ui did d al Áluniversidad de alcalÁ doctorado en ... · ui did d al Áluniversidad de alcalÁ...

U i id d d Al lÁUniversidad de AlcalÁDOCTORADO EN QUÍMICA MÉDICA

ESTRATEGIAS EN SÍNTESIS ESTRATEGIAS EN SÍNTESIS DE FÁRMACOS

SÍNTESIS CON MICRONDAS. ASPECTOS GENERALES

14/06/2011 Juan José Vaquero 1Juan J. Vaquero

SÍNTESIS CON MICRONDAS I

Microondas en Química: Química Analítica Applications of microwave oven sample dissolution in analysisR. A. NadkarniAnal. Chem. 1984, 56, 2233-2237.

Heating in a microwave oven in the presence of acid mixtures dissolves the metals from powderedcoal fly ash 011 shales rocks sediments and biological materials. The dissolution is completecoal, fly ash, 011 shales, rocks, sediments, and biological materials. The dissolution is completewithin 3 min. Nearly 25 elements (Al, As, Ba, Be,Ca, Co, Cr, Cu, Fe, K, Li, Mg, Mn, Na, Ni, P, Pb, Si,Sr, Ti, V,and Zn) from the dissolved samples are determined by inductively coupled plasma emisionspectrometry. The method has been tested on a variety of standard reference materials, withreproducible and accurate results.

Microwave energy for acid decomposition at elevated temperatures and pressures using biological and botanical samplesH. M. Kingston, L. B. Jassie; Anal Chem 1986 58 2534-2541Anal. Chem. 1986, 58, 2534 2541

A closed vessel microwave digestion system is described. In situ measurement of elevatedtemperatures and pressures in closed Teflon PFA vessels during acid decomposition of organicsamples is demonstrated. Temperature profiles for the acid decomposition of biological andbotanical SRMs are modeled by the dissolving acid Microwave power absorption of nitricbotanical SRMs are modeled by the dissolving acid. Microwave power absorption of nitric,hydrofluoric, sulfuric, and hydrochloric acids is compared. An equation is applied to acid microwaveinteractions to predict the time needed to reach target temperatures during sample dissolution.Reaction control techniques and safety precautions are recommended.

14/06/2011 Juan José Vaquero 2

SÍNTESIS CON MICROONDAS I

The use of microwave ovens for rapid organic synthesis

Estudios pioneros en síntesis orgánica

The use of microwave ovens for rapid organic synthesisRichard Gedye,* Frank Smith, Kenneth Westaway, Humera Ali, Lorraine Baldisera, Lena Laberge and John Rousell

AbstractAbstractFour different types of organic reactions have been studied and seven different organic compounds have been prepared, under pressure in a microwave oven. Considerable rate increases have been observed.

CONH2 COOH

CH COOHCH3 COOH

CO2H COOR

Tetrahedron Lett 1986 26 279 282

OHNC OCH2PhNC


Tetrahedron Lett. 1986, 26, 279-282


Application of commercial microwave ovens to organic synthesis


Raymond J. Giguere,* Terry L. Bray and Scott M. Duncan George MajetichAbstractCommercial microwave ovens have been safely used to dramatically reduce the reaction times (at comparable yield) of Diels-Alder, Claisen, and ene reactions. Significant solvent effects were also observed.

CO2MeCO2MeMeO2C

+Diels-Alder

MeO2C

O HO

+

T. Claisen

H

OH

H

OHR. énica

Tetrahedron Lett. 1986, 27, 4945



CO2MeMeO2CDisolvente: dioxanoTemperatura: 101 ºCTiempo: 72 h

Disolvente: p-xilenoTemperatura: 325 361 ºC

MICROONDASEstudios pioneros en síntesis orgánica

MeO2C

CO2Me+

pRendimiento: 90%

Temperatura: 325-361 CTiempo: 10 minutosRendimiento: 87%

O O

+

Disolvente: ----------Temperatura: 200 ºCTiempo: 72 hRendimiento: 20%

Disolvente: ----------Temperatura: 400-425 ºCTiempo: 15minutosRendimiento: 87%

O HO


Disolvente: DMFTemperatura: 325-361 ºCTi 10 i tRendimiento: 85% Tiempo: 10 minutosRendimiento: 92%

H

OHOH


Disolvente: ----------Temperatura: 400-425 ºCTiempo: 15 minRendimiento: 62%


HH Tetrahedron Lett. 1986, 27, 4945


The Rapid Synthesis of Organic Compounds in microwave ovens


• Organic compounds can be synthesized up to 1240 times faster in sealed Teflon vessels

The Rapid Synthesis of Organic Compounds in microwave ovensRichard Gedye,* Frank Smith, Kenneth Westaway

in a microwave oven than by conventional reflux techniques

• All polar molecules absorb microwave energy rapidly and the rate of energy absorption varies with the dielectric constants

• The rates of polar molecules in nonpolar solvents are not increased appreciably by the microwave method

h h f h d ff h h• The homogeneity of the reaction does not affect the rate enhancement

• The rate enhancement arises predominantly because the oven superheats the solvent rapidly

Th h h d h l l d l f h • The maximum rate enhancement is achieved when proper power level and volume of the solvent are used

Can J Chem 1988 66 17


Can. J. Chem. 1988, 66, 17


Aumento de presión al irradiar


Temperatura alcanzada al irradiar durante 1 Aumento de presión al irradiardiferentes volúmenes den-PrOH en un frasco cerrado

Temperatura alcanzada al irradiar durante 1min en un horno de microondas 50 mL dedisolvente en un matraz abierto a 560 watios

180

80100120140160180

pera

tura

Temp.P eb 45

55

65

(psi

) 5 mL

15 L

020406080

2O OH

OH

OH

OH

OH

OAc Cl2

Cl3 Me

MF

2O ano

Cl4

Tem

p P. eb.

25

35

Pres

ión

( 15 mL

20 mL

25 mL

HM

e EtO

n-Pr

On-

BuO

AcO

EtO

CH

2CC

HC

MeC

O DM

EtH

exa CC

Disolvente

15

Tiempo (min)5 10 15

Can. J. Chem. 1988, 66, 17



I i lid i "d di " ffi i t f d l i i i di ti


Inorganic solids in "dry media" an efficient way for developing microwave irradiation activated organic reactionsE. Gutierrez, A. Loupy, G. Bram, E. Ruiz-Hitzky

AbstractAbstract"Dry media" microwave irradiation accelerates pinacol rearrangement (onmontmorillonite) or acetate alkylation (on alumina or silicagel) without the hazardsdue to high pressures in vessels when using solvents

Me

OHOH Me

M

O

M

Me

M

MeMontmorillonita

MeMe MeMe

IMe OAcMe

(Na, Ca)(Al, Mg)6(Si4O10)3(OH)6 - nH2O



Tetrahedron Lett. 1989, 30, 945 948


A li ti f i h ti t h i f d i ti


Application of microwave heating techniques for dry organic reactionsAbdelkrim Ben Alloum, Bouchta Labiad, Didier Villemin

AbstractA commercially available microwave oven operating at 2450 MHz has been used for activation of organic compounds adsorbed on inorganic solids

MW 5 minMe

OH

PhMe

O

Ph

KSF clayTubo cerrado(frasco teflon)

MW, 5 min270 W

95%

Calefacción170 º C

<2%

O

O CHO SO2-Ph

CN O

O SO2Ph

CN+ FK

25 ºC: 2%

J. Chem. Soc. Chem. Comm. 1989, 7, 386 - 387

MW 20 min, 55 W, 95%


J. Chem. Soc. Chem. Comm. 1989, 7, 386 387


Metodologías en síntesis orgánica utilizando microondas

Reacciones en fase homogénea (con disolvente)• En sistemas abiertos (open vessel)• En sistemas cerrados (sealed vessel)

1986

En sistemas cerrados (sealed vessel)

Reacciones en fase heterogénea• Sin disolvente (neat)• Reactivos soportados (dry media)

• Soportes transparentes a MW• Soportes absorben MW• Soportes “dopados”

• Sistemas bifásicos• PTC• Catálisis heterogénea• Fase sólida

2006Escalado y reacciones de flujo continuo


Escalado y reacc ones de flujo cont nuo


APLICACIONES DE MO EN QUIMICA(Articulos 1986-2004)

14001600180020002200

cacion

es

400600800

100012001400

Núm

ero

publ

ica

Reactores

0200400

Año

N

1986

1988

1990

1992

1994

1996

1998

2000

2002

2004

Org. Lett. 2005 Guidelines for authors

Si t lti d l

Reactoresde diseñopara síntesisorgánica

Microondas de cocina

Org. Lett. 2005 Guidelines for authorsMicrowave Experiments:......... Manuscripts describing work done withdomestic (kitchen) microwave ovens will not beaccepted except for studies where the unit is

d f h ti ti i t tSistemas multimodolescontroles de potencia

presión y temperatura Sistemas monomodoles

orgánicaused for heating reaction mixtures atatmospheric pressure.

14/06/2011 Juan José Vaquero 11(focalizados)

SÍNTESIS CON MICROONDAS II

Artículos 2000-2004Tipo de reacción Articulos Tipo de reacción Articulos

Alkylations, Acetylations 12Asymmetric Reactions 6Carbohydrates 6CO Insertions 8

Rearrangements 10Ring-Closing Metathesis (RCM) 6Scavengers 5Simultaneous Cooling (EMS) 4

p p

CO se t o s 8Condensations 9Cyanations 8Cycloadditions 15Heterocycle Synthesis 73Reactions Involving Ionic Liquids 14

S u ta eous Coo g ( S)Solid-Phase Reactions 37Solvent-Free Reactions 25C–H Bond Activation 1Dye Synthesis 2Halide Exchange 1Reactions Involving Ionic Liquids 14

Michael Reactions 6Multicomponent Synthesis 17Nucleoside Synthesis 5General Organometallics 32

Halide Exchange 1Halogenation 4Macrocycles 2Nitration 2SNAr 1

Buchwald-Hartwig 7Heck, Suzuki, Sonogashira 9Fischer Carbenes 1Pauson-Khand 3Oxidations 7

Phosgenation 1Polymerase Chain Reaction (PCR) 1Trypsin Digestion 1Wittig Reaction 2

Peptides, Proteins 7Photochemistry 4Polymers 12Protections/Deprotections 5Radicals 9

Datos tomados de: B. L. Hayes, Recent Advances in Microwave assited Synthesis, Aldrichimica Acta, 2004, 37, 66-76


Radicals 9


Artículos 2007

8080

Artículos 2007

58

3850

6070A

RTI

JACSJOCOL

9 15

32

2030

40ICUL

SYNLETTSYNTHESISTETRAHEDRON

59

6 2

0

10

20OS

1REVISTA

T. LETTERSCCNJC/OBCREVISTA NJC/OBC



¿ Por qué la irradiación con MO acelera las reacciones ?Aspectos básicos

on

Calefacción clásica vs.irradiación con microondas

on



¿ Por qué la irradiación con MO acelera la reacciones ?

Irradiación MO y cinética de reacciones

E

¿ Por qué la irradiación con MO acelera la reacciones ?

La radiación de MO La radiación de MO

+

ET

E

Ener

no modifica la Ea pero

posibilita alcanzar el

no modifica la Ea pero

posibilita alcanzar el +

H

Eagia

ET con mayor rapidezET con mayor rapidez

Coordinada de reacción




+

A (30 mg) B (30 mg) C (30 mg)P 300Pm = 300

Cal necesarias para la transformación (Ea= 50 kcal/mol):

l 50000 cal0.0 3 g x x

mol

300 g

50000 cal

mol = 5 cal

Energía introducida al al sistema al irradiar a 300 W de potencia:

300 W = x = 72 cal/seg300 J 0.239 cal

seg JLa energía transferida a la reacción es mucho mayor La energía transferida a la reacción es mucho mayor seg Jque la requerida por la energía de activación (Ea)que la requerida por la energía de activación (Ea)

B. L. Hayes, Microwave Synthesis, CEM Publishing, Matthews, NC, 28115, 2002


y , y , g, , , ,



Vida media del complejoactivado

Velocidad a laque MO aplicanenergía

Velocidadde relajaciónmolecular

10-13 10-9 10-5

Tiempo (seg)Vida media de intermedios

t bili destabilizados

•Condiciones de no-equilibrio•Temperatura instantáneas•Condiciones de no-equilibrio•Temperatura instantáneasIntermedios polaresIntermedios polares •Temperatura instantáneasmuy elevadas

•Temperatura instantáneasmuy elevadas

Intermedios polareso iónicos se pueden acoplarcon la radiación de MO

Intermedios polareso iónicos se pueden acoplarcon la radiación de MO




ArrheniusArrhenius k = A.e-Ea/RT

• Frecuencia de las colisiones moleculares con la geometría adecuada (A)• Frecuencia de las colisiones moleculares con la geometría adecuada (A)

La radiación de MO no afecta la orientación de las colisiones molecularesLa radiación de MO no afecta la orientación de las colisiones moleculares

• Moléculas con energía suficiente para vencer la barrera de la Ea (e-Ea/RT)

de las colisiones molecularesde las colisiones moleculares

La radiación de MO no afecta la energía de activaciónLa radiación de MO no afecta la energía de activación

La radiación con MO puede modificar el valor de la temperatura en la ecuación de Arrhenius (e-Ea/RT)La radiación con MO puede modificar el valor de la temperatura en la ecuación de Arrhenius (e-Ea/RT)




ArrheniusArrhenius k = A e-Ea/RTEa = 100 kJmol-1A = 4 x 1010 mol-1s-1ArrheniusArrhenius k = A.e a A = 4 x 1010 mol 1s 1

Temperatura Velocidad de reacción (k/s)

Tiempo (90% conversión)

27 1.55.10-7 68 días

77 4.76.10-5 13.4 horas

127 3.49.10-3 11.4 min

177 9.86.10-2 23.4 seg

227 1.43 1.61 seg




ArrheniusArrhenius k = A.e-Ea/RTEa = 50 kcal/molTmedia = 150 ºC

Aumento de la t t

Aumento de la l id d dTemperatura temperatura

(instantánea)velocidad de

reacción

150 +17 x 10150 17 x 10

150 + 35 x 100

150 + 56 x 1000




L i di ió MOL i di ió MO

¿ Qué tipos de reacciones se afectan por irradiación con MO ?

Ea

Ene

La irradiación con MOestá especialmenterecomendada paraaquellas reacciones que

La irradiación con MOestá especialmenterecomendada paraaquellas reacciones que

Ea

aergi

+

q qtienen una energíade activación muy elevada(E2>>E1)

q qtienen una energíade activación muy elevada(E2>>E1)

a




¿ Qué tipos de reacciones se afectan por irradiación con MO ?Irradiación MO y cinética de reacciones

ETLa calefacción

ET1

ET2

Ene

clásica favorece la formación de los productos de

Ea1

Ea2ergi

control cinético

+a

La irradiación conMO favorece la


MO favorece laformación de losproductos de controltermodinámico



¿ Existe un “efecto microondas” responsable de la acelaración de ciertas reaciones?

Microwave induced hydrolysis of phospho anhydride bonds in nucleotide triphosphatesMicrowave-induced hydrolysis of phospho anhydride bonds in nucleotide triphosphatesWei Che Sun, Pamela M. Guy, Jessica H. Jahngen, Edward F. Rossomando, Edwin G. E. Jahngen; J. Org. Chem. 1988, 53, 4414-4416.

....to explain the microwave-induced acceleration of the rate of hydrolysis of the phospho anhydride bond of anp y y p p ynucleotide 5´-triphosphate (NTP), we invoked the concept of spectroscopic heating....

.....in the spectroscopic heating the increase in the kinetic energy is due to the direct absortion of radiated energy.These excited molecules accrue excesive amounts of energy in the form of vibrational and rotational modes ......

....in our studies it is conceivable that the phenomenon of localized spectroscopic heating could occur withoutsignificant increase in the temperature of the system......

Hydrolysis of adenosine triphosphate by conventional or microwave heating

Sun et al. recently reported that the hydrolysis rate of adenosine-5'-triphosphate (ATP) was 25 timesd i i h i h d i i l h i bl (100 105 º

Hydrolysis of adenosine triphosphate by conventional or microwave heatingEdwin G. E. Jahngen, Ronald R. Lentz, Peter S. Pesheck, Patricia Holt Sackett; J. Org. Chem. 1990, 55, 3406-3409

greater during microwave heating than during conventional heating at comparable temperatures (100-105 ºC). This remarkable rate increase was both attributed to and cited as evidence for a nonthermal microwaveeffect. Attempts to replicate those findings, however, lead to the conclusion that the hydrolysis rate isinstead related solely to temperature. There is no need to postulate a nonthermal microwave effect.Accurate temperature measurement within the microwave-heated sample has been found to be crucial and


p pnot trivial.


¿ Existe un “efecto microondas” ?The influence of microwaves on the rate of reaction of propan-1-ol with ethanoic acid

....from the information published , it is not possible to separate the rate enhancement caused by the more rapidand uniform heating, and the consequent high pressures, from the claimed intrinsic effects of the microwave

d h f d

Stephen D. Pollington, Gary Bond, Richard B. Moyes, David A. Whan, John P. Candlin, J. Robert Jennings; J. Org. Chem. 1991, 56, 1313-1314

radiation, such as specific bond activation....

.....Our conclusions are in agreement with those of Jahngen et al. We have shown that, in a carefully controlledsystem, the rates of esterification of propan-1-ol with ethanoic acid are identical in the presence of absence ofmicrowave irradiation......m

Synthese organique sous champ microondes: premier exemple d'activation specifique en phase homogeneJ. Berlan, P. Giboreau, S. Lefeuvre, C. Marchand

The rate of several Diels-Alder reactions under conventionalor microwave heating are compared at the same bulktemperature. At the same bulk temperature, monitored witha fiber optic Luxtron thermometer, the kinetics of threeDiels-Alder reactions have been compared using conventionalDiels-Alder reactions have been compared, using conventionalor microwave heating. Under microwave heating the halfreaction time is reduced by up to 8. This afford the firstevidence for a specific activating effect of microwavesunder homogeneous conditions.

INST: Magnetrón de un horno de cocina(2.5 GHz) con sistema de guiado para MO




¿ Existe un “efecto microondas” ?Specific activation by microwaves: myth or reality?Regis La rent Andre Laporterie Jacques Dubac Jacques Berlan Serge Lefe re Michele A dh ;Regis Laurent, Andre Laporterie, Jacques Dubac, Jacques Berlan, Serge Lefeuvre, Michele Audhuy; J. Org. Chem. 1992, 57, 7099-7102

...... at this time, it is unresolved whether the use of microwaves provides specific activation.......

.......we have investigated this problem further with the ene reaction using carbonyl enophiles. Thisreaction would be a good model for several reasons: a) the polar carbonyl group serves as a good “antennagroup” since this group is at the same time directly involved in the reaction and in the molecularinteraction with the waves; b) the experimental conditions required for this reaction permit acomparative kinetic study with conventional heating; c) it is possible to carry out this reaction undereither homogeneous or heterogeneous conditions with a solid as catalyst......either homogeneous or heterogeneous conditions with a solid as catalyst......

OHCO2EtCO2Et

Me(CH2)6Me(CH2)2CH=CH2 The reactions of diethyl mesoxalate with 1-decene

and β-pinene under homogeneous (neat liquid) orheterogeneous (clay catalyst) conditions have been

O

EtO2C CO2Et OHCO2Et

CO2Et

2 heterogeneous (clay catalyst) conditions have beenstudied. In each case the dependence of reactionyield on time and the stereoisomer ratios of theproducts are unaffected by the heating mode.

...microwave chemistry is still in its infancy, and aty ythis time it is difficult to say whether it is mythor reality specific microwave activation as thereare too many apparently contradictory results....

INST: Magnetrón de un horno de cocina(2.5 GHz) con sistema de guiado para MO


(2.5 GHz) con sistema de guiado para MO


¿ Existe un “efecto microondas” ?A comparison of reaction kinetics observed under microwave irradiation and conventional heating K i D R Ch i t h R St F di d V k L i M kb lKevin D. Raner, Christopher R. Strauss, Ferdinand Vyskoc, Luci Mokbel

Kinetic studies were made of two reactions under microwave heating and underconventional heating. The reactions were the acid-catalyzed isomerization of carvoneto carvacrol and the Diels-Alder reaction between anthracene and diethyl maleate It

...We believe that the earlier observations onnonthermal microwave effects probably resulted

to carvacrol and the Diels-Alder reaction between anthracene and diethyl maleate. Itwas found that the rates of these reactions were the same, within experimental error,under either mode of heating at the same temperature.

nonthermal microwave effects probably resultedfrom inherent experimental difficulties relating totemperature measurement and/or development ofthermal gradients whithin the sample....

we have attempted here to duplicate the result

O OHH+

...we have attempted here to duplicate the resultobtained by Berlan et al., but we found noacceleration in the rate of the reaction undermicrowave conditions.....

CO2Et

CO2EtCO2Et

CO2Et+

INST: tubo cerrado o frasco teflon

J Org Chem 1993 58 950 953


J. Org. Chem. 1993, 58, 950-953.


¿ Existe un “efecto microondas” ?Microwave-mediated Biginelli reactions revisited. On the nature of rate and yield enhancementsAlexander Stadler and C. Oliver Kappe

The microwave-mediated Biginelli dihydropyrimidinesynthesis was reinvestigated using a purpose-builtcommercial microwave reactor with on-line temperaturecommercial microwave reactor with on-line temperature,pressure, and microwave power control. Transformationscarried out under microwave heating at atmosphericpressure in ethanol solution show no rate or yield increasewhen the temperature is identical to conventional thermalh ti I th f h ti b iheating. In the case of superheating by microwaveirradiation at atmospheric pressure the observed yield andrate increases are rationalized as a consequence of athermal (kinetic) effect. Under sealed vessel conditions (20bar, 180 °C) the yield of products is decreased and) y pformation of various by products observed. The onlysignificant rate and yield enhancements are found when thereaction is performed under "open system" conditions wherethe solvent is allowed to rapidly evaporate during microwaveirradiation However the observed rate and yieldirradiation. However, the observed rate and yieldenhancements in these experiments are a consequence ofthe solvent-free conditions rather than caused specificallyby microwave irradiation. This was confirmed by controlexperiments of the solventless Biginelli reaction under

i(Reactor multimodal Milestone ETHOS 1600).


J. Chem. Soc., Perkin Trans. 2, 2000, 7, 1363 - 1368microwave


¿ Existe un “efecto microondas” ?Microwave-Assisted Ring-Closing Metathesis Revisited. On the Question of the NonthermalMicrowave EffectMicrowave EffectStefania Garbacia, Bimbisar Desai, Olivier Lavastre, C. Oliver Kappe*

The ring-closing metathesis reactions (RCM) of six standard diene substrates leading to five-, six-, or seven-membered carbo- or heterocycles were investigated under controlled microwave irradiation. RCM protocols werey g pperformed with standard Grubbs type II and a cationic ruthenium allenylidene catalyst in neat and ionic liquid-dopedmethylene chloride under sealed vessel conditions. Very rapid conversions (15 s) were achieved utilizing 0.5 mol %Grubbs II catalyst under microwave conditions. Careful comparison studies indicate that the observed rateenhancements are not the result of a nonthermal microwave effect.

61 94% INST: Smith Synthesizer Personal Chemistry AB

61-94%

J. Org. Chem., 2003, 68, 9136 -9139



¿ Existe un “efecto microondas” ?Microwave-Assisted Ring-Closing Metathesis Revisited. On the Question of the Nonthermal Microwave Effect

The concept of nonthermal microwave effects has received considerable attention in recent years and is the subject of intense debate in the i tifi it N th l i ff t h b t l t d t lt f di t t bili i i t ti f th l t i fi ld ith

Stefania Garbacia, Bimbisar Desai, Olivier Lavastre, and C. Oliver Kappe

J. Org. Chem., 2003, 68, pp 9136–9139

p y jscientific community. Nonthermal microwave effects have been postulated to result from a direct stabilizing interaction of the electric field with specific (polar) molecules in the reaction medium that is not related to a macroscopic temperature effect. In order to probe the existence of nonthermal microwave effects, four synthetic transformations (Diels-Alder cycloaddition, alkylation of triphenylphosphine and 1,2,4-triazole, direct amide bond formation) were reevaluated under both microwave dielectric heating and conventional thermal heating. In all four cases, previous studies have claimed the existence of nonthermal microwave effects in these reactions. Experimentally, significant differences in conversion and/or product distribution comparing the conventionally and microwave-heated experiments performed at the same measured reaction temperature were found. The current reevaluation of these reactions was performed in a dedicated reactor setup that allowed accurate internal reaction temperature measurements using a multiple fiber-optic probe system. Using this technology, the importance of

ffi i t ti i d i t l t t t i i h t d ti d id t I ffi i t it ti l d tefficient stirring and internal temperature measurement in microwave-heated reactions was made evident. Inefficient agitation leads to temperature gradients within the reaction mixture due to field inhomogeneities in the microwave cavity. Using external infrared temperature sensors in some cases results in significant inaccuracies in the temperature measurement. Applying the fiber-optic probe temperature monitoring device, a critical reevaluation of all four reactions has provided no evidence for the existence of nonthermal microwave effects. Ensuring efficient agitation of the reaction mixture via magnetic stirring, no significant differences in terms of conversion and selectivity between experiments performed under microwave or oil bath conditions at the same internally measured reaction temperatures were experienced. The observed effects were purely thermal and not related to the microwave field.



¿ Existe un “efecto microondas” ?Microwave Specific Wolff Rearrangement of α-Diazoketones and Its Relevance to the Nonthermaland Thermal EffectSurendra G. Sudrik,* Sambhaji P. Chavan, K. R. S. Chandrakumar, Sourav Pal, Sadgopal K. Date, Subhash P. Chavan, andHarikisan R. Sonawane*

Diazoketones possess high electric dipole moments as a consequence of the dipolar nature of the diazocarbonylDiazoketones possess high electric dipole moments, as a consequence of the dipolar nature of the diazocarbonylfunctional group. The vectorial analysis, theoretical calculations (PM3 and ab initio), and literature reports based onexperimental and theoretical calculations reveal a higher dipole moment for the Z-configuration of the diazofunctional group. 3-Diazocamphor on microwave irradiation in benzylamine exhibits nonthermal effects to furnishexclusively the Wolff rearrangement product, equivalent to its photochemical behavior. In the presence of an

di th h l t h ti d i t l di t th f ti f t i li k t th i i laqueous medium, through solvent heating predominates, leading to the formation of a tricyclic ketone as the principalproduct, arising from an intramolecular C-H insertion. This behavior is similar to its known thermal and transitionmetal catalyzed reactivity pattern.

43% 73%

Transposición de WolffInserción C-H

J. Org. Chem., 2002, 67, 1574 -1579INST: MicrowaveAssisted Reactor System-5 [MARS-5 (CEM)]

43% 73%



¿ Existe un “efecto microondas” ?Improvements in Diels–Alder cycloadditions with some acetylenic compounds under solvent-f i i t d diti i t l lt d th ti l h

The Diels–Alder irreversible cycloadditions of 1,3-cyclohexadiene and 3-carbomethoxy-2-pyrone with acetylenicdienophiles under solvent-free conditions are described. By strict comparisons with conventional heating under

l d f ff l d h l h h

free microwave-assisted conditions: experimental results and theoretical approachesAndré Loupy, François Maurel and Andrea Sabatié-Gogová

similar conditions, important specific microwave effects are revealed in the last case whereas they are absentin the first one. They are discussed in terms of asynchronous mechanisms in agreement with ab initiocalculations at the HF/6-31G(d) level indicating dissymmetries in transition states. Specific MW effects can beunderstood by considering the enhancements in dipole moments from ground states to transition states

CO2Et

H

CO2Et CO2Et

CO2Et

CO2Et

CO2Et+ +

Sindisolvente

MW o calefacción1 0 ºC

•Mecanismo isopolar sincrono•No se produce separación de carga

H 2 2150 ºCMW: 37% (52:48)Calef.: 36% (53:47)

CO EtPh Ph Sin

disolvente •Mecanismo polar asincrono

O

CO2Et

HCO2Et+

disolvente

MW o calefacción150 ºCSistema abierto3 horas

MW: 64%Calef.: 19%

Mecanismo polar asincrono•Separación de carga

INST: monomode reactor Synthewave S402 (Prolabo)

14/06/2011 Juan José Vaquero 34Tetrahedron, 2004, 60,1683-1691


¿ Existe un “efecto microondas” ?

Microwaves in organic synthesis. Thermal and non-thermal microwave effects, Antonio de la Hoz, Angel Diaz-Ortiz, Andres Moreno,

Microwave irradiation has been successfully applied in organic chemistry. Spectacular accelerations,higher yields under milder reaction conditions and higher product purities have all been reported. Indeed,higher yields under milder reaction conditions and higher product purities have all been reported. Indeed,a number of authors have described success in reactions that do not occur by conventional heating andeven modifications of selectivity (chemo-, regio- and stereoselectivity). The effect of microwaveirradiation in organic synthesis is a combination of thermal effects, arising from the heating rate,superheating or hot spots and the selective absorption of radiation by polar substances. Such phenomenaare not usually accessible by classical heating and the existence of non thermal effects of highlyare not usually accessible by classical heating and the existence of non-thermal effects of highlypolarizing radiation—the specific microwave effect —is still a controversial topic. An overview of thethermal effects and the current state of non-thermal microwave effects is presented in this criticalreview along with a view on how these phenomena can be effectively used in organic synthesis.

(a) The superheating effect of solvents at atmospheric pressure

(b) The selective heating (strongly microwave absorbingheterogeneous catalysts or reagents in a less polar reaction

Nonthermal microwave effects have been proposed to be the consequence of a direct interaction of the electric field with specific

l l i h i di h i

Chem. Soc. Rev., 2005, 164-178

heterogeneous catalysts or reagents in a less polar reactionmedium, (c) The elimination of wall effects caused byinverted temperature gradients.

molecules in the reaction medium that is not related to a macroscopic temperature effect.



¿ Existe un “efecto microondas” ?Investigating the Existence of Nonthermal/Specific Microwave Effects Using Silicon Carbide Heating Elements as Power Modulators

Tahseen Razzaq, Jennifer M. Kremsner and C. Oliver Kappe

J. Org. Chem., 2008, 73, pp 6321–6329

The use of passive heating elements made out of chemically inert sintered silicon carbide (SiC) allows microwave transparent or poorly absorbing reaction mixtures to be heated under microwave conditions.The cylindrical heating inserts efficiently absorb microwave energy and subsequently transfer the generated thermal energy via conduction phenomena to the reaction mixture. In the case of low to medium microwave absorbing reaction mixtures, the addition of SiC heating elements results in significant reductions (30-70%) in the required microwave power as compared to

i t f d ith t h ti l t t th t t Th th d h b d t b th i flexperiments performed without heating element at the same temperature. The method has been used to probe the influence of microwave power (electromagnetic field strength) on chemical reactions. Six diverse types of chemical transformations were performed in the presence or absence of a SiC heating element at the same reaction temperature but at different microwave power levels. In all six cases, the measured conversions/yields were similar regardless of whether a heating element was used or not. The applied microwave power had no influence on the reaction rate, and only the attained temperature governed the outcome of a specific chemical process under microwave conditions.



¿ Qué condiciones elegir para hacer una reacción con MO ?



Sobrecalentamiento de disolvente comunes al irradiar con MO a presión atmosférica

Disolventes

0 50 100 150 200

al irradiar con MO a presión atmosférica

150170

81MeCOMeDMFClPh

10081

55107

i-PrOHTHF

DCMMeCN

Diso

lven

te

10484

103100

AguaMeOHEtOHPrOH

Incremento temp. MOP. ebullición

0 50 100 150 200T ºC



Disolventes

Irradiación de MeOH (p.e. 65 ºC) en un sistema cerrado (autoclave) a 50 W de potencia (monomodal)

160180200

15P

p ( )

80100120140160

erat

ura

(º C

)

5

10T En un sistema cerradose alcanzan temperaturasmuy superiores al p e del

En un sistema cerradose alcanzan temperaturasmuy superiores al p e del

020406080

Tem

pe

0

5 muy superiores al p.e. del disolvente y elevadas presiones

muy superiores al p.e. del disolvente y elevadas presiones

0

1,00

3,00

5,00

7,00

9,00

11,0

0

13,0

00 60 120 180 240 300 360

Tiempo (seg)



Reacciones a presión atmosférica vs reacciones en sistemas cerradosHigly Accelerated Reactions in a Microwave Oven: Synthesis of HeterocyclesAjay K. Bose,* Maghar S. Manhas, Malay Ghosh, Vegesna S. Raju, Keiko Tabei, Zofia Urbanczyk-Lipkowska

Efficient synthesis of heterocycles on 0.1 to 200 g scale was conducted in organic solvents in a commercialmicrowave oven in a few minutes at a low energy level. Erlenmeyer flaks were adequate since neither highpressure nor high temperature were involved Microwave-Induced Organic Reaction Enhancement Chemistrypressure nor high temperature were involved. Microwave-Induced Organic Reaction Enhancement Chemistry(MORE Chemistry) is not due to thermolysis: one reaction was conducted succesfully in a reaction vialencased in a block of ice.

NH2 NMW2

NH2 NH

N

COMeMe

+ HCO2HMW

3 min

70%

MW

INST: Microondas de cocinaCOMe

CO2Et NH

N

SHOH+ H2NCONH2

MW

EtONa/EtOH2 min68%

Heterocycles, 1990, 30,741-744NHCOPh N

Ph

+ P2O5 XDMF, DCE, tolueno

MW

NN

Ph

Ph COPh

Ph


Phtolueno Ph COPh

TÉCNICAS DE QUÍMICA CON MICROONDAS I

Reacciones a presión atmosférica vs reacciones en sistemas cerrados

Microwave-Induced Organic Reaction Enhancement Chemistry. 2. Simplified Techniquesg y p qAjay K. Bose,* Maghar S. Manhas, Malay Ghosh, Mamta Shah,* Vegesna S. Raju, Shamsher S. Bari,s, Sarder N. Newaz, Bimal K. Banik, Ashok G. Chaudhary, and Khaled J. Barakat

A variety of organic reactions have been conducted efficiently in a few minutes in unsealed vessels y g yat ambient pressure in unmodified microwave ovens by using selected organic solvents.

OO Disol T (min) Rdto (%)

O

O

OO

+ MW

Disol T (min) Rdto (%)

Cl-Ph 3 40

DCB 2 85

O

Ph PhPh

MW MW

Diglime 1 90

J. Org. Chem. 1991, 56, 6968-6970

COClN

PhN

O PhNH

OPh

+HCO2NH4Pd/C(10%)

NMMPh-Cl

70%5 min

ETG

45 seg80%

INST: Microondas de cocina


g , ,

TÉCNICAS DE QUÍMICA CON MICROONDAS I


MORE Chemistry (Microwave-induced Organic Reaction Enhancement in domestic microwave ovens

• Aumento de la velocidad de reacción relativamente modesto en comparación

con los sistemas cerrados

• La temperatura debe mantenerse por bajo del p.e. del disolvente

• Se emplean disolventes polares y de p.e. elevado (DMSO, DMF, NMP, ...)

• Se pueden producir sobrecalentamientos del disolvente• Se pueden producir sobrecalentamientos del disolvente

• Riesgos cuando se emplean disolventes inflamables

• El aislamiento de productos de reacción se complica



Reacciones a presión atmosférica vs reacciones en sistemas cerradosRapid microwave-enhanced synthesis of 4-hydroxyquinolinonesRapid microwave enhanced synthesis of 4 hydroxyquinolinones under solvent-free conditionsJos H. M. Lange,* Peter C. Verveer, Stefan J. M. Osnabrug, Geb M. Visser

EtOH

8-54%

Se precisa trabajar en un sistema abierto para facilitar la eliminación del etanol que se desprende en el proceso de heterociclación. La reacción no se

INST: Microwave reactor Milestone Ethos 900Tetrahedron Lett., 2001, 42, 1367–1369

q p pproduce en un sistema cerrado




En la hidrólisis de benzamida -en la que no seproducen compuestos volátiles no se observanproducen compuestos volátiles- no se observandiferencias de reacción con el cambio de escala o elvolumen de la reacción en un sistema cerrado

E l d ó d h d lEn la condensación de tetrahidroisoquinolina conderivados del ester malónico en la que se generan 2equiv. de EtOH se observan cambios drásticos en lareacción en un sistema cerrado dependiendo de la

lescala• En un sistema abierto se favorece laeliminación de EtOH• El escalado de la reacción sólo es posible en

b d d lun sistema abierto en ausencia de disolvente

Tetrahedron 2002 58 3177 3183INST: Reactor monomodal: Smith Synthesizer Personal Chemistry AB

R t lti d l ETHOS S th L b t ti (Mil t )


Tetrahedron, 2002, 58, 3177-3183Reactor multimodal: ETHOS Synth Labstation (Milestone).


¿ Como elegir el disolvente? Cantidad de energíaproducida en la irradiación

Constantedi lé t i

Pérdida di lé t i

producida en la irradiaciónMO perdida por disipaciónde calor

DISOLVENTE

dieléctrica(ε´)

dieléctrica(ε´´)

ε´´ o tan δ se emplean DISOLVENTEFacilidad de polarización deuna molécula por el campoeléctrico[momento dipolar (μ) elevado

para definir la eficiencia del acoplamiento MO-molécula

se corresponde con valoresaltos de ε´] Factor de

disipación(t t δ)

Capacidad de un determinado materialpara convertir la energía electromagnética

(tangente δ) en calor a una determinada frecuencia ytemperatura

[tan δ = ε´´/ ε´]



¿ Como elegir el disolvente?

ETG, EtOH, DMSO, i-PrOH, HCO2H, 1.35

>0.5

2 BuOH DCB NMP AcOH

, , , , 2 ,MeOH, PhNO2, 1-BuOH

0.570.440.1-0.5

CHCl MeCN EtOAc MeCOMe

2-BuOH, DCB, NMP, AcOH, DMF, DCE, H2O, ClPh

0.1010.091<0.1CHCl3, MeCN, EtOAc, MeCOMe, THF, DCM, Tolueno, Hexano

0.020

Disolventes transparentes a MO: CCl4, C6H6, dioxano



Facile Microwave-Mediated Transformations of 2-Butene-1,4-diones and 2-Butyne-1,4-diones to Furan Derivatives

Disolventes en MO: PGE-200

to Furan Derivatives

H. Surya Prakash Rao* and S. JothilingamPoly(ethylene glycol) (PGE-200) was foundto be a suitable solvent for performing the to be a suitable solvent for performing the microwave mediated conversion....

• Reacción en erlenmeyer

Mi d d i

Se compara con EtOH, DEG, TEG, TETRAEG y PEG-400.

Ventajas:

• Microondas de cocina

• Barato

• Constante dieléctrica de 20

• Punto de ebullición superior a 250 °CPunto de ebullición superior a 250 C

• Se comporta como reactivo de transferencia de fase

• Miscible con aguaJ. Org. Chem. 2003, 68, 5392-5394


J. Org. Chem. 2003, 68, 5392 5394


Disolventes en MO: H2O

A T y P elevadas secomporta como undisolvente orgánico

Ambiente Estado próximo al critico

Estado supercritico

T ºC 25 275 400

P (bar) 1 60 230

ε´ 80 20 2

A T y P elevadas sehace más soluble endisolventes orgánicos

A T y P elevadas seincrementa laácidez y se reducela densidad ε 80 20 2

Kd 1 1000 <0.01

A T y P elevadasPENETRACION DE MO EN AGUA A T y P elevadasse transforma en un líquido apolar

PENETRACION DE MO EN AGUA• A 25 ºC: 1.4 cm• A 95º C: 5.7 cm• A –12 ºC: 11 mTeflon ((t.a.): 9.2 mCuarzo (t A ): 160 m


Cuarzo (t. A.): 160 m


Applications of High-Temperature Aqueous Media for Synthetic Organic Reactions


Preparative organic synthesis was investigated in aqueous media at temperatures upto 300 ºC. Experiments were conducted with a recently disclosed pressurized

h ( ) ll h l

Applications of High Temperature Aqueous Media for Synthetic Organic Reactions Jingyi An, Laurence Bagnell, Teresa Cablewski, Christopher R. Strauss,* and Robert W. Trainor

microwave batch reactor (MBR) or in conventionally heated autoclaves.

•Fischer synthesis•Intramolecular aldol condensation•Decarboxylation of indole-2-carboxylic acid,y y ,•Rupe rearrangement of 1-ethynyl-1-cyclohexanol,•Isomerization of carvone to carvacrol,•Conversion of phenylacetylene to acetophenone.

H O

Microwave batch reactor (MBR)•Multimodal•Control de presión•Control temperatura

NH

CO2HNH

H2OMW, 255 ºC, 20 min

100%

•Control temperatura

J Org Chem ;1997 62 2505 2511

The diversity of reactions indicates that high-temperature aqueous media could playan increasingly important role in the development of new preparative processes.


J. Org. Chem.;1997, 62, 2505-2511


Sceptrin as a Potential Biosynthetic Precursor to Complex Pyrrole-Imidazole Alkaloids:


OR

OR R1

The Total Synthesis of AgeliferinPhil S. Baran, Daniel P. O'Malley, Alexandros L. Zografos

R1

R1

NH

NH

R

R

NH

NH

R

R

NH

NH

R

NH2

H2O

MW, 195 ºC, 1 min

+

RO O

sceptrin ageliferin

40% (52% pp)

La reacción efectuada a 195 ºCsin MO produce descomposición

NH

Br

NH

NH

NH2R = R1 =

+

sin MO produce descomposicióny pp sin reaccionar

Angew. Chem. Int. Ed. 2004, 43, 2674-2677

INST: Biotage (formerly Personal Chemistry) “Emrys Creator” apparatus.



Ligand-Free Palladium Catalysis of the Suzuki Reaction in Water Using Microwave Heating

Disolventes en MO: H2Og y g g

Nicholas E. Leadbeater* and Maria Marco

Org. Lett., 2002, 4, 2973 -2976, INST: CEM Discover Synthesis UnitSistema monomodal (focalizado)

Microwave-Promoted Three-Component Coupling of Aldehyde, Alkyne, and Amine via C-H Activation Catalyzed by Copper in Water Lei Shi, Yong-Qiang Tu,* Min Wang, Fu-Min Zhang, and Chun-An Fan

Org. Lett., 2004, 6, 1001 -1003

INST: 700 W LG microwave oven (model WD 700 (MG 5082M)) t t tti f 40%


(MG-5082M)) set at a power setting of 40%.


Disolventes en MO: Líquidos iónicos• Sales orgánicas líquidas a temperatura ambiente• Mantienen el estado liquido en un amplio rango de

temperatura (300 ºC, de –96 ºC a 200 ºC)• No volatiles• Muy polares• Disuelven compuestos orgánicos e inorgánicos• Inmiscibles con disolventes orgánicos• Ventajas en “química verde”• Se acoplan de forma muy eficiente con MWSe acoplan de forma muy eficiente con MW

X

NNMe Et

X

NNMe Bu

X

NNMe C6H13

R

+

[emim][X]

+

[bmim][X]

+

[6-min][PF6]El mecanismo de transferencia de energía en el casode los líquidos iónicos es por conducción iónica

NNMe OH NNMe

CO H

N

R

R1

[ ][ ]

X = BF4, PF6, NO3, ClO4

[ ][ ]

X = BF4, PF6, AlCl4

+

[6 min][PF6]

+

+

[bp ][Cl]

de los líquidos iónicos es por conducción iónicacomo consecuencia de su carácter iónico (catión ycontraión).El campo eléctrico genera movimiento de los ionesal tratar de alinearse estos con el campo variableaplicado El aumento de temperatura que se produce

Ionic Liquids in Synthesis Ed P Wasserscheid y T Welton Wiley VCH: Weinheim 2003

X XCO2H

[hydemim][BF4] [capemim][BF4]

[bpy][Cl]

[pmpy][BF4]

aplicado. El aumento de temperatura que se producegenera a su vez aumento de conducción iónica.


Ionic Liquids in Synthesis, Ed. P. Wasserscheid y T. Welton. Wiley-VCH: Weinheim. 2003


Disolventes en MO: Líquidos iónicos

Rate accelerations of 1,3-dipolar cycloaddition reactions in ionic liquids

Joan Fraga Dubreuil, Jean Pierre Bazureau

The 1,3-dipolar cycloaddition reactions between imidates derived from diethyl aminomalonate and 2-ethoxybenzaldehyde as dipolarophile has been investigated in various air and moisture stable ionic liquids.Significant rate enhancements and improved yields at 70°C have been observed with [emim][BF4] and [emim][NfO]ionic liquids. The reactivity of dipolarophiles covalently grafted on the ionic liquids were also evaluated.


A polymer-supported thionating reagent

A new polymer-supported reagent for the conversion of carbonyls to thiocarbonyls has been developed and its usedemonstrated on a range of amides. Secondary or tertiary amides are converted cleanly and efficiently through to

Steven V. Ley, Andrew G. Leach and R. Ian Storer

the corresponding thioamides and primary amides are converted to the corresponding nitriles. The reactions can befacilitated by conventional heating. However, if microwave heating is used, in the presence of an ionic liquid,enhanced reaction rates are achieved.

J. Chem. Soc., Perkin Trans. 1, 2001, (4), 358 - 36




A Study of the Ionic Liquid Mediated Microwave Heating of Organic Solvents

The use of ionic liquids as aids for microwave heating of nonpolar solvents has been investigated. Weshow that hexane and toluene together with solvents such as THF and dioxane can be heated way aboveh l l d l ll f l d h ll h

A Study of the Ionic Liquid Mediated Microwave Heating of Organic SolventsNicholas E. Leadbeater* and Hanna M. Torenius

their boiling point in sealed vessels using a small quantity of an ionic liquid, thereby allowing them to beused as media for microwave assisted chemistry. Using the appropriate ionic liquid, the heating can beperformed with no contamination of the solvent. To show the applicability of the system, two testreactions have been successfully performed.

XMe

NNMe Me+

NNMeMe

Me

NMePF6

X

+

+

(5)

X

N

NNMe

X

+

+

X


J. Org. Chem. 2002, 67, 3145-3148INST: CEM Discover Synthesis Unit



A Study of the Ionic Liquid Mediated Microwave Heating of Organic SolventsA Study of the Ionic Liquid Mediated Microwave Heating of Organic SolventsNicholas E. Leadbeater* and Hanna M. Torenius

Temperatura alcanzada al irradiar a 200 W los disolventes indicados en presencia de los líquidos iónicos 1 y 2

MMe

NNMe Me+I

1

NNMeMe+

Br2

J. Org. Chem. 2002, 67, 3145-3148


g , ,



High-Speed Heck Reactions in Ionic Liquid with Controlled Microwave HeatingKarl S. A. Vallin, Per Emilsson, Mats Larhed,* and Anders Hallberg

Abstract:Palladium-catalyzed Heck arylations in the polar and robust ionic liquid, 1-butyl-3-methylimidazolium hexafluorophosphate (bmimPF6), have for the first time been accomplished under microwave irradiation. The couplings were efficiently performed in sealed tubes within 5-45 min of heating. The product was easily removed from the reaction medium by distillation.

X O

OBu

O

OBu+

PdCl2

b i PF6R

OBuR

bminPF6MW

5/54 min

J. Org. Chem., 2002, 67, 6243 -6246

INST: Smith Synthesizer Personal Chemistry AB



Microwave-Assisted Synthesis of Room-Temperature Ionic Liquid Precursor in Closed VesselBhushan M Khadilkar Geeta L Rebeiro


Bhushan M. Khadilkar, Geeta L. RebeiroWe report here the synthesis of various alkylpyridinium and 1-alkyl-3-methylimidazolium halides on a largescale under microwave irradiation, in a closed vessel. The reaction time was drastically reduced as compared toconventional methods, and good yields were obtained.

Org. Process Res. Dev. 2002, 6, 826 - 828

R1

N

R-X

MW N X

+

R

N

NNMe

N

Multimode microwave

Controlled, multimode microwave irradiation has been employed in a generic solvent-free process toprepare a wide range of ionic liquids based on nitrogen containing heterocycles The developed

Improved preparations of ionic liquids using microwave irradiationMaggel Deetlefs, Kenneth R. Seddon

prepare a wide range of ionic liquids based on nitrogen-containing heterocycles. The developedmethod offers a flexible, small to large-scale approach to prepare ionic liquids, in either sealed oropen vessels, in a faster and greener process than any previously described.

Green Chem., 2003, 181-186


, ,


Ionic liquids as reagents and solvents in conjunction with microwave heating: rapid synthesis of alkyl halides from alcohols and nitriles from aryl halides


We show that using ionic liquids as reagents inconjunction with microwave heating it is possible to

lk l h l d f h d

rapid synthesis of alkyl halides from alcohols and nitriles from aryl halidesNicholas E. Leadbeater, Hanna M. Torenius and Heather Tye

prepare primary alkyl halides from the correspondingalcohols rapidly. Using ionic liquids as solvents inconjunction with microwave heating it is possible toprepare aryl nitriles from the corresponding arylbromides or iodides. The scope and limitations of usingm p m f gmicrowave promotion as a tool in these reactions isdiscussed.

La reacción falla con alcoholes secundarios y terciarios

M

NNMeMe

Me

NNMe Me

+

+I 1X

R

CN

R

CuCN

MW

NNMe Bu

Br2

+Cl

R RX = Cl, Br, I 16-75%

INST: CEM Discovere Synthesis Unit


Tetrahedron, 2003,59, 2253-22583y


Reacciones en fase seca (dry media)

DISOLVENTEVOLATIL

REACTIVOSSOPORTEPOROSOPOROSO

AluminaSílica gelClayZeolitas...

Extraccióncon disolventecon disolvente

AISLAMIENTO


AISLAMIENTO



VENTAJAS INCONVENIENTES

• Facilidad experimental

N i i i i l

• Dificultades para medir la T

• Reproductibilidad

VENTAJAS INCONVENIENTES

• No requiere equipamiento especial

• Elevada reactividad en soportes porosos

A i d i i d l di l

• Reproductibilidad

• Problemas para el escalado

• Dificultades con líquidos• Ausencia de riesgos asociados al disolvente

• Procesos más limpios (?)

• Dificultades con líquidos

• Sobrecalentamientos



Reacciones en fase seca (dry media)Microwave Promoted Hydrolysis of Esters Absorbed on Alumina: A New Deprotection Method for Pivaloyl GroupsDeprotection Method for Pivaloyl GroupsSteven V. Ley, Donna M. Mynett

Rapid and efficient deprotection of pivaloyl and other esters can be achieved by absorption t l i d i i di tionto alumina and microwave irradiation.

OH OH OH

O

R1 O-R

O

R1 O-HOH

OH

Al2O3

MW1.5-30 min 61-97%

OOH

OMePivO

PivOPivO

Synlett, 1993, 793





Microwave assisted synthesis of heterocyclic fused quinones in dry mediaA. Acosta, P. de la Cruz, P. De Miguel, E. Diez-Barra, A. de la Hoz, F. Langa, A. Loupy, M. Majdoub, N. Martín, C. Sanchez and C. Seoane

Microwave assisted cyclization of several 2-thenoylbenzoic acids 2 catalysed with clays in dry media isstudied. Some clays were tested and Montmorillonite K-10 free of quarz and feldspar was shown to be anstudied. Some clays were tested and Montmorillonite K 10, free of quarz and feldspar, was shown to be aneffective catalyst for their easy conversion into the corresponding heterocyclic fused quinone in good yields.A specific effect of microwave irradiation accelerating the reaction with respect to conventional heating inthe same conditions is observed

O

OR1

Li 2

R1 CO2H

2

R1

S

O

+MW

Mont K10

OR3R2 S Li

SOR3

R2

R3R2 S

O

Mont K10

21-92%


• Reacción en erlenmeyer

• Microondas de cocina


, ,


Reacciones en fase seca (dry media)Microwave-assisted Suzuki coupling on a KF–alumina surface: synthesis of polyarylsBasudeb Basu, Pralay Das, Md. Mosharef H. Bhuiyan and Satadru Jha



Tetrahedron Letters, 2003, 44, 3817-3820



Magtrieve, MW, 2 minMicrowave-assisted oxidation of alcohols using Magtrieve™ Magtrieve, MW, 2 minD. Bogdal, M. Lukasiewicz, J. Pielichowski, A. Miciak and Sz. Bednarz

365 ºC

Magtrieve, tolueno, MW 2 min

Magtrievee es un oxidante comercializado por DuPont basado en dioxido de cromo (CrO2). MW, 2 min( 2)

La eficacia del proceso en MW comparado con la calefacciónconvencional está relacionada con las elevadas temperaturasque se alcanzan en el soporte en comparación con el mismomaterial irradiado en un disolvente

Figuras tomadas de Tetrahedron, 2003, 59, 649-653(D B d l t ) 140 ºC

INST: multimode microwave reactor (PLAZMATRONIKA)


(D. Bogdal, y otros) 140 ºC


Reacciones sin disolvente

1,3-Dipolar cycloaddition of imidate ylides on imino-alcohols: Synthesis of new imidazolones using solvent free conditionsJean Michel Lerestif, Jacques Perrocheau, François Tonnard, Jean Pierre Bazureau and Jack Hamelin

Imidates derived from α-amino esters as potential azomethine ylides, undergo 1,3-dipolar cycloaddition withimino-alcohols, in tautomeric equilibrium with 1,3-oxazolidines, without solvent at 70°C or under microwaveirradiation.


Tetrahedron, 1995, 51, 6757-6774


Tetrahedron, 1995, 51, 6757 6774


Reacciones sin disolvente (neat)

Synthesis of Pyrazolo[3,4-b]pyridines by Cycloaddition Reactions under Microwave IrradiationAngel Díaz-Ortiz, José. R. Carrillo, Fernando P. Cossío, María J. Gómez-Escalonilla, Antonio de la Hoz,* Andrés Moreno, Pilar Prieto

Microwave irradiation induces the cycloaddition of pyrazolylimines with aromatic and aliphatic nitroalkenes to afford pyrazolo[3,4-b]pyridines in 5–20 min. Some of these reactions do not occur under classical heating.

INST foc sed micro a e reactor (Prolabo MX350)

32-53%

Tetrahedron 2000, 56, 1569–1577

INST: focused microwave reactor (Prolabo MX350)


, ,


Reacciones sin disolvente (neat)Three component condensations catalyzed by iodine–alumina for the synthesis of substituted 3 4 dihydropyrimidin 2(1H) ones under microwave irradiation and solvent free conditions3,4-dihydropyrimidin-2(1H)-ones under microwave irradiation and solvent-free conditionsIra Saxena, Dilip C. Borah and Jadab C. Sarma

Condensation of an aldehyde, ethyl acetoacetated thi d i i di tiand urea or thiourea under microwave irradiation

in the presence of 10% iodine adsorbed onneutral alumina gives substituted 3,4-dihydropyrimidin-2(1H)-ones in excellent yields.

INST: focus microwave reactor (PROLABO)

Tetrahedron Letters, 2005, 46,, 1159-1160



Reacciones en medios bifásicos

CATALISIS DE TRANSFERENCIA DE FASE EN CATALISIS DE TRANSFERENCIA DE FASE EN MEDIO SÓLIDO-LIQUIDO SIN DISOLVENTE

M+, Nu- + R4N+, X- R4N+, Nu- + M+X-Solid phase

R N R N+ X R N+ N R XLiquid organic R-Nu + R 4N+, X- R4N+, Nu- + R-XLiquid organicphase



Reacciones en medios bifásicos (PTC)Coupling focused microwaves and solvent-free phase transfer catalysis: Application to the synthesis of new furanic dietherssynthesis of new furanic diethers Mustapha Majdoub, André Loupy, Alain Petit, Sadok Roudesli

A new family of furanic ethers was obtained by alkylation of 2,5-furandimethanol or furfuryl alcohol undermicrowave in phase transfer catalysis (PTC) conditions in the absence of solvent. Products were synthesized in good

ld ( %) h l d l d d h h lyields (> 80 %) within 10 min or less. Compounds were analysed by NMR, mass spectrometry and their thermalbehaviours were studied by DSC. When compared to conventional heating, everything equal elsewhere, reactiontimes were improved under microwave conditions at a restitute power of 30 Watts when performed under stirring

INST: monomode reactor (Synthewave 402 Prolabo).

Tetrahedron, 1996, 52, 617-628

INST: monomode reactor (Synthewave 402 Prolabo).



Reacciones en medios bifásicos (PTC)Microwave-Assisted Preparation of Benzo[b]furans under Solventless Phase-Transfer Catalytic ConditionsDariusz Bogdal, Marek Warzala

Condensation of salicylaldehyde and its derivatives with various esters of chloroacetic acids in thepresence of tetrabutylammoniumbromide (TBAB) leads to the synthesis of benzo[b]furans by a solventlessphase-transfer catalytic (PTC) reaction under microwave irradiation.p y

65-96%

Tetrahedron 2000, 56, 8769-8773 INST: Microondas de cocina



Reacciones en medios bifásicos (PTC)Selective and efficient fluorination of chlorodiazines under solvent-free phase transfer catalysisSylvain Marque, Hanane Snoussi, André Loupy, Nelly Plé and Alain Turcky q , , py, y

3-Chloro-6-phenylpyridazine, 2,3-dichloroquinoxaline and 1,4-dichlorophthalazine were reacted with KF under solvent-free conditions in the presence of a phase transfer agent, with or without microwave irradiation. The chlorine–fluorine exchanges were obtained with enhanced yields and selectivities when compared with previous methods.

Inst: monomode reactor Synthewave 402 (S 402) (Prolabo)

Journal of Fluorine Chemistry 2004 125 1847 1851


Journal of Fluorine Chemistry, 2004, 125, 1847-1851


Reacciones en medios bifásicos (cat. heterogénea)Microwave accelerated, Ni/C-catalyzed cross-couplings of in situ-derived zirconocenesBruce H. Lipshutz and Bryan Friemanp y

Both vinyl and alkyl zirconocenes undergo rapid couplings with aryl halides under heterogeneous conditions in a microwave reactor using Ni/C as catalyst. Ligand variations both in type and stoichiometry play major roles in the extent of conversion

INST: Emrys Optimizer in 2–5 mL pyrex reaction vessels

Tetrahedron, 2004, 60, 1309-1316



Síntesis en fase sólidaEnhanced coupling efficiency in solid-phase peptide synthesis by microwave irradiationH i Ming Y Sh i Tein Chen K ng Ts ng Wang;Hui Ming Yu, Shui Tein Chen, Kung Tsung Wang; J. Org. Chem. 1992, 57, 4781-4784

....We describe here a novel application of microwave technology to enhance coupling efficiency in solid-phasepeptide synthesis. A significant improvement of the coupling efficiency (a rate increase of at least 2-4-fold),especially in side-chain-hindered amino acids was obtained in the studyespecially in side-chain-hindered amino acids, was obtained in the study. ...

......The custom-made solid-phase reaction vessel was placed in the middle of the microwave oven, and a Teflontube from the side arm of the reaction vessel was connected to a nitrogen source to introduce a stream ofnitrogen. The Fmoc-protected amino acids with two different coupling methods, symmetric anhydride and pre-formed N-hydroxybenzotriazole active eater (HOBt), were used in the synthesis......formed N hydroxybenzotriazole active eater (HOBt), were used in the synthesis......

Mi i t d ll di t l d li f l d h t l b i id ith

Rapid microwave-assisted Suzuki coupling on solid-phaseMats Larhed, Gunnar Lindeberg and Anders Hallberg

Microwave-assisted palladium-catalysed coupling of aryl and heteroaryl boronic acids with iodo- and bromo-substituted benzoic acids, anchored to TentaGel S RAM, provided high isolated yields of coupled products after a reaction time of 3.8 minutes (45 W).

Tetrahedron Lett 1996 37 8219 8222INST: Micro Well 10 single monomode, Labwell AB


Tetrahedron Lett. 1996, 37, 8219-8222g ,


Síntesis en fase sólidaOut of the oil bath and into the oven microwave-assisted combinatorialchemistry h

The application of microwave irradiation to expedite solid-phase organic reactions could be the tool thatallows combinatorial chemistry to deliver on its promise—providing rapid access to large collections of

heats upHelen E. Blackwell

allows combinatorial chemistry to deliver on its promise providing rapid access to large collections ofdiverse small molecules. Herein, several different approaches to microwave (MW)-assisted solid-phasereactions and library synthesis are introduced, including the use of solid-supported reagents,multicomponent coupling reactions, solvent-free parallel library synthesis, and spatially addressable librarysynthesis on planar solid supports. The future impact of MW-assisted organic reactions on solid-phase andcombinatorial chemistry could prove to be immense and methods for further improvement of this strategiccombinatorial chemistry could prove to be immense, and methods for further improvement of this strategiccombination of technologies are highlighted

Org. Biomol. Chem., 2003, 1251-1255



Síntesis en fase sólidaReacción de Ugi-4CC en un reactor monomodo empleando

i l d li (T G l) iaminas ancladas a un polimero (TentaGel) y variosaldehídos, ácidos carboxílicos e isonitrilos para generaruna librería de 18 acilamino amidas en 5 min porcompuesto. A. M. L. Hoel and J. Nielson, Tetrahedron Lett.,1999, 40, 3941–3944, ,

Ley emplea microondas en reacciones en los que losreactivos están anclados a polímeros En un caso empleaun reactivo de tionación y en otro un reactivo para la

INST: Monomodal Microwell 10 (Labwell AB)

un reactivo de tionación y en otro un reactivo para laconversión de isotiocianatos en isonitrilos. Emplea unreactor multimodal en tiempoos muy cortos frente alsistema tradicional (15–150 min vs. 30 h). S. V. Ley, A.G. Leach and R. I. Storer, J. Chem. Soc., Perkin Trans. 1,2001 358 361 S V L d S J T l Bi M d2001, 358–361 S. V. Ley and S. J. Taylor, Bioorg. Med.Chem. Lett., 2002, 12, 1813–1816

INST: Personal Chemistry ‘Smith Synthesizermultimode



Síntesis en fase sólida

R id Mi A i t d S lid Ph Gl tid S th i

Coupling of glycosylated Fmoc-Thr or Fmoc-Ser with N-terminal amino acids on a resin proceeded

Rapid Microwave-Assisted Solid-Phase Glycopeptide SynthesisTakahiko Matsushita, Hiroshi Hinou, Masaki Kurogochi, Hiroki Shimizu, and Shin-Ichiro Nishimura

p g g y y psmoothly under microwave irradiation for 20 min with much higher efficiency (98% yield percoupling) than found in more general conditions. Compared with a conventional protocol, the presentmethod greatly reduces the time required for solid-phase glycopeptide synthesis from 4 days to 7h, as is the case with the synthesis of Muc-1-related 20-residue glycopeptide carrying five core-2trisaccharide chainstrisaccharide chains

Org. Lett.; 2005, 7(5); 877-880



Escalado y sistemas de flujo continuoPreparative Scale Organic Synthesis using a Kitchen Microwave OvenS-T Chen, S-H Chiou, K-T WangJ. Chem. Soc. Chem. Comm. 1999, 807

• Esterificación de ácido p-hidroxibenzoico• Racemización de isoleucina en AcOH• Hidrólisis de sucrosa y fructosa• Hidrólisis de sucrosa y fructosa• Reacción SN2 de fenoxido y cloruro de bencilo



Escalado de reacciones y sistemas de flujo continuoDevelopment and Application of a Continuous Microwave Reactor for Organic SynthesisTeresa Cable ski Alan F Fa Christopher R Stra ss;

A laboratory-scale continuous microwave reactor (CMR) has been developed and used to conduct organic synthesesroutinely, rapidly, and safely in a range of solvents, under pressures up to 1400 kPa and at temperatures up to 200 OC.Advantages and applications of the CMR are discussed along with the rationale for the design Reactions carried out

Teresa Cablewski, Alan F. Faux, Christopher R. Strauss;

Advantages and applications of the CMR are discussed, along with the rationale for the design. Reactions carried outwith the CMR included nucleophilic substitution, addition, esterification, transesterification, acetalization, amidation,base- and acidcatalyzed hydrolysis, isomerization, decarboxylation, and elimination. Name reactions included theMichael addition, Hofmann degradation, Williamson ether synthesis, and the Mannich, Finkelstein, Baylis-Hillman,and Knoevenagel reactions.

1, Reaction mixture; 2, pump; 3,pressure sensor; 4, microwave cavity; 5,

ti il 6 t t 7reaction coil; 6, temperature sensor; 7,heat exchanger; 8, pressure control valve;9, electronic key pad and display; 10,product mixture.

J. Org. Chem. 1994, 59, 3408-3412.



Escalado de reacciones y sistemas de flujo continuoContinuous Flow, Circulating Microwave System and Its Application in Nanoparticle Fabrication and Biodiesel Synthesis

The current research is an attempt to combine reactions in a domestic microwave oven (DMO) with a circulating pump in order to create a continuous circulating flow microwave system. This system allows the reagents and products to circulate in

Y. Groisman, A. Gedanken, J. Phys. Chem. C 2008, 112, 8802–8808

and out of the microwave reactor until the end of the synthesis. In fact, this is the first attempt of its kind to build a continuous flow microwave system for production of nanosized particles.The continuous DMO system has several advantages over batch microwave ovens, such as its ability to work with large quantities of reagents, the possibility to withdraw samples of the product without stopping the process, and the constant stirring of the reagents during the reaction. Various nanoparticles with different particle sizes were prepared. Another reaction g g g p p p pthat was tested in this study was the synthesis of biodiesel. Complete conversion of commercially available vegetable oils to fatty-acid esters and glycerol was accomplished in the newly designed system.

(1) reagent vessel(1) reagent vessel, (2) tubing, (3) circulating pump, (4) reactor vessel, (5) microwave oven, (6) thermometer cell, (7) faucet cell, (8) reflux column,(9) brass choke, (10) heating/stirring plate.


( ) g g p


Síntesis en paraleloMicrowave assisted combinatorial chemistry synthesis of substituted pyridinesy y pyIan C. Cotterill, Alexander Ya. Usyatinsky, John M. Arnold, Douglas S. Clark, Jonathan S. Dordick, Peter C. Michels and Yuri L. Khmelnitsky

A new highly efficient MICROCOS technology(Microwave-assisted Combinatorial Synthesis) forgenerating combinatorial libraries is described. Thetechnology is applied to the high throughput, automated,one-step, parallel synthesis of diverse substitutedone step, parallel synthesis of diverse substitutedpyridines using the Hantzsch synthesis. The advantagesof microwave-assisted chemistry for combinatorialsynthesis include a broad range of available chemistries,simple reaction setup and product recovery readilyamenable to automation extremely short reaction timesamenable to automation, extremely short reaction times,and high product yields.

INST: Horno de cocina

Tetrahedron Lett., 1998, 39, 1117-1120



Irradiación-enfriamientoRapid synthesis of α-ketoamides using microwave irradiation–simultaneous cooling methodJack J. Chen Seema V.Tetrahedron Lett., 2003, 44, 8873-8876

this is the first reported instance that.......this is the first reported instance thatdemonstrated the practical benefits of microwaveirradiation–simultaneous cooling method apart from fewscarce mentions........

INST: Discovery microwave synthesizer with spontaneous air-cooling.



Irradiación-enfriamiento

E h d Mi S th i (EMS)Enhanced Microwave Synthesis (EMS)• Se enfría externamente la reacción con aire a presión mientras se irradia

• Se consigue suministrar un mayor nivel de energía a la reacción

• No se hace necesario suprimir la irradiación cuando se alcanza la temperatura deseadatemperatura deseada

• Se puede mantener un nivel constante de irradiación durante tiempo prolongados

B. L. Hayes, Recent Advances in Microwave assited Synthesis,Aldrichimica Acta, 2004, 37, 66-76



Irradiación-enfriamientoSolid-Supported Cyclohexane-1,3-dione (CHD): A "Capture and Release" Reagent for the Synthesis

A three-step synthesis of cyclohexane-1,3-dione (CHD) resin on polystyrene resin is described. Resin wasused to prepare an amide library of high purity by microwave-assisted serial "capture and release" and can be

l d f h h l d l h ll l l

of Amides and Novel Scavenger ResinCara E. Humphrey, Morag A. M. Easson, Jason P. Tierney, and Nicholas J. Turner

recycled for this purpose. High-loading CHD resin was also shown to scavenge allyl cations in solution.

INST: CEM Discover Microwave Synthesiser with Explorer Carousel.

14/06/2011 Juan José Vaquero 83Org. Lett, 2003, 5, 849 - 852


Irradiación-enfriamiento

1 3-Dipolar cycloadditions of organic azides to ester or benzotriazolylcarbonyl1,3 Dipolar cycloadditions of organic azides to ester or benzotriazolylcarbonyl activated acetylenic amidesAlan R. Katritzky,* Yuming Zhang, Sandeep K. Singh, Peter J. Steelb

INST: Microwave heating was carried out with a single modecavity Discover Microwave Synthesizer (CEM Corporation,NC, USA), producing continuous irradiation at 2455 MHzand equipped with simultaneous external air-cooling

ARKIVOC, 2003 (xv) 47-64


a d equ pped t s u ta eous e te a a coo gsystem.


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