Microwave in Organic Synthesis

AIN SHAMS UNIVERSITY

SECOND YEAR PHARMACY

FACULTY OF PHARMACY

1ST SEMESTER

DEPARTMENT OF PHARMACEUTICAL CHEMISTRY

MICROWAVE IN ORGANIC SYNTHESIS EDITED BY

4.

1.

5.

2.

6.

3.

Shimaa Sayed Mohammad 262 Shimaa Abd Elmged Ibrahem 264 Shimaa Ali Saad 265

Doha Ashour Abdulwahab 267 Aliaa Adel Abdulsalam 278 Fatma Abd El-Aziz

INDEX MICROWAVE IN ORGANIC SYNTHESIS

1

INTRODUCTON

3

2

GENERAL BRINCIBLES

4

THEORY OF MICROWAVE HEATING

1

DIPOLAR POLARIZATION

5

2

CONDUCTION MECHANISM

5

3

SUPERHEATING EFFECT

6

4

SPECIFIC MW EFFECT

7

5

MW EFFECT ON SELECTIVITY OF REACTION

8

6

MW- Accelerated Homogeneous Catalysis

9

APPLICATIONS

10

CONCLUSION

17

REFERENCES

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2

Introduction In 1986 Richard Gedye and coworkers published a short communication in Tetrahedron Letters, entitled "The Use Of Microwave Ovens for Rapid Organic Synthesis" which for the first time described the utilization and advantages of microwave irradiation for organic synthesis . In this original publication four different types of reactions were studied, including the hydrolysis of benzamide to benzoic acid under acidic conditions (Scheme 1). Considerable rate increases (5 1000 fold) were observed for all investigated transformations when compared to classical thermal reflux conditions. The same year, an independent study by the groups of Giguere and Majetich describing similar rate-enhancements in microwave-promoted Diels-Alder, Claisen, and ene reactions was published in the same journal .

Scheme 1 The advantages of using microwave dielectric heating for performing organic reactions were soon realized by many different groups and as a consequence the amount of articles describing high-speed chemical synthesis promoted by microwave irradiation has grown quickly from ~200 in 1995 to ~1000 in 2001. In addition an unusually large number of review articles and commentaries (~60) has been published on this subject covering various aspects of microwave-assisted synthesis Importantly, many of the early microwave-assisted reactions, such as the process shown in Figure 1, were carried out in sealed Teflon or glass vessels using unmodified domestic household ovens . Due to the nature of microwave dielectric heating accurate temperature measurements using conventional means of temperature determination during the irradiation process were not possible at the time. Therefore the reasons for the observed rate-enhancements were in many cases not fully understood and led to a lot of speculation and fierce debate on the existence of so-called non-thermal or specific microwave effects . Today, a variety of dedicated microwave reactors for chemical synthesis are commercially available that incorporate built-in magnetic 3

stirring, direct temperature control of the reaction mixture with the aid of fluoroptic probes, shielded thermocouples or IR sensors, and software that enables online temperature/pressure control by regulation of microwave output power

4

General Principles

• Electromagnetic Spectrum MW have wavelengths 1mm - 1m , frequencies of 0.3 - 300 GHz. • To avoid interfernce with telecommunication, cellular phones and radar, by International convention most domestic and commercial MW heating operate at wavelength of 12.2 cm, 2.45 GHz. • MW can be divided in an electric field and a magnetic field component and the former is responsible for heating. • MW is generated by vacuum tubes, magnetron, multimode or mono-mode Commercial ovens - multimode, distribution of electric field is not homogeneous.

5

Theory of Microwave Heating

Dipolar Polarization: • For MW heating to occur the matrix should be dipolar or ionic Polar solvents e.g. water, DMF, CH2Cl2 with a dipole moment, i.e. high dielectric constant are MW-active whereas non-polar solvents like toluene, diethyl ether, benzene are MW-inactive. • In the presence of an electric field - dipole moment tend to align parallel to the applied field by rotation. • If the electric field oscillates, the dipole realigns and rotates in respond to the alternate electric field. • The molecules are extremely agitated, the molecular friction and collisions give rise to dipolar heating, ~10 oC per second. • Note - gases are not microwave active because the rotating molecules are far apart • MW heating occurs via dipolar polarization or conduction mechanism

Conduction Mechanism: • This applies for ions in solutions. • The ions will move through the solution under the influence of an electric field, the increased collision rate generates heat. • Heat generated is stronger than the dipolar mechanism, e.g. tap water will have higher temperature than distilled water at the same MW radiation power. • Problem - non polar solvents are MW-inactive.

6

Superheating effect: • The combination of temperature and frequency of the MW causes the loss tangent to increase. This causes the heating rate to increase during MW heating by limiting the formation of "Boiling nuclei". Superheating may result in a raised of boiling point by up to 26 oC • This phenomenon is believed to be responsible for the rate increases in solution phase MW reaction.

• MW produces efficient internal energy transfer (in situ heating) Compared to the wall heat transfer in the conventional Thermal heating. As a result the tendency for seed formation (The initiation of boiling) is reduced and superheating is possible.

• Temperature profiles of MW flash-heated palladium catalyzed alkylation in acetonitrile (bp, 81- 82oC). The reaction was performed in Septum-sealed Pyrex vessels.

7

Is There A Specific MW effect ? • Since the introduction of MW in organic chemistry in 1986, the main debate still reamains,what alter the outcome of the synthesis. Is it merely a thermal or a specific MW effect? Arrhenius Equation k = Ae^(-Ea/RT)

• Does not decrease reaction (Ea) but Increases pre-exponential factor (A ) The pre-exponential factor, A, describes the molecular mobility and depends on the frequency of vibrations of the molecules. Since, MW induces an increase in molecular vibrations, it's been proposed that this factor, A, can also be affected

8

MW effect on selectivity of reactions: • Since MW can interact with a polar TS. The product formed via a more polar TS will be favored • Regioselectivity in Cycloaditions of C70 fullerene under MW can be altered.

Classical heating: ODCB, 120 min, 32% yield 46% 8% MW 50%

:

ODCB, 120W, 30 min, 39% yield 0%

46%

50%

• Theoretical studies suggest that under kinetic control, 1a and 1b have a more polar TS. N.B: ODCB is ( - o-dichlorobenzene). 9

MW- Accelerated Homogeneous Catalysis Homogeneous palladium-catalyzed reactions: 1-Heck coupling :

2-Sonogashira Coupling:

3-Suzuki Cross Coupling:

10

4- Stille Coupling:

Applications Acetals and ketals are readily deprotected under neutral conditions in the presence of acetone and indium(III) trifluoromethanesulfonate as catalyst at room temperature or mild microwave heating conditions to give the corresponding aldehydes and ketones in good to excellent yields. 1)

Palladium-phosphinous acids catalyze the microwaveassisted conjugate addition of arylsiloxanes to a wide range of α,β-unsaturated substrates in water. The described procedure eliminates the need for stoichiometric additives and an excess of arylsiloxane, and does not require an inert atmosphere.

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2)

Gold N-heterocyclic carbene complexes, in conjunction with a silver salt, were found to efficiently catalyze the rearrangement of allylic acetates under both conventional and microwave-assisted heating. The steric hindrance of the ligand bound to gold was found crucial as only extremely bulky ligands permitted the isomerization. 3)

Hoveyda-Grubbs catalyst in combination with BF3·OEt2 efficiently promotes tandem cross metathesis intramolecular aza-Michael reaction between enones and unsaturated carbamates resulting in the creation of β-amino carbonyl units. The use of microwave irradiation dramatically accelerates the process, but also inverts the stereoselectivity in the addition process.

12

4)

An effective and mild microwave-assisted route to 2substituted benzofurans directly from carboxylic acids allows the preparation of α-alkyl-2-benzofuranmethanamines from N-protected α-amino acids without racemization in good yields. 5)

A Lewis acid catalyzed and solvent free procedure for the preparation of imides from the corresponding anhydrides uses TaCl5-silica gel as Lewis acid under microwave irradiation. 6)

A series of primary alcohols and aldehydes were treated with iodine in ammonia water under microwave irradiation to give the intermediate nitriles, which without isolation underwent [2 + 3] cycloadditions with dicyandiamide and sodium azide to afford the corresponding triazines and tetrazoles in high 13

yields.

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7)

Zirconium(IV)-catalyzed exchange processes of dialkyl carbonates and carbamates in the presence of amines gave carbamates and ureas using 2-hydroxypyridine (HYP) and 4methyl-2-hydroxyquinoline (MeHYQ) as catalytic additives, respectively. A microwave acceleration effect was observed in Zr(IV)-catalyzed carbamate-urea exchange. 8)

A one-pot reaction between nitriles, hydroxylamine and Meldrum’s acids under microwave irradiation and solventfree conditions gives 3,5-disubstituted 1,2,4-oxadiazoles in good to excellent yields.

15

9)

The Gewald reaction of PEG-bound cyanoacetic ester, elemental sulfur, DIPEA and carbonyl compounds carried out under microwave irradiation afforded PEG-supported thiophenes, which were acylated and treated with 1% KCN in methanol to give free thiophenes in good yields. This synthetic method is simple and mild. 10)

Addition of Grignard reagents to pyridine N-oxides in THF at room temperature and subsequent treatment with acetic anhydride at 120°C afforded 2-substituted pyridines in good yields. By exchanging acetic anhydride for DMF in the second step, 2-substituted pyridine N-oxides were obtained, enabling the synthesis of 2,6-disubstituted pyridines.

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11)

Lawesson’s reagent is an efficient promoter in the solventfree microwave-assisted synthesis of 2-substituted benzoxazoles and benzothiazoles from carboxylic acids and 2-aminophenol or 2-aminothiophenol, respectively. Various aromatic, heteroaromatic and aliphatic carboxylic acids react under the conditions developed with good yields. 12)

Trapping of β,γ-alkynyl aldehydes, generated in situ by treatment of alkynyloxiranes with a catalytic amount of Sc(OTf)3 or BF3·OEt2, by a variety of allyl nucleophiles affords homopropargylic homoallylic alcohols in good yield and selectivity. Subsequent enyne metathesis gives functionalized vinylcyclopentenols.

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13)

A novel and efficient synthesis of pyrimidine from β-formyl enamide involves samarium chloride catalysed cyclisation of β-formyl enamides using urea as source of ammonia under microwave irradiation. 14)

]A very simple and efficient, microwave-assisted procedure is reported for the synthesis of 1,3-diarylimidazolinium chlorides by cyclization of N,N′-diarylethylenediamines dihydrochlorides with triethyl orthoformate. 15)

N-Vinylpyridinium and -trialkylammonium tetrafluoroborate salts represent a new class of electrophilic coupling partner for Pd(0)-catalyzed Suzuki cross-coupling reactions with various boronic acids in high yields. The crystalline, airstable, and nonhygroscopic salts are easily prepared from activated acetylenes and pyridinium or trialkylammonium tetrafluoroborates. 18

conclusion 1-MW provides an interesting alternative for heating chemical reactions.

2- The drastic rate enhancement observed confims the usefulness of the MW technique.

3-Solvent-free reactions under MW promising future

4-The availability of commercial MW instrument for organic chemistry make this technique a routine use in the laboratory.

5- The existence of a specific MW effect is still a debate.

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References: • • •

www.organic-chemistry.org/topics/microwavesynthesis.shtm www.mdpi.org www.euchems-torino2008.it/download/WTLI.3HLehmann.pdf

•

en.wikipedia.org/wiki/Microwave_chemistry

•

www.chemistry-conferences.com

•

www.microwavesynthesis.net

•

www.biotage.co.jp

•

www.cem.de

•

www.encyclopedia.com

•

www.jasco.hu

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