Prashant Chavan Reserach Scholar M.S.(Pharm) in Medicinal Chemistry National Institute of Pharmaceutical Education and Research Mohali, Punjab (India) 160062 mcm20_prashant@niper.ac.in

1. Water as a solvent in Organic Synthesis
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GROUP-F
Presented By- Prashant Mahadu Chavan
Reg. No: 20MCM3144
M.S. First Year (Semester-II)
Department of Medicinal Chemistry
NIPER S.A.S Nagar, Mohali, Punjab

2. Flow of Presentation
1 • Introduction
2 • Water as Organic Solvent
3 • Microwave Assisted Organic Synthesis
4 • Microwave Chemistry in Water- General Aspects
5 • Transition-Metal Catalyzed reactions
6 • Mannich Multicomponent Reaction
7 • Epoxide Ring Opening Reaction
8 • Protection/ Deprotection Reaction
9 • Reactions in Near-critical Water
10 • Summary
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3. Introduction
 In today’s world, synthetic chemists in both academics and industry
constantly challenged to consider more environmentally benign
methods for generation of the desired target molecules
 Solvent usage is often an integral part of a chemical or
manufacturing process
 The need to develop alternative solvents to some extent originates
from these implications and constitutes an essential strategy under
the emerging field of green chemistry
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Simon, M. et al, Chem. Soc. Rev. 2012, 41(4), 1415-1427

4. Water as organic solvent
 Nontoxic
 Readily available
 Available in low cost
 Nonflammable
 Environmentally benign
 Prevent Pollution
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Chanda, A. et al, Chem. Rev. 2009, 109(2), 725-748

5. Microwave Assisted Organic Synthesis
 First report use of Microwave heating to accelerate organic chemical
transformations by Gedye and Giguere in 1986
 After the 1990 number of publications related to MAOS increased
 So we can assume that in a few years there will be increased MAOS on
laboratory scale
 Controlled microwave heating under sealed vessel condition reduces
reaction time, increase product yield and purity by reducing side reactions
compare to conventional method
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Chanda, A. et al, Chem rev, 2009, 109(2), 725-748

6. Microwave Chemistry in Water- General
Aspects
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Figure 1. Microwave heating profiles for pure water and 0.03 M sodium
chloride solution at constant 150 W power: single mode microwave
irradiation, 5 ml sample volume, fiber-optic temperature measurement, sealed
10 ml quartz reaction vessel, magnetic stirring, also shown is the rapid
cooling by compressed air
Dallinger, D. et al, Chem. Rev. 2007, 107(6), 2563-2591
Kremsner, J. et al, Eur. J. Org. Chem. 2005, 3672

7. Transition-Metal Catalyzed reactions
 Homogeneous and heterogeneous transition-metal-catalyzed C-C and
C-heteroatom bond-forming reactions represent one of the most
important reaction types performed in MAOS
 These reactions, which are known to need hours or days for completion,
often in an inert atmosphere, can be conducted very efficiently in a rapid
manner under microwave heating
 In recent years, use of water as a solvent for microwave-assisted metal-
catalyzed transformations in the high-temp water region (<200 °C)
gained considerable interest because of the many advantages over
organic solvents
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Kremsner, J. et al, Top. Curr. Chem. 2006, 266, 233
Glasnov, T. et al, Macromol. Rapid Commun. 2007, 28, 395

8. Suzuki Reaction
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Suzuki reaction is one of the most often used C-C cross-coupling reaction
In the year 2002 on ligand free Pd-cat. suzuki coupling of aryl halides with
boronic acids using water as solvent
Pd acetate 0.4 mol % with 1 equiv TBAB phase transfer catalyst reaction
with aryl chloride temp. 175 °C lower yield obtained
Applying same protocol 10-fold scale up was posiible under MW assisted
open vessel reflux condition for 10 min at 110 °C identical to closed vessel
yield obtained
Leadbeater, N. Chem. Commun. 2005, 2881

9. Heck Reaction
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Pd-cat. vinylic substitution also known as heck reaction generally performed
with aryl halides and alkenes
Heck coupling of aryl halides with styrene and acrylic acid, Pd conc. down
to 0.5-1 ppm are sufficient for coupling at 170 °C for 10-20 min
Better yields were obtained without stirring of reaction
10 fold scale up performing reaction in stop-flow microwave approach was
possible if change time and solvent
Leadbeater, N. et al, Org. Lett. 2002, 4, 2973

10. Sonogashira Reaction
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Pd and Cu cocatalyzed coupling of terminal alkynes with aryl and vinyl
halides is general method for unsymmetrical alkyne synthesis
Aq. Cu-free coupling of aryl bromide and iodides with phenylacetylene
using polymer complex and pyrrolidine as base, TABA additive
MW heating for reaction of 4-chloro-bromobenzene with
phenylacetylene for 0.1% catalyst yield obtained 47%
Gil-Molto, J. et al, Tetrahedron , 2005, 61, 12168

11. Stille Reaction
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In the course of scaffold decorations of of the 2(1H)-pyrazinone core
Stille reaction at C-3 position was perfomed by Van der Eycken
A great acceleration compared to conventional heating in refluxing
toluene could be reached (3 days vs 15 min), albeit the yields being
somewhat lower for the aqueous microwave synthesis
Kaval, N. et al, Mol. Diversity, 2003, 7, 125.

12. Carbonylation Reaction
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For the Pd cat. carbonylations of aryl halides give aromatic acid derivatives
(e.g., acids, amides, esters) Larhed developed MW assisted procedure
Aryl iodides, bromides, and even the otherwise unreactive chlorides could be
reacted with diverse 1° and 2° amines to the aryl amide in excellent yields
Lesma, G. et al, Synthesis, 2006, 594

13. Cyanation reaction
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Leadbeater and co-workers was performed preparation of aryl nitriles from
aryl iodides using CuCN, TBAB as phase-transfer agent and high conc of
cyanide, resulting from a 1:2 ratio of aryl halide/CuCN
Conventional heating under identical conditions resulted in no product;
also, activated aryl bromides did not show any conversion
The reaction can also be performed when less expensive NaCN in
combination with CuI is employed, forming CuCN in situ
Arvela, R. et al, Org. Biomol. Chem. 2003, 1, 1119

14. Mannich-Type Multicomponent Reactions
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The Mannich reaction is one of the most important transformations leading
to β–aminoketones
The group of Song reported on the Mannich reaction of acetophenones, 2°
amines form of hydrochloride salt, trioxymethylene as formaldehyde source
By MW heating, β-aminoketones obtained in 1.5-11 min in moderate to
good yields
Slightly higher yields in shorter reaction times (20-50 s) could be achieved
by performing the reaction under combined MW and ultrasound conditions
Peng, Y. et al, J. Synlett. 2005, 2245

15. Epoxide Ring Opening Reaction
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Pironti and Colonna reported the synthesis of β-hydroxy sulfides via aq.
thiolysis of epoxides with thiophenol in presence of catalytic amount of NaOH
The ring opening proved to be completely anti stereoselective, and the trans
products were obtained in excellent yields (85-98%)
Addition of 2 equiv of tert-butyl hydroperoxide to the reaction mixture of
already formed β-hydroxy sulfide and subsequent irradiation at 100 °C
generated the oxidized product 89% yield as a 25:75 mixture of diastereomers
Pironti, V. et al, Green Chem. 2005, 7, 43

16. Protection/ Deprotection Reaction
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In the course of a re-evaluation study of the synthesis of 1-acetyl-
thiohydantoins, which can be obtained by reaction of unprotected amino
acids with acetic anhydride and ammonium thiocyanate, Reyes and
Burgess disclosed the deacylation at the N1-position of 1-acetyl-
thiohydantoins
The deprotection step was performed in a 3M aqueous HCl solution and
furnished products thiohydantoin in high yields
Pourjavadi, A. et al, J. Chem. Res. 1999, 562

17. Reactions in Near-critical Water
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Reactions in the near-critical water (NCW) region between 200 and 300 °C
that are presented in this section of the review have to be performed with
higher pressure limits (80-100 bar)
The combination of 10 mol % CuI as cat. and 5 mol % L-proline as additive
was found to be the optimum cat. system and NaOH to be the best base
If aryl iodides are employed the reaction mix. is ramped to 300 °C in 10 min
 The reactions also performed at 200 °C under the same conditions, resulting
in a small decrease in yield and slightly longer reaction times (30 min)
Kormos, C. et al, Tetrahedron 2006, 62, 4728

18. 18
Synthesis of (Z)-5-benzylidenethiazolidine-2,4-dione
Entry Solvent Time (min) Yield (%)
1 EtOH 4 91
2 Water 2 92
3 DMF 7 67
4 DMSO 6 66
Optimization of diff. solvents for synthesis of (Z)-5-benzylidenethiazolidine-2,4-dione
model product
Bhat, A, et al, Current Reseach in Green and sustainable chemistry, 2020, 3, 100008

19. Summary
 The use of MW irradiation as heating source and water as solvent for synthetic
organic transformations
 The entry of microwave ovens using water as solvent in the chemistry laboratory
has made it possible to carry out many transformations with greater efficiency and
ease of workup
 It shows faster reaction, uniform and selective heating
 It gives better yield and high purity by avoiding side reaction
 In order for microwave chemistry to be valuable tool for the process chemist, new
MW scale-up technology needs to be developed, which is both economically viable
and environmentally sustainable if one considers the energy balance
 The future of microwave technology looks bright because of its efficiency and its
potential to contribute clean product
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20. Thank You
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