanpaa, F. Fulop, Tetrahedron Lett.
2006, 47, 9113.
[14] For a general review on the Passerini reaction see: L. Banfi, R.
Riva, Org. React. 2005, 65, 1.
[15] For earlier comparison of “on water” versus “in water” Diels–
Alder reactions, see: R. Breslow, U. Maitra, D. Rideout,
Tetrahedron Lett. 1983, 24, 1901.
[16] Considering the nasty nature of isocyanides, it was preferable to
use a slight excess of the aldehyde rather than the isocyanide to
achieve high conversions.
[17] For the aldehyde/gem-diol equilibrium data, see: a) S. H. Hilal,
L. L. Bornander, L. A. Carreira, QSAR Comb. Sci. 2005, 24, 631;
b) R. P. Bell, Adv. Phys. Org. Chem. 1966, 4, 1.
[18] A dependence of aqueous phase multicomponent reactions on
the mixing rate has been reported: M. C. Pirrung, Chem. Eur. J.
2006, 12, 1312.
[19] For leading discussions on the effect of water in aqueous organic
chemistry, see: a) R. Breslow, Acc. Chem. Res. 1991, 24, 159;
b) S. Otto, J. B. F. N. Engberts, Org. Biomol. Chem. 2003, 1, 2809;
c) Y. Jung, R. A. Marcus, J. Am. Chem. Soc. 2007, 129, 5492; also
see Ref. [18].
[20] The formation of gem-diols as intermediates in metal-catalyzed
aldehyde oxidation in water has been proposed: M. Besson, P.
Gallezot, Catal. Today 2000, 57, 127.
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 Lecture 14: Green Chemistry and
Technology

Course Instructor: Prof. Abu Taleb Khan

Course code: CH 426
Credit: 6

10/13/2022 1
 Lecture 14:

Learning Objectives of the this Lecture:

To discuss four green chemistry principles: namely-
• Renewable sources
• Derivative reduction

10/13/2022 2
 Principle 7: Renewable Resources
This principle states that, “A raw material or feed stock
should be renewable rather than depleting wherever
technically and economically practicable.”
The chemical industry in earlier times depended mostly on
renewable resources such as wood, crops, animal excreta
and others. The discovery of the effective distillation of
crude oil led to our dependence on petroleum and natural
gas. Starting materials for any synthesis are either obtained
from non-renewable or renewable resources.

10/13/2022 3
 Principle 7: Renewable Resources
The demand for petrochemical and other materials is
increasing due to increase in population and
industrialization. These petrochemicals and materials are
synthesized from fossil fuels, oils, coal, and natural gas, and
these are depleting. Although vegetation is renewable, but
it takes millions of years to convert it into fossil fuel along
with animal remains. This is not practical, and time is the
constraint, so these fossil fuels are considered to be
depleting and non-renewable.

10/13/2022 4
 Principle 7: Renewable Resources
If we obtain starting materials from agricultural or biological
produce, then these are referred to as renewable starting
materials. CO2 generated from natural resources and
methane gas obtained from marsh gas, another natural
resource, is available in the large amounts and also falls in
the category of renewable resources.

10/13/2022 5
 Sustainability and Environmental Issues
Sustainability issue: As the fossil fuels are depleting, we
have to find alternatives to fossil fuels to resolve
sustainability issue. As our natural resources are depleting,
we have to find ways to make these resources available for
our future generations. This principle becomes important as
we use renewable feed stock in the form of biomass
making all our fuels, chemicals, and materials. This biomass
is in the form of plants, trees, crops, algae, etc.

10/13/2022 6
 Sustainability and Environmental Issues
Although all living may be considered biomass, only non-
animal renewable resources may be used for biomass
economy. It is observed that about 170 billion tonnes of
biomass is produced annually in nature. Out of this only
3.5% is used for everyday need. Only 25% is used for bio-
based economy. It is the need of the hour to advance the
research in this direction to develop fuels, chemicals, and
renewable feed stock from biomass.

10/13/2022 7
 Sustainability and Environmental Issues
There are problems sometimes associated with biological
feed stock, as they are seasonal. These feed stocks should
be available as and when required. There are sometimes
crop failures due to which there may not be continuous
supply of starting materials for production. Another
important aspect is availability of land to cultivate a large
quantity of crops.

10/13/2022 8
 Sustainability and Environmental Issues
Environmental issue: The effects of fossil fuel are well known
on human health and the environment. Air pollution due to
refining, coal mining, oil spills, etc., is one of the problems
associated with synthesis of petrochemicals. Other factors
related to pollution includes oxidation of petroleum
hydrocarbons to the other functional groups. These use
heavy metals, such as, chromium, which are toxic.
Generation of chromium compounds waste contributes to
the human health and the environment.

10/13/2022 9
 Sustainability and Environmental Issues
Some examples of renewable raw materials are as follows:
(a) Ethanol from plants.
(b) Polyethylene can be made from ethylene, which is a
product of bio-ethanol.
(c) Polyurethane can be synthesized from soya
(polyhydroxy compounds known as polyols).
(d) Enzymes from biomass.

10/13/2022 10
 Sustainability and Environmental Issues
Some examples of renewable raw materials are as follows:
(e) Oils and carbohydrates from plants are used for
surfactants.
(f) Starch-based plastics.
(g) Biodiesel from plant oil.
(h) 2-MeTHF as a solvent (under greener solvents).

10/13/2022 11
 Some Alternative Chemicals Derived from Natural
Resources
Adipic Acid from Corn Starch
Almost 2 billion kg of adipic acid is needed every year to
make nylon, polyurethane, lubricant, and plasticizers.
Traditionally, it is made from benzene, which is
carcinogenic. Now, glucose obtained from corn starch can
make adipic acid. This is a green substituted for benzene.

10/13/2022 12
 Some Alternative Chemicals Derived from Natural
Resources
• Bioethanol and Biodiesel
During the last few years, significant progress has been
made to develop fuel, chemicals, and materials from
renewable resources. Sugarcane production in Brazil is
very good and bioethanol production from it is helping
them attain energy independence as well as in generating
employment. Europe is producing biodiesel from rapeseed
oil.

10/13/2022 13
 Some Alternative Chemicals Derived from Natural
Resources
Biofuel Production from Microalgae
Interest in recent research is focused on microalgae. Lipid-
extracted biofuel production from microalgae is due to
high lipid and carbohydrate content. Also, there is
increased productivity per unit land and water compared
to higher plants. The raw material processing is a challenge
among algae versus sugar versus lignocelluloses.

10/13/2022 14
 Some Alternative Chemicals Derived from Natural
Resources
Green Plastic made from Corn
Annually, Nature Works LLC produces 300 million pounds of
poly (lactic) acid (PLA) polymer from renewable resources.
This process avoids the use of organic solvents common to
the synthesis of petrochemical-based chemicals and helps
in reducing to 40% less greenhouse gases (GHGs) released
to the atmosphere. Degradation of PLA takes 47 days.

10/13/2022 15
Principle 8: Derivative Reduction

“Unnecessary derivatisation (blocking group,

protection/deprotection, temporary modification of
physical/chemical processes) should be avoided
whenever possible.”

10/13/2022 16
 Derivative Reduction
• Thederivatization principle is illustrated on an example from
the beginning of organic chemistry. Starting from compound
1, which has a keto and ester groups, we need to make
compound 2, in which the ester group is converted to
alcohol, whereas the keto group is preserved.

• The reaction requires a reduction of the ester group to an

alcohol. Two reducing agents that we are familiar with sodium
borohydride (NaBH4) and Lithium aluminium hydride (LiAlH4).
The latter will reduce the ester group, whereas the former will
not. However, both reducing agents will reduce the keto
group to alcohol, because keto function is more easily
reduced than the ester.

10/13/2022 17
 Derivative Reduction

• Tosolve this synthetic problem, one can react 1 with

ethylene glycol (3) under the acidic condition to give
compound 4, in which the keto group is transformed to
the acetal, whereas the ester group is unchanged (it
does not react with 3). One can then reduce the ester
group with LiAlH4 , which will convert it to the desired
alcohol 5, while leaving acetal group intact. Finally, the
acetal group is removed by an acid hydrolysis to give
the desired product 2. The terms chemists use are that
the keto group is protected against reduction by
‘derivatisation’ into an acetal, which is later removed to
‘deprotect’ the ketone.

10/13/2022 18
Transformation of a keto ester 1 to a keto alcohol
2 via a protection/ deprotection scheme

10/13/2022 19
Why should we avoid protection and deprotection
strategy?

•A quick examination of the reaction sequence

reveals a poor atom economy, because ethylene
glycol will go to waste. Alternatively, a possible
recycling of ethylene glycol would require an
extraction from the aqueous waste and purification
for its reuse, which may not be economical at all.

10/13/2022 20
Why protection and deprotection strategy is mandatory?
• Another type of derivatisation that the beginning
organic students are familiar with is the introduction of a
functional group that renders the molecule more
reactive, and then replacement of this group is carried
out with another group, which is desired. We wish to
convert a primary alcohol RCH2OH (6) to the
corresponding chloride, RCH2Cl (7) via a nucleophilic
substitution SN2 with Chloride ion. The reaction will fail,
because the OH is a poor leaving group. However, if we
derivatize the alcohol, by converting the OH group into
a good leaving group such as tosylate, the reaction will
occur.

10/13/2022 21
 Derivatization to facilitate the substitution
reaction

10/13/2022 22
 Why should we look for greener alternatives?

• Inthis example, we see also a poor atom economy

because tosylate will go to waste.

10/13/2022 23
 Lecture 15: Green Chemistry and
Technology

Course Instructor: Prof. Abu Taleb Khan

Course code: CH 426
Credit: 6

10/13/2022 1
 Lecture 15:
Learning Objectives of the this Lecture:

To discuss four green chemistry principles, namely-

• Catalysts

• Degradability

• Pollution Prevention

• Accident Prevention

10/13/2022 2
 Principle 9: Catalysis

Anastas and Warner (1998) give the definition of this

principle as follows:
“ Catalytic reagents (as selective as possible) are
superior to stoichiometric reagents”

10/13/2022 3
 Role of Catalysts

• Inmany cases, the formation of waste is linked to the

traditional use of a stoichiometric amount of reagents.
Switching from stoichiometric methodlogies to catalytic
processes is perceived as one major way to improve the
efficiency of the synthetic toolbox.

• Catalysts typically lower the activation energy barrier for

the reaction, thus enabling reactions to occur faster and
become feasible at the lower temperatures. This translates
into the greener energy requirements.

10/13/2022 4
 Role of Catalysts

• Many catalysts have been developed to either

enable or enhance selectivity of the reaction.
Stereo-selectivity and achievement of enantiomeric
excess (ee) are necessary in the syntheses of fine
chemicals, especially drugs.
• Oftenonly one of the enantiomers has the desired
biological properties, and the other one may either
be toxic or place burden on the organism’s
detoxification system.

10/13/2022 5
 Role of Catalysts

• The production of the undesired enantiomers creates

waste, but the more serious problem is the required
separation of enantiomers for the purpose of isolating
the biologically active one. This process is often
difficult, lengthy and expensive. It is often a major
factor that drives up the cost of drugs. It is therefore
very important that the chemical synthesis yields the
desired enantiomer either exclusively or in excess. This
is often achieved with special catalysts.

10/13/2022 6
 Selectivity of the catalyst

When alkyne reacts with H2 in the presence of Pt

catalyst, the reaction does not stop at the alkene
stage, but gives the alkane, a completely saturated
product. If less than two equivalents of H2 were used,
one would still get the alkane, but would have some
unreacted alkyne. No alkene would be obtained. In
contrast, when a less reactive catalyst is used, such
as Ni2B, the reaction stops at the alkene stage. In
both cases, the hydrogenation takes place at the
surface of the catalyst. This accounts for the cis
stereochemistry.

10/13/2022 7
 Selective hydrogenation

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 Comparison between stoichiometric and catalytic
reduction

• Reduction employing DIBAL-H as the hydride donor

is a well-established procedure used by organic
chemists. It generates a significant amount of waste
since a stoichiometric amount of reducing agent is
needed to complete the reaction. Switching to
catalytic hydrogenation like the Noyori
hydrogenation eliminates the need for
stoichiometric reagents and in consequence
decreases the amount of feedstock needed and
the amount of waste generated

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 Comparison between stoichiometric and
catalytic reduction

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 Advantages of the catalyst

• Beyond efficiency, catalysis can allow for otherwise

unfavorable reactions to be realized. This was the
case for the metathesis reaction and the development
of the Grubbs catalyst. The development of a
metathesis catalyst allowed a groundbreaking
approach to the formation of unsaturated
compounds. The environmental benefit was significant
and the innovation was important.

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 Usefulness of Grubb’s catalyst

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 Importance of Biocatalyst

• Biocatalysis
is yet another example of ‘‘green chemistry” as it
is a biomimetic approach relying on natural or modified
enzymes. It usually refers both to the direct use of purified
enzymes and the transformations accomplished by
engineered living organisms. Reaction conditions are
relatively mild as the transformation can be performed in
water at atmospheric pressure and ambient temperature.
Moreover, enzymes have proven to be more chemo-, regio-
and stereoselective.

10/13/2022 13
 Advantages using a catalyst

• Catalysis can improve the efficiency of a reaction

by lowering the energy input required, by avoiding
the use of stoichiometric amount of reagents, and
by greater product selectivity. This implies less
energy, less feedstock and less waste. Moreover, it
often opens the door to innovative chemical
reactions and bring unconventional solutions to
traditional chemical challenges.

10/13/2022 14
 Principle 10: Degradability
“ Chemical products should be designed so that at the end
of their function they do not persist in the environment and
breakdown into innocuous degradation products”
The problem of persistence has been known for a long time
and became apparent in the early stages of industrial
development. In the 1950s for instance, tetrapropylene
alkylbenzene sulfonate (TPPS) was used as a surfactant for
laundry detergents and accumulated into the water supply
due to an incomplete degradation. The situation was so
critical that there were examples where ‘‘water tended to
foam when coming out of the tap.” The public outcry
prompted the industry to seek an immediate solution and it
was found that replacing the methyl branched chain of TPPS
by a linear carbon chain reduces the bio-persistence.

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 Non-biodegradable versus Biodegradable
surfactants

A common example is the replacement of TPPS by

linear alkylbenzene sulfonate (LAS).

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 Non-biodegradable versus Biodegradable fabric
softener

• Designing biodegradable materials and chemicals is not

a simple task as illustrated by continuing problems of
environmental pollution. Trends have emerged following
decades of data collection. Certain chemical structures
such as halogenated moieties, branched chains,
quaternary carbons, tertiary amines, and certain
heterocycles may possess enhanced persistence and are
avoided. Integrating functional groups such as esters or
amides which are recognized by ubiquitous enzymes
may help the design of environmental degradable
products. This strategy was applied to surface-active
quaternary ammonium compounds used as household
fabric softeners.

10/13/2022 17
 Non-biodegradable versus Biodegradable fabric
softener

• Untilthe 1990s, long chain ammonium salts such as

di(hydrogenated)tallow dimethyl ammonium chloride
(DHTDMAC) were released into the environment. It was
then discovered that their rate of biodegradation in
aqueous sediment was low and the intrinsic eco-toxicity,
high. In response, hydrolyzable amide or ester linkages
were introduced. The new ammonium salts have proven
to be more biodegradable. DHTDMAC was replaced by
di(ethyl-ester) dimethyl ammonium chloride (DEEDMAC)
which was followed by a 70% increase in the
biodegradability.

10/13/2022 18
Non-biodegradable versus Biodegradable fabric
softener

10/13/2022 19
 Principle 10: Degradability

• Many useful products, such as various plastics, have

been found to be persistent in the environment. This
has created multiple problems, from overflowing
landfills, to the danger for wild life, such as sea
birds, which ingest these products, often with
consequences that are detrimental for their health.
For such reasons, chemists started creating plastics
that can be degraded in the environment, often
with the help of various microbes (thus the term
“biodegradable”)

10/13/2022 20
 Principle 10: Degradability

• Some other useful products, such as pesticides, tend to

accumulate in living organisms (thus the term
bioaccumulation), especially in the lipid tissues. The
organisms are thus exposed such chemicals over a
prolonged period of time, which can exacerbate toxicity. It
can also lead to the transfer of such chemicals from mothers
to their nursing infants via milk. Degradability in cases of
pesticides is therefore a desired property.
• Degradationof chemical products should give benign end
products. The design of chemical products needs to fulfil the
degradability requirement. Green Chemistry considers
chemical degradation that often occurs in the environment
via hydrolysis, photolysis, and oxidation, among other
means. Also, various microbes and plants may be used to
remove/degrade toxic chemicals.

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 Principle 11: Pollution Prevention

The short definition of this principle was given by

Sanderson (2011) and was further expanded on as follows:
“Develop methods for real-time monitoring and control of
chemical processes that might form hazardous
substances.”
Anastas and Warner (1998) give the definition of this
principle as follows: “ Analytical methodologies need to
be further developed to allow for real-time, in-process
monitoring and control prior to the formation of hazardous
substances”

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 Principle 11: Pollution Prevention
This principle focuses on the development of accurate and
reliable analytical techniques that can be used to monitor
the generation of hazardous by-products and occurrences
of side reactions. Once these are observed, parameters of
such reactions and processes can be adjusted to eliminate
or reduce their formation. Especially important is the
determination of the completion level of the reactions, so
that one can intervene before quenching them.
One simple example, which is familiar to most students, is
to follow the reaction progress by thin-layer
chromatography. If the starting material is still present, the
reaction time is increased to allow for all the materials to
react. Modern analytical techniques are capable of
detecting minute amounts of hazardous or undesirable
chemicals. Technological capabilities exist for interfacing
analytical sensors within process control, and thus
minimizing hazards in an automated fashion.
10/13/2022 23
 Principle 11: Pollution Prevention

• Itis the goal of green analytical chemistry to measure

chemicals without generating waste. The environmental
issues associated with analytical chemistry are usually
linked to the analytical approach itself. Real time direct
analysis is unfortunately not systematic as many
methodologies still require a pre-treatment of the
sample or rely on what one may call ‘‘ex situ analysis.’’
Process analytical chemistry is defined as the ability to
monitor a transformation and act immediately upon it to
prevent unwanted outcomes. It is not always possible,
and therefore waste may be generated when the
sample is analyzed.
•

10/13/2022 24
 Principle 11: Pollution Prevention

• Green chemists must take into consideration the

functional requirements of analytical methods since it will
be counterproductive if the chosen methods contribute to
further environmental problems. Green analytical
chemistry can be defined as the use of analytical
procedures that generate less waste and are safer to
human health and the environment. This definition
includes both aspects of ‘‘live’’ monitoring of a chemical
transformation and the environmental shortcomings
associated with traditional analysis. In situ monitoring of a
reaction has significant advantages in terms of Green
Chemistry. When action can be taken quickly, it may
prevent accidents, save energy, and/or prevent the
formation of significant amounts of by-products that
would otherwise require additional purifications.

10/13/2022 25
 Principle 11: Pollution Prevention
• When it comes to the analytical methods themselves, most
of them share two problems linked to the two major steps of
a method: a pretreatment of the sample which includes
extraction, separation or even sometimes chemical
modification of the sample, and a signal acquisition step.
Since the pretreatment step usually calls for large volumes of
solvent, it has been the center of analytical chemists
concerns. If the use of solvents can not be avoided for an
extraction step, benign alternatives such as Accelerated
Solvent Extraction (ASE) or SCF extraction should be
considered.
• Material used in the manufacture of analytical apparatus
should be taken into consideration. Both green chemists and
green engineers building new sensors should be aware of
the toxicity and any potential environmental problems
related to the material they handle. Mercury electrodes, for
example, are often used for electrochemistry. Replacing
them with carbon-based electrodes such as nanotubes or
nanofibers
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has proven to be an effective solution. 26
 Principle 12: Accident Prevention

This principle is given by Anastas and Warner (1998)

as follows: “Substances and the form of a substance
used in a chemical process should be chosen so as
to minimize the potential for chemical accidents,
including releases, explosion, and fires.”

10/13/2022 27
 Principle 12: Accident Prevention

• Dangerous substances and processes have

multiplied in our working environment. According to
the ‘‘Chemical accident prevention and the clean
air act amendments of 1990,’’ preventing accidents
starts by identifying and assessing the hazards. All
types of hazards whether it is toxicity, physical
hazards such as explosivity or flammability, and
global hazards should be addressed in the design
of chemicals and processes in order to prevent
accidents such as Bhopal or the Love Canal
incident.

10/13/2022 28
 Principle 12: Accident Prevention

• A recent and shocking illustration of these dangers

and hazards can be found in the UCLA accident
that occurred in January 2009. Handling of the very
common and highly flammable n-butyl lithium
reagent resulted unfortunately in a terrible outcome
with the death of the research assistant involved.
This accident should be a strong reminder to the
scientific community that many chemicals we still
use present serious hazards and should be replaced
by safer alternatives to prevent accidents wherever
possible.

10/13/2022 29
 Principle 12: Accident Prevention

• This
is an important principle that broadens the scope of
green chemistry to prevention/minimization of hazards
above and beyond toxicity. Other hazardous properties,
such as flammability and tendency to explode, are often
responsible for injuries and large scale releases of
chemicals into the environment.
• Itis important to evaluate some other green chemistry
principles in light of this one. For example, recycling of
solvents is green according to principle 7, but solvents are
often flammable and pose fire or explosion hazards.
• One green technology is a rapid consumption of hazardous
substances, so that they do not need to be stored.

10/13/2022 30
Lecture 16: Green Chemistry and
Technology

Course Instructor: Prof. Abu Taleb Khan

Course code: CH 426
Credit: 6

10/13/2022
 Lecture 16: Innovative Aspects of Green Chemistry

Incredibility escapes recognition

Heraclitus
The Fragment LXXXVI

2 10/13/2022
 Lecture 13: Innovative Aspects of Green Chemistry

The learning objectives today’s lecture are as follows:

• Learn about innovation in general and in green chemistry.
• Does innovation require special type of thinking?
• To get this answer, we should learn about some common types of
thinking and their potential for fostering innovation.
• Those are deductive thinking, inductive thinking, critical thinking,
linear and non-linear thinking, lateral and vertical thinking, and
complex thinking.

3 10/13/2022
 About innovation in general and in green chemistry
 The common dictionary meaning of “Innovation” is the introduction of
something new, such as ideas, devices, methods or processes.
 Innovation usually refers to the implementation and application of novel idea,
method, and so on, whereas invention typically describes the creation of
these.
 According to Padgett and Powell (2012), something is novel if it does not exist
in the current practice and is not anticipated. Novel works are those not
obvious to others skilled in the same field.
 There are also business definitions of Innovation. These definitions are suitable
for describing innovations in green chemistry either in the form which they
stated or with some modifications.
Padgett, J. F. Powell, W. W. (2012): The Emergence of Organizations and Markets,
Princeton University Press, Princeton, NJ pp 1-15.

4 10/13/2022
 About innovation in general and in green chemistry

 Innovation is defined as follows: “The process through which economic and

social value is extracted from knowledge through the generation, development,
and implementation of ideas to produce new or improved strategies,
capabilities, products, services or products,” and “To be called an innovation, an
idea must be replicable at an economic cost and must specify a specific need.”
These definitions/descriptions resonate well with the principles of green
chemistry, which include economic aspects either implicitly or explicitly

5 10/13/2022
 About innovation in general and in green chemistry
 Some innovations in green chemistry are general, such as a focus on prevention
rather than protection. Some others are specific for a particular chemical
reaction of process. These involve both the design of new green reactions and
the greening of existing ones.
 Importantly, green chemistry draws much of its innovation from the existing
knowledge, which has not been previously recognized to have practical
applications (e.g. organic reactions in aqueous suspensions).
 The design of green reactions consists of several steps. First, chemists write
down the synthetic reaction sequence on paper. This step is traditionally termed
“paper chemistry” (although it can be done on computer!)
 To verify the proposed reaction in the laboratory, chemists first need to devise
the reaction protocol.

6 10/13/2022
 About innovation in general and in green chemistry

 The latter consists of detailed instructions on executing the reaction in the

laboratory, and on the isolation and identification of products.
 Typically, the protocol describes the equipment, reaction conditions (heating,
cooling etc.), quenching the reaction (with water, acid, or base), the work up
(e.g. extraction with solvents), isolation (e.g. removing of solvent), purification
(such as crystallization or distillation or sublimation or column chromato-
graphy), analytical procedures for monitoring the reaction progress, and
determining the purity of the product (e.g. chromatography, spectroscopy) and
structural identification (e.g. spectroscopy, single XRD).

7 10/13/2022
 About innovation in general and in green chemistry

 After the protocol is established, the reaction is run in the laboratory following
the proposed protocol. If the proposed protocol does not work in the
laboratory, chemists modify both the reaction steps and the protocol until the
reaction realized in practice. The reaction may still need to be optimized to give
maximum greenness. Often, the devil is in the details.
 Innovation may be required in execution of the seemingly minor aspects of the
original design and protocol, but without which the implementation of the
reaction in practice may fail.

8 10/13/2022
 About innovation in general and in green chemistry
 The task of designing a novel green reaction as a series of steps is shown Table 1.
In practice, the overall design requires going back and forth between the steps,
changing, adjusting and tweaking (fine tuning) them. Although steps 1-3 are
applicable to the development of any novel reaction, for a novel green reaction
we need to consider also step 4 and include the 12 principles of green
chemistry in all the steps.
 Table 1: Design of a Novel Green Reaction
 1. Design the reaction “on paper.”
 2. Design the laboratory protocol.
 3. Verify if the reaction works in the laboratory, by following the protocol. If
not, modify the previous steps necessary.
 4. Evaluate if the reaction and protocol are as green as proposed; if necessary

9 10/13/2022
 About innovation in general and in green chemistry
 What appeared to be a relatively straightforward stepwise process, moving from
step 1 to step 4, now becomes a rather elaborate interconnected system. This is
in Figure 1.

1 2 3 4

12 Principles of
Green chemistry
Figure 1: Interconnections between the steps for the design of a
novel green reaction with inclusion of 12 principles of green
chemistry

10 10/13/2022
 About innovation in general and in green chemistry

 The scheme shown in Fig. 1 is simplified. The interconnection between the

individual 12 principles of green chemistry are not shown. In a real design, we
need to include interactions of these principles with each other and also with
each of steps 1 through 4. Showing all of these interactions in the scheme would
make it extremely complicated, and it may obscure the steps of the process.
 A question arises: How can we think about the necessary steps and their
interconnections at the same time, and how can we organize our thinking
process to avoid frustration and to achieve success? Further, is there a thinking
method that will help us to innovate, or is innovation some sort of inspiration,
which may or may not happen? Selected materials on thinking methods, which
should help students navigate through innovating aspects of green chemistry and
build up their own innovative capabilities, are presented in next.

11 10/13/2022
ABOUT THINKING IN GENERAL AND FOR GREEN CHEMISTRY
INNOVATIONS

We briefly summarize various ways of thinking and reasoning in a

simplified manner but provide some useful references for all of us. We
point out various reasoning errors, which can derail our thinking about
green chemistry. Finally, we show that all types of thinking need to be
integrated and used in an inclusive way to be able to tackle the complex
problems found in green chemistry.

12
 DEDUCTIVE THINKING
 Deductive thinking is commonly used, especially in the sciences and
mathematics. This type of thinking was formulated by Aristotle
(Lawhead, 2001) and is based on his logic rules.
Lawhead, W. F. (2001): The Voyage of Discovery: A Historical Introduction to
Philosophy
 One starts from the accepted premise, such as a general principle
assumed to be true. One then examines a specific case, following the
rules of logic in a stepwise manner. One concludes that something must
be true if it is a special case of the general principle that is known to be
true.
 An example of a deductive inference is that if all birds lay eggs, then
pigeons must lay them too, because pigeons are birds (Reif, 2010, p. 111).

13 10/13/2022
 DEDUCTIVE THINKING

 Reif gives an example from mathematics. The number π is defined as the ratio
of the circumference C of a circle compared to its diameter D, namely, π =
C/D. This definition is the starting point in our reasoning, and we accept it as
true without questioning it. Then a simple deductive inference gives a
conclusion that a circumference of a particular circle can be obtained by
multiplying its diameter by π. This reasoning is presented by an equation, C =
πD. Likewise, D = C/π.
 Reif reminds us that it would be foolish to remember these conclusions as
separate facts when they can be easily inferred from the definition of π. The
deductive method can thus be looked at as formulaic (algorithmic).
Reif. F. (2010) Applying Cognitive Science to Education: Thinking and Learning in Scientific
and Other Complex Domains

14 10/13/2022
 DEDUCTIVE THINKING

 We give another familiar example of deductive inference, starting

from an equation that defines force as F = ma (force is mass times
acceleration). If we plug in specific values for mass and
acceleration into this equation, we should obtain the value for the
force in a predictable and reliable manner, and can be confident
that the answer is correct.
 If force is equal to mass times acceleration in general, then this
must hold for the specific cases of mass and acceleration.
Alternatively, if we know, for example, force and acceleration, we
can obtain mass from the same equation.

15 10/13/2022
 DEDUCTIVE THINKING

 The major shortcoming of deductive reasoning is that it is based on

premises that are not questioned. If the premise is incorrect, following the
rules of logic will provide a logically correct answer, which, however, will be
a wrong answer!
 Examination and questioning of already accepted premises
may lead to innovation. The green chemistry movement examined
and rejected the premise that protection is the exclusive way of dealing
with the problem of toxic chemicals. The protection premise was wrong,
and its substitution with a new premise, that of prevention, was
innovative.

16 10/13/2022
 INDUCTIVE THINKING
 The weakness of the deductive reasoning, that it becomes a house
of cards if the original premises are incorrect, was pointed out by
Francis Bacon, who formulated a different way of thinking, that of
induction (Lawhead, 2001).
 Inferring by induction starts with a limited knowledge of a few
specific cases and arrives at plausible conclusions. The process of
induction involves making specific observations; looking for similarities,
differences, and possible analogies to what is already known; identifying
patterns and regularities; examining quantitative relationships and
comparing them with the known phenomena, and finally formulating a
hypothesis. However, Bacon’s system also becomes a house of cards if
the supposedly unrelated phenomena are considered related.

17 10/13/2022
 INDUCTIVE THINKING

 Inferring by analogy involves observing that two systems have some

similar features, and then concluding that other properties of the two
systems are probably also similar. This may lead to a wrong conclusion
(Reif, 2010, pp. 110-110).
 Nickerson et a1. (1985) list various specific instances of making errors
in induction: failing to sample enough information, failing to sample in
an unbiased way, ignoring negative information or not exploiting it,
failing to discard and clinging to the unlikely hypotheses, considering
too few alternatives, and failing to view one’s own opinion or hypothesis
objectively, among others.
Nickerson et a1. (1985):TheTeaching of Thinking

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 INDUCTIVE THINKING

 Novelty can come from identification and careful examination of

reasoning errors.We give here one example from organic chemistry.
 Numerous observations have shown that organic chemicals that are
water insoluble react in organic solvents. An inductive generalization was
made that organic chemicals that are insoluble in water necessitated that their
reactions be run in organic solvents. This was based on well-known solubility
rules and the kinetic requirement that reactant molecules need to
collide in order to react.

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 INDUCTIVE THINKING

 Some isolated examples of organic materials that are not water soluble
but still react in water existed, but were not included in the reasoning,
which was erroneous.
 Green chemistry examined these isolated reactions and found them to
be representative of a much larger class of similar reactions. Thus,
previously stated generalization that one needs organic solvent was not
correct. Green chemistry exploited its discovery and started an entirely
new subfield of organic reactions in water.

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 CRITICAL THINKING
 Critical thinking has various definitions and numerous attributes, which
is not surprising, because it is a subject of an entire relatively recent
educational movement. We select here some definitions and descriptions
that are representative and are useful for green chemistry applications.
 Critical thinking is used to decide if a claim is true, partially true or
false. It is concerned primarily with judging the true value of statements
and is seeking errors. It is thinking that is rational, open-minded, and
informed by evidence. It results in a judgment by analyzing and
evaluating relevant criteria. Critical thinking calls for the ability to
reconstruct one’s beliefs on the basis of new evidence (see Wikipedia).

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 CRITICAL THINKING

 Critical thinking is necessary but not a sufficient condition for creativity.

However, when creativity generates novel possibilities, we need critical
thinking to evaluate them (Nickerson et al., 1985, pp. 88-89).
 Critical thinking helps us reevaluate the accepted paradigms. This can lead to
innovation, as shown previously on the example of green chemistry. We add
here another important feature of critical thinking that is essential for green
chemistry innovation, namely, the ability to reconstruct one’s belief based on
new evidence.
 Just because things were done in a certain way in the past and were justified by
then available evidence, it does not mean that we have to cling to these ways. We
should constantly reevaluate the ways based on new evidence. For example,
toxic solvents were once thought to be unavoidable, but the new evidence
showed that water, the ultimate benign solvent, can be used in many cases.

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 LINEAR AND NONLINEAR THINKING
 Terms “linear thinking” and “nonlinear thinking” have become popular
relatively recently, especially in the field of management (see, e.g.,
Osterman et al., 2013).
 These two types of thinking show different preference of methods for
comprehending information. Linear thinking is based on rationality,
logic, and analytical reasoning, whereas nonlinear thinking utilizes
preferentially intuition, insight and creativity.
Digital Literacy: A demand for nonlinear thinking.

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 LINEAR AND NONLINEAR THINKING
 Linear thinking is valued for its efficiency. However, it is prone to the
same problems as deductive thinking, because both depend on logic.
Linear thinking is not well suited for solving problems in complex
systems in which various parts are interconnected and influence each
other.
 Although we can apply linear thinking to a single connection within a
complex system, this does not guarantee success and often leads to a
dead end. The sum of the individual connections often does not
represent the system adequately, because different parts of the system
may be changed by the interactions with other parts, and thus cannot be
considered in isolation.

24 10/13/2022
 LINEAR AND NONLINEAR THINKING
 One example is the application of 12 principles of green chemistry to
the greening of a chemical system. If we think in a linear fashion, we
shall focus only on one principle and will try to do green optimization
based only on this selected principle.
 For example, we choose to focus only on atom economy, but do not
include other principles, such as economic factors. By following the
linear path, we may design a novel reaction with high atom economy,
and thus no waste. However, if we did not consider economic factors,
the reaction may be too expensive to be implemented in practice.
 Nonlinear thinking uses multiple perspectives and often examines
connections that are not immediately obvious. This approach may lead to
novel and unexpected solutions to the problem. A demand for this type
of thinking style is growing, especially in business, management, and the
workplace in general.

25 10/13/2022
 LINEAR AND NONLINEAR THINKING
 Multiple perspectives are often obtained from interdisciplinary
approaches. We have already seen that looking at green chemistry
reactions and processes, we need to look at them also from the points of
view of toxicology, environmental science, and economy, for example.
 Both linear and nonlinear thinking should be practiced. We should strive
to utilize the best aspects of each as appropriate for the problem that we
are examining. The same is true for deductive and inductive reasoning.

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 LATERAL AND VERTICAL THINKING

 The terms “lateral thinking” and “vertical thinking” were coined by

Edward de Bono.
 Vertical thinking is traditional thinking in which one takes a position and
then builds on the basis of that position, in a stepwise and logical
manner.
 Vertical, deductive, and linear thinking are related because they share
the tools of logic. In lateral thinking, we search for different approaches
and different ways of looking at things, and we move “sideways” to
perceive things differently and to try different concepts and points of
entry (de Bono, 1993, p. 53).
de Bono, 1993: Serious Creativity: Using the power of lateral thinking to Create
New Ideas

27 10/13/2022
 LATERAL AND VERTICAL THINKING

 Lateral thinking challenges assumptions and generates alternative ways

of looking at the problem. It breaks out of the concept prison of old
ideas (de Bono, 1990, p. 11). It is involved in creating something new,
rather than analyzing something old. It explores multiple possibilities
and approaches, instead of pursuing a single approach.
 Lateral thinking is creative and leads to innovation. This type of
thinking is best captured by de Bono’s description: “You cannot dig a
hole in a different place by digging the same hole deeper” (de Bono,
1993, pp. 52-53). Lateral thinking corresponds to digging the hole in a
different place, whereas vertical thinking corresponds to digging the
hole in the same place.
 Green chemistry can be well described by “digging the hole” in a
different place, that of prevention, whereas traditional chemistry just
“dug the hole” in the same place, that of protection, but deeper and
deeper.

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 COMPLEX THINKING
 The term “complex thinking” has been used in different contexts. We present
here a simplified coverage of this topic and pick and choose some elements that
are useful for green chemistry.
 Complex thinking combines various aspects of thinking, among which are the
following four: problem solving, critical thinking, creative thinking, and finally
decision making, in which one chooses the best alternative (Puccio et a1.,
2011).
 These aspects of thinking are in common within other types of thinking.
However, the key challenge here is that the problems that require complex
thinking are also complex. They are typically ill-defined and new, and depend on
multiple variables, which are interconnected. The difficulty lies not only in the
number of variables but also in the degree in which they are interconnected.
 We can now recognize that a green synthesis, which requires the consideration
of the 12 principles of green chemistry, is an example of a complex problem.
The interconnection between the 12 principles is dependent also to a degree on
the type of synthesis. Thus, complex thinking is well suited for green chemistry
applications.

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 CONCLUSION ABOUT THINKING THAT IS SUITABLE
FOR GREEN CHEMISTRY
 As we described the various types of thinking, it became clear that we
need to depart quickly from the formulaic methods of deductive
thinking even though they provide the comfort of known equations and
known methods of solution.
 Although this is the most commonly required type of thinking for the
sciences and mathematics, we have shown its limitations. We have
presented other types of thinking, from the inductive to complex. These
types of thinking are less straightforward and more complicated than
deductive thinking.
 Creative and novel solutions can be generated by ways of multiple
thinking approaches.
 Knowledge of different ways of thinking should allow the persons to
develop, exercise, and finally contribute creativity and innovation to the
field of green chemistry.

30 10/13/2022
 About innovation in general and in green chemistry

Examples of Innovations in Green Chemistry

 Reactions in Water (Deductive Thinking)
 Reactions in Superheated Water (Inductive Thinking)
 Reactions in Water in Nanomicelles (Critical Thinking)
 Design of Halogen-free Firefighting Foam (Linear and Non-linear
Thinking)

31 10/13/2022
 Reaction in Superheated Water
At 150oC water behaves like dimethyl sulfoxide (DMSO),
at 175oC as N,N-dimethylformamide (DMF), at 200oC as
acetonitrile (CH3CN), and at 300oC as acetone

32 10/13/2022
 Reactions in water in Nanomicelles

33 10/13/2022
 Reactions in water in Nanomicelles

34 10/13/2022
 Reactions in water in Nanomicelles

35 10/13/2022
Lecture 18: Green Chemistry and
Technology

Course Instructor: Prof. Abu Taleb Khan

Course code: CH 426
Credit: 6

10/13/2022
 Green Organic Reactions “on Water”
 Learning Objectives:
 Learn about different types of reactions in the aqueous
medium
 Learn about specific examples of on-water reactions Diels–
Alder reaction
 Passerini reaction
 A sampler of other “on-water” reactions

2 10/13/2022
 Green Organic Reactions “on Water”

… the major real reason to pursue water as a solvent is that the

hydrophobic effect leads to such remarkable new chemistry not
otherwise achievable.
Ronald Breslow (2010)

3 10/13/2022
 Unique Properties of Water

8 10/8/2020
 2. Water based chemistry- the ultimate green solvent?

9 10/8/2020
 Types of Reactions in Aqueous Medium and
Associated Nomenclature
 We start with the simplest and most familiar concept of organic
reactions in water.
 Some categories of organic compounds are soluble in water. Such
compounds include small molecules, typically five carbon atoms or less,
which have hydrophilic groups present, for example, -hydroxyl (-OH),
carboxyl (-COOH) or amino (-NH2). Charged organic compounds,
such as salts of carboxylic acids (carboxylates; -COO-), phenols
(phenolates; PhO-), amines (amine salts; -NH3+), are typically also
soluble. This is the case providing that the hydrophobic portion of these
salts is not disproportionally large.

10 10/8/2020
 Types of Reactions in Aqueous Medium and
Associated Nomenclature
 Familiar examples of water-soluble organic compounds include simple
sugars such as glucose, amino acids such as glycine, and alcohols such as
ethanol or methanol. Water soluble compounds can react in water. Such
reaction are classical in-water reactions.
 This simple concept of organic reactions in water has been the accepted
paradigm until relatively recently. Because the vast majority of organic
compounds are not water soluble, this paradigm implied that such
compounds cannot react in water. This view changed in 1980, when it
was demonstrated that water-insoluble organic compounds can react in
water, but that water can also accelerate such reactions.

11 10/8/2020
 Types of Reactions in Aqueous Medium and
Associated Nomenclature
 Much more worked followed, which showed that this phenomenon is
widespread. These findings brought a whole new meaning to the concept
of organic reactions in water.
 A new nomenclature that would make a distinction between in-water
reactions of soluble versus insoluble reactants was needed. The new
nomenclature introduces terms “on water,” “in water,” “water
promoted.” and “in the presence of water,” among others. These
terms are often used interchangeably, although they refer to reactions
that may occur under different conditions.

12 10/8/2020
 Types of Reactions in Aqueous Medium and
Associated Nomenclature
 The nomenclature that is used most often is as follows:
 The “in-water” reactions describe the cases in which the reactants are
water soluble, but also the cases in which the reaction occurs in micelles
that are dispersed in water.
 The “on-water” reactions are those in which the insoluble reactants are
stirred in aqueous emulsions or suspensions. Thus they occur in
heterogeneous systems.
 “Water-promoted” organic reactions are those that show an outcome
that is superior when the reactions are performed in water compared to
traditional organic solvents.

13 10/8/2020
 Types of Reactions in Aqueous Medium and
Associated Nomenclature
 “In the presence of water” can be used broadly, but also more
specifically, for the cases in which water is added to traditional organic
solvents.
 In simple terms the hydrophobic effects, which enable reactions of
water-insoluble reactants to occur in water. Now we introduce a
common nomenclature for the hydrophobic effects and the associated
phenomena, which will facilitate the reaction on water.

14 10/8/2020
 Types of Reactions in Aqueous Medium and
Associated Nomenclature
 Hydrophobic effect: The tendency of nonpolar compounds or their
segments to cluster in water, to diminish the interface with water.
 Hydrophobic acceleration: The acceleration of the reaction rate due to
the hydrophobic effect.
 Prohydrophobic additives: Additives that increase hydrophobic effects.
They decrease the solubility of nonpolar reactants in water.
 Antihydrophobic additives: Additives that decrease hydrophobic
effects.They increase the solubility of nonpolar reactants in water.

15 10/8/2020
 Diels-Alder Reaction
 Traditionally, the Diels-Alder reaction has been performed in organic solvents. However,
in many cases, it may occur in water too. The water-insoluble hydrophobic reactants,
when placed in water, are driven toward each other to avoid water. In this process, they
experience hydrophobic interactions. These are well known in biology, especially for the
interaction of peptides. Such hydrophobic interactions increase the probability of a close
interaction between reactants. This process is sometimes referred to as the increase in
the effective concentration due to hydrophobic “packing.” The close proximity of the
reactants also facilitates a proper alignment of their molecular orbitals, which increase
both the reaction rate and stereo-specificity. When the reaction is performed in organic
solvents, the reactants dissolve in the solvent and become diluted. This dilution decreases
the probability of the reactants to encounter each other, which is reflected in the
decreased reaction rate.The endo specificity of the reaction is also adversely affected.

16 10/8/2020
 Diels-Alder Reaction
 Traditionally, the Diels-Alder reaction has been performed in organic
solvents. However, in many cases, it may occur in water too. The water-
insoluble hydrophobic reactants, when placed in water, are driven
toward each other to avoid water. In this process, they experience
hydrophobic interactions. These are well known in biology, especially for
the interaction of peptides. Such hydrophobic interactions increase the
probability of a close interaction between reactants. This process is
sometimes referred to as the increase in the effective concentration due
to hydrophobic “packing.”

17 10/8/2020
 Diels-Alder Reaction Between Cyclopentadiene and
Maleic Anhydride

The close proximity of the reactants also facilitates a proper alignment of their
molecular orbitals, which increase both the reaction rate and stereo-specificity.
When the reaction is performed in organic solvents, the reactants dissolve in the
solvent and become diluted. This dilution decreases the probability of the
reactants to encounter each other, which is reflected in the decreased reaction
rate.The endo specificity of the reaction is also adversely affected.

18 10/8/2020
 Water based chemistry

19 10/8/2020
 Examples of Prohydrophobic and Antihydrophobic
Additives

Prohydrophobic Additives Antihydrophobic Additives

LiCl, NaCl, NaBr, KCl Guanidium Chloride, (NH2)2C=NH2+Cl-
MgCl2, CaCl2, Na2SO4 Urea, (NH2)2C=O, ethanol
Glucose, Saccharose, Sucrose LiI, Perchlorate ion

20 10/8/2020
 Passerini Reaction Between Benzaldehyde, Tert-
Butylisocyanide and Benzoic Acid
O O

H N C + OH
+

Benzaldehyde tert-Butyl isocyanide Benzoic acid

O
H
N
O
O

Benzoic acid, tert-butylcarbamoyl-phenyl-methyl ester

21 10/8/2020
 Passerini Reaction on Water

22 10/8/2020
 Results of Passerini Reaction on Water

 In dichloromethane at 25oC for 18h gives 50% conversion and eventual yield
45%
 In contrast, the reaction run in water at the same temperature for 3.5 h gives
100% conversion and a 95% yield. The reaction in water is approx. 18 times
faster than that in dichloromethane.
 Again, the reaction rate is increased in presence of prohydrophobic additives
such as LiCl and glucose.The factor is 16 and 7 respectively.
 When the temperature was increased from 25oC to 50oC, the reaction rate
decreased for 44%
 When the temperature was lowered from 25oC to 4oC, the reaction rate
increased by 11%

23 10/8/2020
 Claisen Rearrangement on-Water

24 10/8/2020
 Air oxidation of aldehydes on-water

25 10/8/2020
 Water can also be used in biphasic systems

26 10/8/2020
 Classical Oxidations of Alcohols

27 10/8/2020
 Venn and the Art of Green Chemistry

28 10/8/2020
 Green, Catalytic Oxidation of Alcohols

29 10/8/2020
 Mechanism of oxidation of ketone On-Water

30 10/8/2020
 Aerobic Oxidation of Alcohols with Pd(II)-Diamine Catalysts

31 10/8/2020
 Steric Effects

32 10/8/2020
 Steric Effects

33 10/8/2020
 Cuproin/Pd(OAc)2: Functional Group Tolerance

34 10/8/2020
 High temperature water

35 10/8/2020
Lecture 20: Green Chemistry and
Technology

Course Instructor: Prof. Abu Taleb Khan

Course code: CH 426
Credit: 6

10/30/2022
 Lecture 20: Green Organic Reactions in Superheated Water

The learning objectives today’s lecture are as follows:

• Understand the fundamental properties of water and the basic features
of the phase diagram for water, with a special focus on the regions for
superheated water.
• Become familiar with the special properties of superheated water,
which make it a green reaction medium and appreciate the innovative
aspects of performing organic reactions in superheated water.
• Become familiar with types of organic reactions, which can be
performed in superheated water.

2 10/30/2022
 Important Remarks on Supercritical Water
“Water near its critical point possesses properties very different from those
of ambient liquid water.”
Philip E. Savage
Akiya N. Savage, P. E. Chem. Rev. 102, 2725-2750, 2002

“Supercritical water is a special and very extraordinary solvent, as it

consists of polar molecules but behaves like a nonpolar solvent.”
A. Kruse and E. Dinjus
Sub- and supercritical water, in Water in Organic Synthesis, Kobayashi, S. ed.
Thieme, Stuttgart, Germany p-750.

3 10/30/2022
 Fundamental Properties of Water
The familiar Lewis structure of water, which depicts the oxygen has lone electron
pairs. These are responsible for the ability of water to act as a hydrogen
(proton) acceptor. Due to a large electronegativity differences between oxygen
and hydrogen, which makes the hydrogens partially positive, water also acts as a
hydrogen donor. This enables water to make hydrogen-bonded networks
between its molecules. These networks are responsible for a relatively high boiling
point of water, among other properties.

4 10/30/2022
 Fundamental Properties of Water
Water is highly polar which is reflected in its high dielectric constant (78.4
at 25 °C). Water dissociates to proton (H+, which hydrates to H3O+) and
hydroxide (OH-) ions. The ionic product if water (Kw = [H+][ OH-]) is very
small. At room temperature, it is 10-14. This means that the concentrations
of both protons and hydroxide ions are very small (10-7 M). Water is
neutral, because the concentrations of both acidic and basic hydroxide ions
are the same.
All these properties of water will be dramatically changed when water
becomes superheated.

5 10/30/2022
 Phase Diagram of Water and Associated Terms and
Definitions

An approximate and simplified phase diagram for water, shown

on a non-uniform scale

6 10/30/2022
 Phase Diagram of Water and Associated Terms and
Definitions
Each solid line in the phase diagram represents the phase boundary. An
equilibrium condition exists between the two phases on either side of the
line. Interestingly, the solid-liquid equilibrium line for water has a negative
slope, which is unusual. For most other substances, for example, CO2, the
slope for this line is positive.
The “triple point” is indicated by Tp on the phase diagram. This is a unique
pressure and temperature condition in which all the three phases coexist.
For water, it is at 0.006 atm and 0.01 °C.

7 10/30/2022
 Phase Diagram of Water and Associated Terms and
Definitions
We focus on the liquid /gas equilibrium line. The symbol Cp denotes the
critical point at which the boundary line between the liquid and gas
phases terminates. At Cp , these two phases become indistinguishable and
form a single phase, which is known as a supercritical fluid. The Cp for
water occurs at 374 °C and 218 atm. The region in the phase diagram
between the dashed lines, which start at Cp, is for the supercritical fluid
phase. It can occur along or above and to the right of the dashed lines,
which represent the values for the critical temperature and pressure.

8 10/30/2022
 Phase Diagram of Water and Associated Terms and
Definitions
Now we contemplate the path toward Cp by following the liquid/gas
equilibrium line, and then to the supercritical fluid region, after the
equilibrium line stops. We notice that the high temperature that are
achieved in conjunction with an increase in pressure. The approach to
the critical point has some well-defined temperature and pressure region
that are associated with the various types of superheated water, such as near
critical, critical, and supercritical.

9 10/30/2022
 Terms and Definitions Associated with Phase
Diagrams and Superheated Water
Terms Definitions
Phase-diagram A diagram that shows the regions of pressure
and temperature at which various phases of a
substance are thermodynamically stable
Phase boundaries The lines that separate the regions in the phase
diagram; they show the values of pressure and
temperature at which two phases coexist in
equilibrium
Boiling point of water 100 °C at 1 atm

10 10/30/2022
 Terms and Definitions Associated with Phase
Diagrams and Superheated Water
Terms Definitions
Critical temperature, Tc A temperature at which the density of vapor
(gas) of a substance is equal to that of its liquid,
and the surface between the two phases dis-
appears.
Critical Pressure, Pc A pressure at the the critical temperature.

Critical Point A point on the phase diagram at which the

liquid and vapor (gas) phases merge together
into a single phase.
Critical point for water 374oC and 218 atm

11 10/30/2022
 Terms and Definitions Associated with Phase
Diagrams and Superheated Water
Terms Definitions
Supercritical fluid A single uniform phase at and above the critical
point
Triple point, Tp A point on the phase diagram at which the
solid, liquid, and vapor (gas) boundaries coexist
in equilibrium
Triple point, Tp for Water 0.01oC and 0.006 atm

HTW (High temp. Water at temperature above its normal boiling

water) point (100oC and 1 atm)

12 10/30/2022
 Terms and Definitions Associated with Phase
Diagrams and Superheated Water
Terms Definitions
SCW (Supercritical water) Water above its critical temperature
(374oC) and Pressure (218 atm).
Distinct gaseous phase and liquid
phases no longer exist; there is only a
single phase.

NCW (Near Critical Water) Water at temperatures of 200oC-

300oC

UCST (Upper Critical The temperature above which the

Solution Temperature) organic and water are miscible in all
proportions

13 10/30/2022
 Terms and Definitions Associated with Phase
Diagrams and Superheated Water
Terms Definitions
Gas versus Vapor, These two terms are often used inter-
as related to the changeably. For example, Atkins …
Phase diagram use vapour. Some other sources use
gas

14 10/30/2022
 Selected Properties of Water under Different
Temperature and Pressure
Property Ambient HTW SCW
Water
Temperature 25 250 400 400
(°C)
Pressure 1 50 250 500
(bar)
Density 997 800 170 530
(Kg/m3)
Dielectric 78.5 27.1 5.9 10.5
constant
Kw 10-14 10-11.2 10-19.4 10-11.9

15 10/30/2022
 Selected Properties of Water under Different
Temperature and Pressure
We make an approximation that 1 bar = 1 atm. Inspection of the values
from this table shows the following:
 Compared to the ambient liquid water at 25 °C and 1 atm, HTW, at 250
°C and 50 atm, has decreased values of density and dielectric constant,
but a substantially increased value of Kw.
 For SCW at 400 °C, these properties vary with pressure, and thus can
be modulated by the changes in pressure. For example, SCW at 250 atm
shows a dramatic decrease in Kw compared to the ambient water,
whereas at 500 atm, Kw is substantially increased.

16 10/30/2022
 Selected Properties of Water under Different
Temperature and Pressure
 The increased Kw of HTW and SCW under specific conditions means
that water becomes more acidic than the ambient water. If a reaction
requires acid catalysis at ambient conditions, in many cases it will
occur in superheated water with no external catalyst, because the
H+ provided by the superheated water is sufficient. This would be true
also for the base-catalyzed reactions. This has been amply demonstrated
by numerous experiments in superheated water.

17 10/30/2022
 Selected Properties of Water under Different
Temperature and Pressure
 The sensitivity of the water parameters to the variations in temperature
and pressure has also been reported by Liotta et al. (2007), who use the
term near-critical water (NCW) to cover water from 200 °C to
300 °C. These authors point out that VCW is also referred to as HTW
“Hot Water,” “Subcritical water,” and “near-subcritical water” in
different literature sources. We retain the NCW term in the examples
below which are from Liotta et al.
 Liotta et. al. Reactions in near-critical water, in Organic Reactions in
Water: Principles, Strategies and Applications, Lindstroem, U. M.
Oxford, pp 256-300, 2007.

18 10/30/2022
 Selected Properties of Water under Different
Temperature and Pressure
 Under the near-critical conditions, water loses ~55%-60% of its
hydrogen-bonding network as the temperature is increased from 25 °C
to 300 °C. The decrease in hydrogen-bonding causes a decrease in the
dielectric constant, thus, the dielectric constant at 300 °C is ~ 20, or a
75% reduction from the value under ambient conditions. The NCW
value for the dielectric constant corresponds most closely to a
moderately polar solvent, such as acetone (dielectric constant of 21.4 at
25 °C). This enables enhanced solubility of nonpolar organic in
NCW.

19 10/30/2022
 Selected Properties of Water under Different
Temperature and Pressure
 In NCW, the Kw increases by as much as order of magnitude, from 10-14
at 25 °C to nearly 10-11 at 250 °C, where a maximum occurs. This
allows a fine-tuning of the Kw by the pressure and temperature changes,
to meet specific demands for the acid/base catalyst of various organic
reactions.

20 10/30/2022
 Innovative Aspects of Using Superheated Water as a
Green Reaction Medium
 The basic knowledge of superheated water has been applied only
relatively recently to green chemistry. This happened when innovative
breakthrough was achieved, in which the examination of the possibilities
of superheated water as a medium for green chemistry reactions found
literally a green gold mine. These possibilities are more than
compensated for other aspects of the superheated water medium, which
are not green. The latter include energy requirements to achieve high
temperatures and pressures, high cost of the special reaction containers
and other equipment, and inherent hazard of pressurized high-
temperature systems. The green innovations as related to the use of
superheated water are described in the recommend references. A
particularly clear description by Liotta et al is given in the text that
follows. It also reiterates the important properties of the superheated
water, which we have already covered in this chapter.
21 10/30/2022
 Innovative Aspects of Using Superheated Water as a
Green Reaction Medium
 Superheated water behaves as acetone in terms of dissolving organic
compounds. Acetone is as close to universal solvent as we know it. Thus,
all of the sudden, water, which is typically quite poor in dissolving
organic compounds, becomes a terrific solvent. As we know, water is
inherently a benign solvent. However, there is more. We have shown that
superheated water has both acid and base catalytic properties. A
maximum of Kw occurs in NCW at 250 °C.
 This provides us with green possibilities of performing organic reactions
that require acid or base catalysis without adding any mineral acids or
bases. The enormous increase in the concentrations of H+ and OH- ions
provides a green catalytic medium.

22 10/30/2022
 Innovative Aspects of Using Superheated Water as a
Green Reaction Medium
 After the reactions is done, simple cooling of the reaction mixture to the
ambient conditions restore the neutral conditions, without addition of
any external acids or bases that would normally needed for
neutralization. This also enables the ease of separation because there are
no catalysts to be removed or recovered. The workup procedure is
simplified because no neutralization is required. Waste reduction is
achieved because there is no salt to be disposed.

23 10/30/2022
 Innovative Aspects of Using Superheated Water as a
Green Reaction Medium
The innovative factor for the use of superheated water in green chemistry
is also the use of an inherently non-green system for green applications, in
a way to achieve an overall positive green effect. This requires complex
thinking. If we think linearly and focus only on the undesirable properties of
superheated water, we would not even consider superheated water as useful for green
chemistry.

24 10/30/2022
 Overview of Organic Reactions in Superheated Water
Reaction Type/ Examples of Substrates
Name and Resulting Products
Hydrolysis Amides (to corresponding carboxylic acid),
nitriles (to corresponding amides and
carboxylic acid), esters (to corresponding
acids and alcohols), aryl ethers (to phenols)
 Rearrangements: Beckmann: oximes (rearranged to lactams);
Pinacol (pinacol rearranged to pinacolone);
Claisen: allyl phenylether (rearranged to2-allyl phenol)

25 10/30/2022
 Overview of Organic Reactions in Superheated Water
Reaction Type/ Examples of Substrates
Name and Resulting Products
Denitration 4-Nitroaniline (to aniline) and
(removal of nitro group) N,N-dimethyl-4-nitroaniline (to N,N-
dimethyl aniline)
Alkylations Phenol and t-butyl alcohol (to give
phenol with t-butyl group in the ring)
Condensations Benzaldehyde and acetone;
Aldol type, benzaldehyde and 2-butanone (to give
Claisen Schmidt dehydrated aldol)

26 10/30/2022
 Overview of Organic Reactions in Superheated Water
Reaction Type/ Examples of Substrates
Name and Resulting Products

Dehydration Alcohols to alkenes

Dehalogenation Dechlorination of 1-chloro-3-phenyl

propane, 2-chlorotoluene, 4-chlorophenol

Oxidation Toluene to benzaldehyde

27 10/30/2022
 Organic Reactions in Superheated Water
 Hydrolysis of Esters

28 10/30/2022
 Organic Reactions in Superheated Water
 Hydrolysis of Ethers

29 10/30/2022
 Organic Reactions in Superheated Water
 Beckmann Rearrangement and Claisen Rearrangement

30 10/30/2022
 Organic Reactions in Superheated Water

Friedel-Crafts type

31 10/30/2022
 Useful Application of Superheated Water

 We have noted that there are many practical green applications of

reactions in superheated water. Notably, hydrolytic decomposition
of various polymers can be achieved to give more environmentally
friendly products, or for recycling. For example, polyethylene
terephthalate, a polymer that is used in plastic soft drink bottles,
can be hydrolyzed “quantitatively” back to the starting materials in
less than 1 h in superheated water.

32 10/30/2022
 Useful Application of Superheated Water

 Other polymers, such as polyesters, polyamides (such as nylon),

polycarbonates, polyethers, polyurethanes, and phenolic resins are
likewise hydrolyzed. For example, polyurethanes foams can be
hydrolyzed to reusable diamines and glycols. Polyacrylonitrile can
be hydrolyzed to low-molecular-weight water-soluble products.
This hydrolysis gives ammonia instead of the toxic hydrogen
cyanide, which is formed by thermolysis.
 Hydrolysis in superheated water is also used to remove sulfur or
nitrogen from organic compounds typically found in coal or oil,
thus reducing their environmental pollution.

33 10/30/2022
Lecture 21: Green Chemistry and
Technology

Course Instructor: Prof. Abu Taleb Khan

Course code: CH 426
Credit: 6

10/30/2022
 Lecture 21: Green “Solventless” Organic Reactions

The learning objectives today’s lecture are as follows:

• Learn that organic reactions may not need a solvent to occur.
• Learn about solventless reactions.
• Learn about solventless reactions that are based on the melting
behaviour of the reaction mixtures.
• Revisit the familiar concepts of melting point and eutectic point, and
the phase diagrams to better understand solventless reaction.
• Learn about challenges of solventless reactions to green chemistry.
• Learn about various examples of solventless reactions.

2 10/30/2022
 Important Remarks on Solventless Organic Reactions
“The remarkable versatility and success of using solventless reactions to
prepare several classes of compounds demonstrates that this methodology
has an important place in the toolbox arsenal of Green Chemistry”
Gareth W. V. Cave, Colin L. Raston, Janet L. Scott
Recent advances in solventless organic reactions: Towards
benign synthesis with remarkable versatility, Chem. Commun. 21,
2159-2169, 2001
“….. it is remarkable that chemists still carry out their reactions in
solution, even when a special reason for the use of solvent cannot be
found.”
Kochi Tanaka and Fumio Toda
Solvent-free Organic Synthesis, Chem. Rev. 100, 1025-1074, 2000

3 10/30/2022
 Another Green Chemistry Paradigm Shift: Organic
reactions may not need a solvent to occur
The use of organic solvents as a reaction medium was considered necessary,
unavoidable and thus mandatory.
Chemists believed that solvents increase mobility of the reactants’ molecules. Such
mobility then facilitates molecular collisions in general and successful collisions in
particular, because the latter usually require specific orientations of molecules.
Because the organic reactions were always done in solvents, a dogmatic view was
established that this practice is correct and should be questioned. However, with
the birth of the green chemistry movement, the negatives about the use of organic
solvents as a reaction medium (or in any other capacity, such as for separation and
purification of the reaction products) came to light.

4 10/30/2022
 Another Green Chemistry Paradigm Shift: Organic
reactions may not need a solvent to occur
Many organic solvents are toxic to humans and other life, and may be hazardous to
the environment. In addition, they may be flammable or explosive. Notably, many
solvents are volatile organic compounds (VOCs), which can easily escape to the
environment. Containment of VOCs is often difficult, costly, and risky.
With a rapid growth of organic chemistry and its industrial applications, pollution
with organic solvents in general, and especially with VOCs , became a rather
serious problem. Pollution cleanup became quite costly and it was not even
economically feasible in many cases.
As a consequence of these negative features of many organic solvents, the green
chemistry founders and practioners asked a bold question: “ Can we run
organic reactions without solvents?”

5 10/30/2022
 Another Green Chemistry Paradigm Shift: Organic
reactions may not need a solvent to occur
As a search for the answer was conducted, the paradigm that organic solvents are
necessary for running reactions started crumbling. Ultimately, green chemistry
overturned the old paradigm and has introduced a new one: not only can organic
reactions be run without solvents, but often such reactions gave unexpected benefits for the
reaction outcomes, such as faster reactions, higher yields, and improved selectivity.
The green advantages are numerous. In addition to the elimination of solvents, and
thus the need for their disposal or recycling, there is a reduction in pollution and a
simplification of chemical processes.

6 10/30/2022
 Definition of Solventless Reactions and Related
Nomenclature
The literal meaning of “solventless” is “without solvent.”
Many organic reactions have been shown to occur without organic solvents and
often give better results than those occurring in a solvent. There are many different
ways solventless reactions can occur. Mechanism of these reactions differ and many
are still under study. Further, different investigators use different terms for the
same or similar solventless reaction conditions. The definition and a proper use of these
terms are important, especially for the literature searches, which often depend on the use of
very specific key words.

7 10/30/2022
 Definition of Solventless Reactions and Related
Nomenclature
The terms that are often used interchangeably with “solventless” are “solvent-free.”
“in the absence of solvents,” and “neat.” The latter term is used to cover the
reactions between neat reagent combinations, such as gas/solid, solid/liquid,
liquid/liquid, and solid/solid.
Our main focus on today lecture is on solventless solid/solid reactions that are
affected by mixing or grinding of two or more reactants, which results in the
melting of the reaction mixture.
Solid/liquid and liquid/liquid reactions are easier to understand, because the
liquid phase acts as a “solvent.”

8 10/30/2022
 Solventless Reactions Based On The Melting Behaviour of
Reaction Mixtures: Innovative Aspects of This Method
 As an introduction to the mechanism by which solid/solid solventless
reactions occur, we first review the melting behaviour of organic solids,
which is at the core of this mechanism.
 One of the basic organic laboratory skills is a determination of melting
point of solid organic compounds, for the purpose of their identification
and evaluation of their purity.
 Students learn that if the melting point of a compound is lower than its
literature value, and the melting occurs over a wide temperature range,
the compound is impure. In contrast, pure compounds give sharp
melting points, which do not deviate from the literature values by more
than 1oC-2oC.

9 10/30/2022
 Solventless Reactions Based On The Melting Behaviour of
Reaction Mixtures: Innovative Aspects of This Method
 For impure compounds, a large melting point range could be partially
explained by residual solvents that were used for isolation or
recrystallization, unreacted starting materials, and side products, among
others.
 The melting point can also be used for characterization of unidentified
organic compounds (“the unknown”) via determination of a so-called
mixed melting point.

10 10/30/2022
 Solventless Reactions Based On The Melting Behaviour of
Reaction Mixtures: Innovative Aspects of This Method
In this procedure, one prepares approximately a 1:1 mixture of the
unknown compound with a known compound that one believes the
unknown could be. Then one takes a melting point of such a mixture. If the
melting point of the mixture is the same as for the unknown, then the
unknown compound is identical to the suspected known compound. If the
melting point of the mixture is substantially lowered and broadened, then
the guess about the identity of the unknown is incorrect.

11 10/30/2022
 Solventless Reactions Based On The Melting Behaviour of
Reaction Mixtures: Innovative Aspects of This Method
The lowering of the melting point by impurities appears to be such a
common, well-known, and often observed phenomenon that one wonders
if there is anything that one can add to the usefulness of this basic and
routine organic laboratory tool.
However, green chemistry researchers have found a major innovative
application of this principle, which resulted in the discovery of solventless
reaction.

12 10/30/2022
 Solventless Reactions Based on the Melting Behaviour of
Reaction Mixtures: Innovative Aspects of this Method
The description of this innovation as it follows. Suppose that we do not
have a desired solid compound A mixed with the annoying solid impurity
B, but, instead that solids A and B are the reactants in a reaction that will
give a desired product. If A and B acts as each other’s impurities to the
extent that the melting point of the mixture is lowered below room
temperature, the mixture then becomes a liquid. The liquid phase then will
act as a “solvent.” The reaction that occurs in such a melted state is
“solventless.” This is very clever and ingenious. As in the case of many other
innovations, we are prone to ask ourselves: “ This was rather simple and
obvious, why did I not come up with this?”

13 10/30/2022
 Solventless Reactions Based on the Melting Behaviour of
Reaction Mixtures: Innovative Aspects of this Method
The reaction between 4-aminotoluene and o-vanilline is pedagogically
friendly and it dramatically illustrates the principle of the solventless
reaction.

14 10/30/2022
 Solventless Reactions Based On The Melting Behaviour of
Reaction Mixtures: Innovative Aspects of this Method
Both starting materials, o-vanillin and p-toluidine, are low melting solids;
they melt at 40oC-42oC and 44oC-45oC, Both are nearly colourless. When
the two solids are put in contact, even before they are thoroughly mixed
and ground, a bright orange colour is observed, which signifies the
formation of imine product. This makes a very nice demo. It is done in
about 5 min. The reaction is exothermic. Water that is formed as a side
product is rapidly evaporated by the heat that is generated in the reaction.
After 5 min., one is left only with the solid orange imine.

15 10/30/2022
 Solventless Reactions Based on the Melting Behaviour of
Reaction Mixtures: Innovative Aspects of this Method

16 10/30/2022
 Solventless Reactions Based on the Melting Behaviour of
Reaction Mixtures: Innovative Aspects of this Method
 In another scenario, the reaction components upon mixing melt into a
liquid as before. However, at this point, a reaction catalyst is added and
the reaction now starts to occur and yield product(s). This is illustrated
in another popular solventless reaction, an aldol condensation. The
procedure for this reaction calls for mixing and grinding together the
two reactants, which will then melt to give an oil. Next, solid NaOH is
added to catalyse the reaction. The reactants are again low melting
solids.The aldehyde melts at 41oC-42oC and the ketone at 45oC-48oC.

17 10/30/2022
 Solventless Reactions Based on the Melting Behaviour of
Reaction Mixtures: Innovative Aspects of this Method

 Solventless aldol condensation between 3,4-dimethoxybenzaldehyde and

i-indanone with solid NaOH as a catalyst.

18 10/30/2022
 Solventless Reactions Based on the Melting Behaviour of
Reaction Mixtures: Innovative Aspects of this Method
 Notice that in both the examples given above, the molar ratio of
reactants 1:1, and the melting points of the reactants are low. A question
arises about applicability of such solventless method to reactions in
which a different stoichiometric ratio of reactants is required and in
which the melting points of the reactants may be much higher. To
evaluate the feasibility of such reactions as solventless, we need to learn
more about the relationship between the melting point and the
composition of the mixture.

19 10/30/2022
 A New Look at the Familiar Concepts of Melting point and
Eutectic point and Their Relevant Phases

 The phenomenon of the decrease of a melting point by an impurity that

is present is best understood by an examination of a melting point-
composition diagram for a mixture of two components, A and B (thus a
binary mixture). The figure represents such a diagram. It should be
noted that a mixture comprising more than two compounds may also be
considered, but the corresponding diagram would be more complicated.
 Although A and B in principle may react upon melting, as shown in
figure, we shall exclude this possibility for now. This will simplify the
diagram.

20 10/30/2022
 A New Look at the Familiar Concepts of Melting point and
Eutectic point and Their Relevant Phases

21 10/30/2022
 A New Look at the Familiar Concepts of Melting point and
Eutectic point and Their Relevant Phases

 The diagram shows a case in which a mixture of A and B, whose

structures and melting point are not specified, melts sharply at the point
E, at a specific molar composition of A and B, which is here assigned
arbitrarily as 60% : 40%. The point E is called a “Eutectic Point.” This
term comes from the Greek Word for “easily melted.” A solid with the
eutectic composition melts at the lowest temperature of any mixture.
The melting occurs without change of composition. Below the eutectic
temperature, there is a solid phase.

22 10/30/2022
 A New Look at the Familiar Concepts of Melting point and
Eutectic point and Their Relevant Phases

 The eutectic point can occur at any ratio between two compounds,
which depends on their structures and melting points. It should noted
that some mixtures of compounds may show no eutectic point or a
more complex behaviour, in which there is more than one eutectic
point.
 The diagram shown is valid only under a restriction that A and B are
soluble in the liquid Phase. A more in-depth coverage of this
phenomenon is given by Pederson and Myers.
Understanding the Principles of Organic Chemistry: A Laboratory
Course, Brooks/Cole, Belmont, CA, pp 60-68.

23 10/30/2022
 A New Look at the Familiar Concepts of Melting point and
Eutectic point and Their Relevant Phases

 The melting point is recorded as a range between the first appearance of

a liquid and the complete melting point. However, the application of the
diagram from figure shown above would not be realistic in this respect.
One needs to use another figure, which includes the experimental curve
at which the melting starts.
 Harding K. E. (1999), Melting point range and Phase diagrams-
Confusing laboratory text book descriptions, J. Chem. Ed., 76, 224-225.

24 10/30/2022
 A New Look at the Familiar Concepts of Melting point and Eutectic
point and Their Relevant Phases

 The experimental curve (xxx) at which the melting starts. The line Z-X
is the theoretical melting range, and the lineY-X is the observed range

25 10/30/2022
 A New Look at the Familiar Concepts of Melting point and Eutectic
point and Their Relevant Phases

From earlier figure, the melting range would start at the tE horizontal line
and would end at the curve that denotes a boundary with the pure liquid
phase.This would give an unrealistically broad and incorrect melting range.
This is illustrated in next figure as the line joining points Z and X . Further,
and unrealistically, the melting range would become increasingly broad as
the purity of the compound increases.This is contrary to what is observed.
By the introduction of the experimental curve in the diagram in next
figure, this problem is eliminated. Thus, the melting point is observed to
start not at Z, but at Y, and it finishes at X. The observed melting point
range is thus Y-Z. It can also be seen that the melting range for an almost
pure A or an almost pure B is in a very narrow range and is thus sharp.

26 10/30/2022
 A New Look at the Familiar Concepts of Melting point and Eutectic
point and Their Relevant Phases

It should be noted that the diagram from first figure is not wrong. It is just
that the amount of liquid that is formed at the beginning of melting may be
so small that we cannot observe it visually, We observe the melting at the
experimental curve.
A practical illustration of the above discussion is shown in some cases of
solventless reactions, especially in those that give coloured compounds.
Although we may not observe any melting at the interface of the two
solids, the reaction may nonetheless start there as evidenced by an
observed colour development. This phenomenon can be easily explained by
the experimental difficulty of observing a very small amount of liquid at
the beginning of melting, whereas colour development can be detected
much more readily.

27 10/30/2022
 A New Look at the Familiar Concepts of Melting point and Eutectic
point and Their Relevant Phases
In summary, the melting behaviour shown in figure 2 blurs the division
between solventless and solid/solid reactions. The solid/solid reactions
may actually occur in a liquid film that is formed by the local melting.
When we mix and grind two solids, we create many liquid interfaces, we
may be able to observed the local melting better, but not always.

28 10/30/2022
 Baeyer Villiger Oxidation

Formation of lactones

29 10/30/2022
 Ether Formation

Etherification of alcohols with p-toluenesulfonic acid

30 10/30/2022
 C-C Bond formation

Oxidative coupling of naphthols

31 10/30/2022
 Green Chemistry Challenges With Respect to
Solventless reactions
Organic solvents, despite showing serious negative characteristics for green
chemistry have numerous, otherwise positive aspects. For example,
Solvents allow for an easy transfer of starting materials to the reaction
vessel, for a gradual (e.g. dropwise) addition of reactants (e.g. for control
of competing reactions), for taking aliquots out of a reaction mixture (e.g.
for the purpose of following reaction progress), for absorption and
dissipation of heat in cases of exothermic reactions, for diluting the
reaction mixture to slow down the reaction if necessary, and for
influencing reaction outcome (e.g. Promote SN2 vs SN1 reactions).

32 10/30/2022
 Green Chemistry Challenges With Respect to
Solventless reactions
Next, we address more fully a rather serious problem of exothermic
solventless reactions. We have learned from the discussion the formation of
an imine by a solventless condensation reaction is quite exothermic. At a
small laboratory-scale experiment, water, which is a side product, is
rapidly boiled off and lost to evaporation. A scale-up of such a reaction for
industrial purposes would be quite challenging, because an uncontrolled
evolution of heat without the benefit of a solvent to absorb and dissipate it
could be quite hazardous.
 Exothermic reactions can be dangerous on large scale – need close
collaboration with chemical engineers to overcome such
problems.
 Efficient mixing can be a problem, particularly when have solid
reagents or products.

33 10/30/2022
Lecture 23: Green Chemistry and
Technology

Course Instructor: Prof. Abu Taleb Khan

Course code: CH 426
Credit: 6

11/11/2022
 Lecture 23: Application of Green Chemistry in Engineering

The learning objectives today’s lecture are as follows:

• Become familiar with the basics of engineering and its main branches.
• Learn about the 12 principles of green engineering.
• Compares principles of green chemistry and green engineering.
• Learn essentials of sustainability and how it relates to green
engineering.
• Learn about types of thinking which are useful in green engineering.

2 11/11/2022
 Important Remarks on Sustainability
“An important point, often overlooked, is that the concept of
waste is human. Green engineering focuses on how to achieve
sustainability through science and technology”

Paul T. Anastas and Julie B. Zimmerman (2003), Design through the twelve
principles of green engineering, Environ. Sci.Technol., 37, 94A-101A.
Tang, S. et al. Green Chemistry, 10, 268-269, 2008

3 11/11/2022
 Engineering and Its Branches
A common definition of engineering, as used in everyday life and as found in the
dictionaries, is given broadly as follows:
Engineering is a branch of science which is concerned with practical
applications of the knowledge of pure sciences, such as physics or chemistry or
mathematics, which result in designing and constructing engines, bridges,
buildings, ships, chemical plants, mines, etc. Engineering sometimes includes
art, such as in its architectural applications. (Wikipedia)

4 11/11/2022
 Engineering and Its Branches
The word “engineering” comes from Latin ingenium, which means
“cleverness,” and ingeniare, which means “to devise.”
A broader definition of engineering includes application of scientific,
economic, social, and practical knowledge, with the objectives to invent,
design, build, and improve structures, machines, devices, systems,
materials, and processes. This particular definition resonates well with
many of the green chemistry objectives in general. For example, we notice
the invention factor, which is at the core of the green chemistry movement
This definition is still quite broad, because it encompasses all branches of
engineering. Typically, engineering is divided into four main branches:
Chemical, Civil, Electrical and Mechanical.

5 11/11/2022
 Engineering and Its Branches
 Chemical engineering is most relevant for the objectives of the
green chemistry. It covers chemical processes on a commercial
scale.
 Civil engineering is concerned with design and construction of
roads, railways, bridges, dams, building, for example.
 Electrical engineering focused on electrical and electronics
systems, telecommunication, generators and motors, and similar.
 Mechanical engineering deals with mechanical systems, such as
power, energy, aerospace, and transportation, as some examples.

6 11/11/2022
 Engineering and Its Branches
There are numerous subspecialties of engineering, such as automotive,
computer, architectural, agricultural, biomedical, petroleum, textile, and
nuclear, among many others. Many of these fields and subfields are
interconnected.
For our purposes, we shall focus on chemical engineering, and then we
shall emphasize organic chemistry within a broad class of chemical
manufacturing processes. Still, many organic chemical processes may
cross boundaries with other engineering branches.

7 11/11/2022
 A Brief Description of the 12 Principles of Green
Engineering
 1. Inherent rather than circumstantial:
Designers need to strive to ensure that all materials and energy
inputs and out puts are as inherently nonhazardous as possible.
 2. Prevention instead of treatment:
It is better to prevent waste than to treat or clean up waste after it is
formed.
 3. Design for separation:
Design separation and purification operations to minimize energy
consumption and materials use.
 4. Maximize efficiency:
Design products, processes, and systems to maximize efficiency of
mass, energy, space, and time.

8 11/11/2022
 A Brief Description of the 12 Principles of Green
Engineering
 5.Output-pulled versus input-pushed:
Design products, processes, and systems to become “Output-pulled” rather
than “input-pushed” by an appropriate use of energy and materials.
 6. Conserve complexity:
Consider conservation of embedded entropy and complexity while making
choices on recycling, reuse or beneficial disposition of materials.
 7. Durability rather than immortality:
Target durability rather than immortality while designing materials and
products.
 8. Meet need, minimize excess:
Design only to meet need. Design for unnecessary capacity or capability
should be considered a design flaw. This includes “one-size-fits-all”
solutions.

9 11/11/2022
 A Brief Description of the 12 Principles of Green
Engineering
 9. Minimize material diversity:
Design multicomponent products in such a way to minimize material
diversity, to promote should be minimized to promote disassembly (for
reuse or recycling), and to value retention.
 10. Integrate material and energy flows:
Design of products, processes, and systems in such a way to include
integration and interconnectivity with available energy and materials flows.
 11. Design for commercial after life:
Design products, processes, and systems for performance in a commercial
“afterlife.”
 12. Renewable rather than depleting:
Material and energy inputs should be renewable rather than depleting.

10 11/11/2022
 PRINCIPLE 1: INHERENT RATHER THAN CIRCUMSTANTIAL
Engineers should first evaluate the inherent (intrinsic) characteristics
of the materials they intend to use. If the materials exhibit hazardous
characteristics, this will become a serious drawback of the design.
Hazardous materials can cause harm to life and the environment. In
addition, their handling, removal, and disposal may be extremely
costly and risky, and it would require time, material, special
equipment, and energy resources. This is not an economically or
environmentally sustainable approach.

11 11/11/2022
 PRINCIPLE 1: INHERENT RATHER THAN CIRCUMSTANTIAL

Instead, a prudent approach would be to search for other materials

that are inherently as nonhazardous to life and environment as
possible. In addition, designers need to ensure also that all energy
inputs and outputs are inherently as nonhazardous as possible. This
especially important for large-scale manufacturing processes.

12 11/11/2022
 PRINCIPLE 1: INHERENT RATHER THAN CIRCUMSTANTIAL
The present day energy sources are typically electricity and steam.
These energy sources are based on primarily the fossil fuels, which
are not renewable. The choice of energy also matters in terms of
placing hazardous materials into the environment. One can think
about gases that are generated by burning coal as one example. To
minimize the output of toxic materials, engineers need to look at the
type of energy that is used, in addition to the chemical reactions.
Engineers need to choose intentionally both materials and energy, so
as to give as nonhazardous an outcome as possible.

13 11/11/2022
 PRINCIPLES 2: PREVENTION INSTEAD OF
TREATMENT
This principle states that it is better to prevent waste than to treat it
or clean it up after it is formed. We recognize this principle as
principle 1 of green chemistry, which we have discussed in previous
chapter. Here, we show more goals and applications that are
characteristic for green engineering.
Dr. Marin Abraham brings up several specific points on how to
prevent waste. First, one should make only the amount that is
needed, and not an excess. The latter can be quite costly, because one
pays first for the extra starting materials that are not needed, and
then pays later for their safe disposal.

14 11/11/2022
 PRINCIPLES 2: PREVENTION INSTEAD OF
TREATMENT
In another example, Dr. Abraham emphasizes the need to achieve
selectivity in chemical reactions. If a reaction can give two products,
where only one is desired, it is often possible to achieve selectivity in
favour of the desired product. This often can be done by manipulating
the temperature at which the reaction is performed.
To enforce this important point, we briefly review one of the classical
reactions whose outcome can be modulated by the temperature, and
which is covered in every beginning organic chemistry textbook. The
reaction is an addition reactions, which gives the 1,2-addition
product as the main product at a low temperature, whereas at the
higher temperature, the 1,4-addition product predominates.

15 11/11/2022
 PRINCIPLES 2: PREVENTION INSTEAD OF
TREATMENT

Addition of HBr to 1,3-butadiene at different temperature

16 11/11/2022
 PRINCIPLES 2: PREVENTION INSTEAD OF
TREATMENT
At a low temperature (-80°C), the major product, which is obtained
in 80% yield, is formed by a 1,2-addtion of HBr. The minor product,
which is the result of 1,4-addition of HBr, is obtained in a 20% yield.
At the higher temperature (40°C), the same products are obtained,
but the yields are reversed. Further, upon warming of the mixture of
1,2- and 1,4-products that are at -80°C to temperature of 40°C, the
products are equilibrated to give the same mixture as originally
obtained at 40 °C. if the desired product is 1,2-adduct, one should
run the reaction at low temperature. Should one desire the 1,4-
adduct, one should run the reaction at a higher temperature.

17 11/11/2022
 PRINCIPLE 3: DESIGN FOR SEPARATION
This principle addresses the observation that separation, isolation, and
purification of products generally consume most of the materials and
energy requirements in manufacturing processes. Typically, separation
methods require the use of toxic solvents, which then necessitate large
amounts of energy to evaporate the solvents and to retrieve the products.
One example on laboratory scale that students are familiar with is the
separation and purification of mixtures by column chromatography. This
method requires the collection of multiple fractions as they are eluted from
the column by the mobile phase, which is typically composed of volatile
organic solvents. The latter may be hazardous, toxic, and/or flammable.
Later, the solvents are removed from the individual fractions by distillation,
which consumes energy.

18 11/11/2022
 PRINCIPLE 3: DESIGN FOR SEPARATION
Design for separation avoids the above problem because it
focuses on self separation of products. One such example is the
multicomponent Passerini reaction in which three starting
materials are placed in an aqueous medium, and a single product
separates as a precipitate, in a quantitative yield. This reaction is
one of the “on-water” reaction. Other on-water reactions, such
as Diels-Alder reaction, also lend themselves to an easy self-
separation process, because they give water-insoluble products.
All that is required is to filter the solid products from the
aqueous medium.

19 11/11/2022
 PRINCIPLE 3: DESIGN FOR SEPARATION
 It should be pointed out that in the past, classical Passerini and Diels-
Alder reactions, as well as many of the on-water reactions, have
traditionally been performed in organic solvents, which then required
separation of products from them. Only after these reactions were
greened by performing them on water, the design for separation was
realized. However, not all chemical reactions can be run on-water, and
for many reactions the use and distillation of solvents are still common.
For such cases, green engineering offers other successful strategies.
 For example, we give here a couple of such strategies. Distillation can be
made more efficient by designing the fractional distillation towers such
that the heat of condensation that is released is reused. Distillation may
be avoided by using alternative separation techniques, such as the reverse
osmosis membrane separation for desalination of saltwater to freshwater.

20 11/11/2022
 PRINCIPLE 4: MAXIMIZE EFFICIENCY
This principle states that products, processes and systems should be
designed to maximize efficiency of use of mass, energy, space, and
time. Specifics are provided, for examples, by Dr. Michael A.
Gonzalez.
To achieve mass efficiency, the reactions should be designed in
such a way so as to use as much of the reactants as possible. Desired
properties of the reactions include high conversions and selectivity to
give the desired products and to give a minimal amount of by-
products.

21 11/11/2022
 PRINCIPLE 4: MAXIMIZE EFFICIENCY
Energy efficiency is achieved by employing room temperature and
pressure, when possible. This eliminates the need for expensive
cooling or heating. Minimization of movement of the materials also
saves energy, for example, for pumping the materials for transport.
Further, if the design minimizes separation and purification steps, this
also saves energy that would be otherwise needed for the distillation
of solvents.

22 11/11/2022
 PRINCIPLE 4: MAXIMIZE EFFICIENCY
Saving space is important, because it saves on cost and reduces
hazards. For example, constructing large reaction vessels is expensive
in terms of cost and energy. Large volumes of the produced materials
may pose unacceptable hazards. The smaller the better, providing that
it meets the need.
Time efficiency strives to perform chemical reactions as fast as
possible, to liberate the reactor for use of the other reactions. Thus,
reactions should be catalytic, if possible.
All these different aspects of efficiency---mass, energy, space, and
time-are interconnected to a degree.

23 11/11/2022
Lecture 24: Green Chemistry and
Technology

Course Instructor: Prof. Abu Taleb Khan

Course code: CH 426
Credit: 6

11/11/2022
 PRINCIPLE 5: OUTPUT-PULLED VERSUS INPUT-PUSHED

This is a concept related to chemical equilibrium and states that

products, processes, and systems should be “output-pulled” rather
than “input-pushed” through the use of energy and materials.
Anastas and Zimmerman (2003) provide a clear example of this
principle by invoking the well-known Le Chatelier’s principle. First,
we review this important principle in its general form. Then we apply
it to an organic reaction, because the emphasis of Green Chemistry is
on the organic chemistry. Finally, we show its applications to green
engineering.

2 11/11/2022
 PRINCIPLE 5: OUTPUT-PULLED VERSUS INPUT-PUSHED

A general equation for a reversible reaction is shown below,

which would be a subject to Le Chatelier’s principle.

3 11/11/2022
 PRINCIPLE 5: OUTPUT-PULLED VERSUS INPUT-PUSHED
An example of a generalized reversible reaction, which is the subject
to the Le Chatelier’s principle. K is the equilibrium constant. Q is the
reaction quotient, whether or not the system in at equilibrium.
Q = K when system is at equilibrium. a-d are the stoichiometric
coefficients for the reacting species A-D.

4 11/11/2022
 PRINCIPLE 5: OUTPUT-PULLED VERSUS INPUT-PUSHED

Le Chatelier’s principle summarizes the ways in which a system

at equilibrium responds to changes. When stress is applied to
such a system, the system responds by reestablishing the
equilibrium in order to relieve, reduce, or offset the applied
stress.
Common ways to introduce stress on the system at equilibrium
are changes in concentrations and temperature. For a gas-phase
reactions, changes in pressure/volume also cause stress,
providing that the number of moles of gas differs between the
reactants and products.

5 11/11/2022
 PRINCIPLE 5: OUTPUT-PULLED VERSUS INPUT-PUSHED
We summarizes the stress and the system’s response in Tables 1
through Table 3, which are based mostly on material. We discuss the
relevance to principle 5 for each type of stress and the system’s
response.
The reversible reaction from Figure 1 at equilibrium would give us a
mixture of starting materials and products. Typically, only one
product is desired. How can we achieve getting only the desired
product, instead of a mixture, which is the consequences of the
equilibrium?

6 11/11/2022
 PRINCIPLE 5: OUTPUT-PULLED VERSUS INPUT-PUSHED
Inspection of the system responses from Table 1 shows us the options
on how to achieve this goal and helps us make a green choice of
output-pulled versus input-pushed. One can shift the equilibrium
towards the products by two means: (1) by decreasing concentrations
of the products, for example, by removing them from the reaction
mixture, or (2) by increasing concentration of reactants, for
example, by adding extra reactants.

7 11/11/2022
 PRINCIPLE 5: OUTPUT-PULLED VERSUS INPUT-PUSHED
Table 1
Response of the System at Equilibrium from Figure 1 to Changes in
Concentration and By Addition of Specific Components
Concentration Change Resulting Changes Shift in Consequences
in Q and K Equilibrium
Increase in [products] Q>K To the left More reactants are
formed
Decrease in [products] Q < K To the right More products are
formed
Increase in [reactants] Q < K To the right More products are
formed
Decrease in [reactants] Q > K To the left More reactants are
formed

8 11/11/2022
 PRINCIPLE 5: OUTPUT-PULLED VERSUS INPUT-PUSHED
Table 1
Response of the System at Equilibrium from Figure 1 to Changes in
Concentration and By Addition of Specific Components
Component Added Consequences as Equilibrium is Established
[A] [B] Decreases [C] Increases [D] Increases
[B] [A] Decreases [C] Increases [D] Increases
[C] [D] Decreases [A] Increases [B] Increases
[D] [C] Decreases [A] Increases [B] Increases

9 11/11/2022
 PRINCIPLE 5: OUTPUT-PULLED VERSUS INPUT-PUSHED
The choice 1 is output-pulled and is green, whereas the choice 2 is input-
pushed and is not green. One can easily see that in choice 2 at the end of
the process, we would be stuck with extra unused reactants. The output-
pulled option can be used to select only one of the products. We show an
example in Figure 2 for a Fischer esterification reaction, a common
esterification process, in which a alcohol and a carboxylic acid react under
acidic catalysis to give an ester.

10 11/11/2022
 PRINCIPLE 5: OUTPUT-PULLED VERSUS INPUT-PUSHED
In the reaction shown Figure 2, the desired product is isoamyl acetate. The
equilibrium can be shifted towards the product by removing water from
the reaction mixture. This can be done by using concentrated H2SO4
beyond the catalytic amount, typically, in a stoichiometric quantity. Other
ways exist to remove water. Examples include use of molecular sieves or a
specialized distillation technique using a Dean-Stark trap.

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 PRINCIPLE 5: OUTPUT-PULLED VERSUS INPUT-PUSHED
Molecular sieves are porous materials of specified pore sizes. These
sieves absorb small molecules, such as water that can fit into the
pores, whereas large molecules stay outside the pores. Thus,
molecular sieves can act as desiccants. Examples of molecular sieves
include various zeolites, which are microporous aluminosilicate
minerals.
In distillation that uses Dean-Stark trap, water co-distills with
organic material and falls on the bottom of the trap, whereas a less
dense organic layer collects on the top of the trap, and then flows
back to the distilling flask.

12 11/11/2022
 PRINCIPLE 5: OUTPUT-PULLED VERSUS INPUT-PUSHED
These methods of shifting the equilibrium by removing water are
output-pulled green methods. In some esterification experiments,
an excess of carboxylic acid is used to shift the equilibrium towards
the products. This would present an input-pushed non-green
method, because one would have unreacted carboxylic acid left,
which would need to be removed at the end. Still, one has to
evaluate the entire process of shifting the equilibrium, because not all
output-pulled methods are necessarily green.

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 PRINCIPLE 5: OUTPUT-PULLED VERSUS INPUT-PUSHED
If one has to conduct additional steps to make the output-pulled
method work, and if such steps are not green, this has to be
taken into account. The above-mentioned extra distillation step
to remove water is inherently not green, but may be made
more efficient, and thus, the overall process is greener, by
reusing the heat of condensation that is released. This would be
an implementation of principle 3.

14 11/11/2022
 PRINCIPLE 5: OUTPUT-PULLED VERSUS INPUT-PUSHED
Output-pulled design can also be achieved via temperature control of
reversible reactions. One can consider exothermic and endothermic
reactions in a way in which one imagines that heat itself behaves as a
chemical reactant or product. Chemical equations that include heat are
termed thermochemical.
Such equations allow us to predict the response of a system with change in
temperature in the same way as we have done previously for the change in
concentration.

15 11/11/2022
 PRINCIPLE 5: OUTPUT-PULLED VERSUS INPUT-PUSHED
Am important difference, however, is that the temperature change
alters the value of the equilibrium constant. Table 2 shows the
response of a system in equilibrium upon a change in temperature.
For the green output-pulled design, one would need to decrease the
temperature of exothermic reaction, but to increase it for it for endothermic
reaction.

16 11/11/2022
 PRINCIPLE 5: OUTPUT-PULLED VERSUS INPUT-PUSHED

Response of a system at equilibrium upon temperature change for reactions that

are exothermic (Reactants Products + Heat) and endothermic (Reactants +
Heat = Products)
Type of reaction Temp. Change Shift in Consequences
Equilibrium
Exothermic (Heat is a product) Increase (adding heat) To the left More reactants are formed

Exothermic (Heat is a product) Decrease (removing heat) To the right More products are formed

Endothermic (Heat is a reactant) Increase To the right More products are formed

Endothermic (Heat is a reactant) Decrease To the left More reactants are formed

17 11/11/2022
 PRINCIPLE 5: OUTPUT-PULLED VERSUS INPUT-PUSHED
Finally, changes in pressure can affect the equilibria of gas reactions. The
effect is observed only if number of the moles of gas differs between
reactants and products.

18 11/11/2022
 PRINCIPLE 5: OUTPUT-PULLED VERSUS INPUT-PUSHED
If an inert gas is added to a system, it will not affect the equilibrium,
because it does not change the partial pressure of the gasses in the reaction.
Figure 3 shows two gas reactions whose equilibria are affected by change in
pressure, whereas, Table 3 summarizes the effect of changing pressure on
equilibria of these reactions.
For the output-pulled green design, one needs to decrease the pressure if
the total number of the mole of the products is larger than that of the
reactants, such as in reaction 1, and to increase the pressure when the total
number of the moles of the products is smaller than that of the reactants, as
in reaction 2.

19 11/11/2022
 PRINCIPLE 5: OUTPUT-PULLED VERSUS INPUT-PUSHED
It should be noted that the equilibrium constant for a reaction is not
affected by the presence of a catalyst or an enzyme, which acts as a
biological catalyst. Catalysts increase the rate by which the equilibrium is
established, but do not affect its position.

20 11/11/2022
 PRINCIPLE 6: CONSERVE COMPLEXITY
This principle states that embedded entropy and complexity must be
viewed as investment while making choices on recycling, reuse, or
beneficial disposition of materials.
Complexity is related to the number of atoms and functional groups in a
molecule used to produce the molecule or item. It is also a function of
expenditure of materials, energy and time. Thus, chemicals and products in
general have a certain amount of complexity that is built into them.

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 PRINCIPLE 6: CONSERVE COMPLEXITY
Many complex materials have high economic value. It would make no
business sense to take a material with high economic value and convert it
into with lower value. Highly complex materials should be reused, rather
than recycled. In contrast, materials with minimal complexity should be
recycled or disposed of.
A decision to reuse, recycle, or dispose of the products needs to be made based on
the evaluation of multiple factors that are involved in these processes. Anastas and
Zimmerman bring up the example of a brown paper bag, which is made of a highly
complexed natural material.

22 11/11/2022
 PRINCIPLE 6: CONSERVE COMPLEXITY
However, the complexity of this material does not warrant the time,
energy, and cost for collection, sorting, processing, remanufacturing,
and redistribution of the bag for its reuse. In another example, they
discuss silicone computer chips. These chips have a significant
amount of complexity built into them. Such complexity represents
most of the economic value of this product. Recycling a silicon chip
in order to recover the value of the starting materials makes no
economic sense, but reusing the chip, which preserves its
complexity, does. In conclusion, even though we strive to preserve
complexity, we must evaluate such preservation from an economic
point of view.

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 PRINCIPLE 7: DURABILITY RATHER THAN IMMORTALITY
This principle states that product should be designed to be durable
rather than immortal. “Immortal” products are those that last well
beyond their useful commercial life and that persist in the
environment because they are not biodegradable. Such products may
even have a short or single use. Immortality of product should be
avoided. Instead, product need to be designed for useful lifetime and
a capability for biodegradation.

24 11/11/2022
 PRINCIPLE 7: DURABILITY RATHER THAN IMMORTALITY
A good example of a successful design for durability but not
immortality is that of a starch-based packing material. Such material
is made of natural, nontoxic, biodegradable, and sustainable sources.
At the end of its use, the so-called product’s end of life, this product
can be placed in compost piles. It is water soluble and is easily
biodegradable. It is competitive with polystyrene packing which is
non-biodegradable and has been shown to be persistent in the
environment.

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 PRINCIPLE 8: MEET NEED, MINIMIZE EXCESS
Based on this principle, the design of materials, processes, and systems
should be optimized for the anticipated need. A design that includes added
capacity based on unrealistic assumptions or “worst-case” scenarios has
negative and costly consequences. Making extra products that are not
needed incurs the cost of unnecessary materials and energy, the cost in time
and salaries for the workers, the cost for shortage, the burden on the
environment in terms of produced waste, and the cost of disposal and
recycling of waste, among others. To avoid the problem of overproduction
and the associated cost and other negative consequences, the green
alternative target specific needs and demands of the end users should be
implemented.

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 PRINCIPLE 9: MINIMIZE MATERIALS DIVERSITY

This principle seeks to minimize material diversity of products,

namely, to make products from as few types of materials as
possible. Material diversity is taken into account when
considering options for the end of the useful life of the product,
such as reuse or recycling. A good description of this principles
provided by Anastas and Zimmerman.

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 PRINCIPLE 9: MINIMIZE MATERIALS DIVERSITY
Many products are built of multiple components, and such components may
be composed of a variety of materials. For example, cars have components
made of metal, glass, plastic, paint and so on. Individual plastics typically
contain additional materials such as thermal stabilizers, plasticizers and
flame retardant. At the end of the useful life of the product, decisions about
disassembly for reuse of parts and recycling need to be made. Such
decisions ultimately depend on material diversity, because different
materials have different requirements and potential for green reuse and
recycling. Lowering the material diversity in the product and choosing or
designing material with good potential for reuse and/ or recyclability
enable the implementation of the end-of-useful life options.

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 PRINCIPLE 10: INTEGRATE LOCAL MATERIAL AND ENERGY
FLOWS
This principle states that optimization of mass and energy requirements for
a given processes is best accomplished via integration of heat exchange
networks (HENs) and mass exchange networks (MENs).
As an example, let us consider existing framework of energy and material
flow at a local chemical production facility. The application of the principle
10 can be understood as an integration of HENs and MENs. HEN uses hot
streams to heat cold streams, for example. If one production unit generates
heat, and another one requires heating, two should be integrated.

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 PRINCIPLE 10: INTEGRATE LOCAL MATERIAL AND ENERGY
FLOWS
MENs are analogous to Hens, but instead of exchanging energy, they
exchange mass. For example, we may need to separate unreacted material
from the product, both to purify the product and to recover the unreacted
material so that we can use it again in the reaction. One option is to use
additional material, such as a solvent, to remove the unreacted material and
to send it back to the reactor. However, such an option is costly, and the
solvent may be toxic or otherwise hazardous.

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 PRINCIPLE 10: INTEGRATE LOCAL MATERIAL AND ENERGY FLOWS
A better option would be to implement MEN, namely, to use streams with
low concentrations of high of a given material (lean streams) to separate and
recover material from streams that have high concentrations of the material
in question. We should use as much of the lean stream as possible to recover
the material, before we resort to using additional materials, such as
solvents.
Although, HENs and MENs appear to be quite simple and straightforward
in principle, it takes a lot of expertise and creativity to implement them.

31 11/11/2022
 PRINCIPLE 11: DESIGN FOR COMMERCIAL “AFTERLIFE”
This principle states that design of a product should include the
commercial “afterlife.” This means that the product at the end of its
commercial life should still has value, which can be extracted from it,
if the product is properly designed.
For example, many products reach their commercial end of life
because they become technologically or stylistically obsolete. They
may still have perfectly good and valuable working components. The
latter can be recovered for reuse, if it is economically feasible.
Valuable components can be refurbished and sold, or may be
disassembled to extract other valuable parts. Various examples are
given in the work of Anastas and Zimmerman. A good example is that
approximately 90% of Xerox equipment is designed for
remanufacturing.

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 PRINCIPLE 12: RENEWABLE RATHER THAN DEPLETING
This principle states that the materials and energy inputs should be
renewable rather than depleting. The ultimate goal is sustainability. For
example, fossil fuels, such as petroleum, natural gas, and coal are not
renewable and their continuous use is not sustainable. In contrast, solar,
wind, and hydro energy sources that generates electricity are renewable.
In terms of materials, bio-based plastic is one example of use of a renewable
feedstock. It is important to go through all the steps of the process by which
a product is obtained, before one decides on sustainability of the product.
One should not automatically assume that bio-based products are always
more sustainable than identical products that are manmade. Sometimes,
extracting the product from natural sustainable resources, such as plants,
may be extremely costly in terms of energy and auxiliary materials, and a
green synthetic organic path may be preferred.

33 11/11/2022
 PRINCIPLE 12: RENEWABLE RATHER THAN DEPLETING
This principle states that the materials and energy inputs should be
renewable rather than depleting. The ultimate goal is sustainability. For
example, fossil fuels, such as petroleum, natural gas, and coal are not
renewable and their continuous use is not sustainable. In contrast, solar,
wind, and hydro energy sources that generates electricity are renewable.
In terms of materials, bio-based plastic is one example of use of a renewable
feedstock. It is important to go through all the steps of the process by which
a product is obtained, before one decides on sustainability of the product.
One should not automatically assume that bio-based products are always
more sustainable than identical products that are manmade. Sometimes,
extracting the product from natural sustainable resources, such as plants,
may be extremely costly in terms of energy and auxiliary materials, and a
green synthetic organic path may be preferred.

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 COMPARISON OF PRINCIPLES OF GREEN CHEMISTRY AND
GREEN ENGINEERING
A quick comparison between these principles and the 12 principles of green
engineering reveals a substantial overlap. Examples include green chemistry
principle 1 and green engineering principle 2, both of which focus on waste
prevention. Green chemistry principle 7 and green engineering 12 both
cover a need for renewable resources. Green chemistry principle 3 and
green engineering principle 1 both state a goal of non-hazardous processes.

35 11/11/2022
 Green Chemistry Vs Green Engineering

 1. Waste prevention 1. Inherent rather than circumstantial

 2. Atom economy
 3. Safer syntheses
 4. Safer products
 5. Safer auxiliaries
 6. Energy efficiency
 7. Renewable feedstock
 8. Derivative reduction
 9. Catalysis
 10. Degradability
 11. Pollution prevention
 12. Accident prevention
1 Vs 2 , 3 Vs 1, 7 Vs 12, 10 Vs 7
2. Prevention instead of treatment
3. Design for separation
4. Maximize efficiency
5.Output-pulled versus input-pushed
6. Conserve complexity
7. Durability rather than immortality
8. Meet need, minimize excess
9. Minimize material diversity
10. Integrate material and energy flows
11. Design for commercial afterlife
12. Renewable rather than depleting

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 COMPARISON OF PRINCIPLES OF GREEN CHEMISTRY AND
GREEN ENGINEERING
Green chemistry principle 10 calls for design for degradation so that
products do not persist in the environment. This goal is embedded also in
green engineering principle 7, which calls for durability rather than
immortality. The green aspects, such as sustainability and design for
biodegradation are common themes for both green chemistry and green
engineering.
They differ in that green engineering emphasizes the practical requirements
for sustainability, renewability of resources, end of life and afterlife of
products, durability versus immortality, material diversity, efficiency,
conservation of complexity, and other individual factors which are
described in principles.

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