Nuevas metodologías en síntesis orgánica y sus aplicaciones · Nuevas metodologías en síntesis...
Transcript of Nuevas metodologías en síntesis orgánica y sus aplicaciones · Nuevas metodologías en síntesis...
Nuevas metodologías en síntesis orgánica y
sus aplicacionesDr. W. Porcal, Dra. G.V. López
Grupo de Química Medicinal, Facultad de Ciencias; Departamento de Química Orgánica, Facultad de Química,
UdelaR, Montevideo, Uruguay
IntroductionR. Gedye, F. Smith, K.
Westaway, H. Ali, L. Baldisera, L. Laberge, J. Rousell (1986) The use of microwave ovens for
rapid organic synthesis. Tetrahedron Lett. 27(3):279-282.
R.J. Giguere, T.L. Bray, S.M. Duncan, G. Majetich (1986) Application of commercial microwave ovens to organic synthesis. Tetrahedron Lett.
27(41):4945-4948.
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Microwave furnaces consist of three major components: the source, the transmission lines, and the applicator. The microwave source generates the electromagnetic radiation, and the transmission lines deliver the electromagnetic energy from the source to the applicator. In the applicator, the energy is either absorbed or reflected by the material.
Equipment
Thostenson E.T., Chou T.-W. Composites: Part A 1999, 30:1055-71
Generation of electromagnetic radiation results from the acceleration of charge. To achieve the high power and frequencies required for microwave heating, most microwave sources are vacuum tubes. Some vacuum tubes that have been used for microwave heating include magnetrons, traveling wave tubes (TWTs), and klystrons.
Microwave sources
MagnetronsDeveloped by the end of the 30s, the magnetron is a device that converts electrical energy into electromagnetic energy to microwave form.
Traveling wave tubes (TWTs)For variable frequency microwaves, high power traveling wave tubes are used as the microwave source. The TWT consists of two main components: the electron gun and the helical transmission line.
Transmission lines
The transmission lines couple the energy of the microwavesource to the applicator. Waveguides are often the transmission line of choice in microwave heating systems. Waveguides are hollow tubes in which the electromagnetic waves propagate.The most commonly used cross-sections are rectangular.Two modes of microwave propagation are possible in waveguides: transverse electric (TE) and transverse magnetic (TM).
In addition to waveguides, there are several other transmission line components that are used for equipment protection, sensing purposes, and coupling microwaves with the material in the applicator: circulators, directional couplers, tuners.
Applicators
Commercially available single mode, multi-mode, and variable frequency multi-mode processing systems are all used for microwave processing research, and each of these systems has advantages and disadvantages.
The size of single mode applicators is of the order of approximately one wavelength, and to maintain the resonant mode, these cavities require a microwave source that has little variation in the frequency output.
Single mode applicators
Single mode applicators have nonuniform, but predictable, electromagnetic field distributions.In general, single mode cavities have one ‘‘hot spot’’ where the microwave field strength is high.Through proper design, single mode applicators can be used to focus the microwave field at a given location.
Multi-mode applicators
It is used in home microwave ovens. The design of multi-mode applicators are often based on trial and error, experience, and intuition.As the size of the microwave cavity increases, the number of possible resonant modes also increase. Consequently, multi-mode applicators are usually much larger than one wavelength. The presence of different modes results in multiple hotspots within the microwave cavity. Like single mode cavities, local fluctuations in the electromagnetic field result in localized overheating.
Uniformity: turntables, mode stirrers (reflectors)
Perreux, L et al Tetrahedron 2001, 57:9199-9223; Lidström, P. et al Tetrahedron 2001, 57:9225-83.
water
dioxane
Two major mechanisms: Dipolar polarization mechanismConduction mechanism
Dipolar polarization mechanism: Molecules having permanent or induced dipoles align with the electric field of the radiation. At 2450 MHz the field oscillates 4.9x109 times a second and dipolar molecules try to follow. If rotation is delayed molecules absorb electromagnetic field energy dissipated as heat.
Conduction mechanism: This mechanism is due to the migration of dissolved ions under the influence of an oscillating electric field.
water
Destilled water
Polar solvents and/or ions are needed for MW heating
acetone= 20.6ethanol= 24.6
ethanol
acetone
How does the MW heating effect differ for different solvents?
'
"tan
That is, the tendency of a sample to be heated with microwaves is highly dependent on dielectric properties: the higher the value of the dissipation factor, tan , the greater the susceptibility to microwaves.
where: ε” represents the loss factor and ε’ is equal to the dielectric constant under the influence of a static electric field.
The energy is transferred to the materials by interaction of the electromagnetic field at the molecular level, and the dielectric properties determine the final effect of the electromagnetic field in the material.
The dielectric properties of materials in combination with the applied electromagnetic fields results in the conversion of electromagnetic energy to heat. As energy is absorbed within the material, the electric field decreases as a function of the distance from the surface of the material. If the depth of penetration of the microwaves is much less than the thickness of the material only the surface is heated. The rest of the sample is heated through conduction.
2"2 EfP "2
0
f
cd
If the electric field is assumed to be uniform:
P is power. d is penetration depth
Materials with a high conductance and low capacitance (like metals) have high dielectric loss factors (ε”) d ~ 0 REFLECTORSMaterials with low dielectric loss factors have very large penetration depth very little of the energy is absorbed in the material TRANSPARENT. Microwaves transfer energy most effectively to materials that have dielectric loss factors in the middle of the conductivity range.
...the sample must contain dipoles or ionic species to allow the heating to occur. ... can be said that compounds with large dielectric constants tend to be rapidly heated with a microwave, while slightly polar or non polar substances and highly ordered crystalline compounds poorly absorbed.
In brief....
The inherent advantages of this method can be summarized as:
- Radiation is absorbed directly by the reagents - Solid supports which absorb radiation but are thermally insulating can be used. - Can be coupled with other synthesis techniques - No solvent is used (with all that entails) - The isolation and purification steps are simplified - Solid supports are recyclable - Easy Scale-up (no solvent)
MW effects on the reactions
Acceleration of reactions by microwave exposure results from material-
microwave interactions by: thermal effects
nonthermal effects
Thermal effects
Boiling point of polar solvents commonly used:
Overheating effectObserved in multi-mode systems in the absence of agitation
Solvent Normal conditions Exposure to MW Difference H2O 100 105 5
1-Butanol 117 138 21 2-Butanol 98 127 29 Methanol 65 84 19
1-Pentanol 136 157 21 1-Heptanol 176 208 32
Acetone 56 89 33 Ethyl acetate 77 102 25
THF 67 103 36 Acetonitrile 82 120 38
Boiling points (ºC) of some polar solvents under the influence of MW in the absence or in the presence of boiling chips:
The effect of overheating is clearly related to the effect of the agitation and the presence of nucleation regulators. It is also related to the MW power. This effect is expected to disappear with good agitation and low power. Prevails in the absence of stirring.
Solvent b.p. Exposure to MW
Multi-mode Single mode
(100W) Single mode + boiling chips
H2O 100 105 100 100 1-Heptanol 176 208 180 173 Ethyl acetate 77 102 92 77 Chloroform 61 89 85 62
Cyclohexanone 155 186 168 155
Effect of the addition of ionic liquids on the temperature increment of dioxane at 300W power.
Dioxane
Dioxane +
2% 1-butyl-3-methylimidazolium hexafluorophosphate
Susceptors
Hot spots
Intervention of localized microscopic high temperatures ("hot
spots") generated by the dielectric relaxation at the molecular
level.
de la Hoz, A. et al Chem. Soc. Rev. 2005, 34:164-78; Zhang X. et al Chem. Commun. 1999, 975.
Nonthermal effects
)/( RTGAek
☺ Increase of pre-exponential factor A☺ Decrease of activation energy (G≠)
Increase of pre-exponential factor A
Microwave synthesis of titanium carbide:
TiO2 + 3C → TiC + 2CO(g)
Authors concluded that molecular mobility can increase in thepresence of a microwave field and that in this case it is the Arrhenius pre-exponential factor A that changes and not the energy of activation. An increase by a factor of 3.3 in the Arrhenius preexponentialfactor could explain the acceleration in reactionrate obtained with microwaves.
Binner, J.G.P.; Hassine, N.A.; Cross, T.E. The possible role of the pre-exponential factor in explaining the increased reaction rates observed during the microwave synthesis of titanium carbide J. Mater. Sci. 1995, 30, 5389-5393.
Decrease of activation energy (G≠)
STHGIncrease in MW assisted
reactions, more organized than conventional heating.
Reaction medium effects☺Polar solvents: protics (alcohols) and aprotics
(DMF, CH3CN, DMSO)Influence of MW on the rate of the reaction of propan-1-ol with ethanoic acid or propan-2-ol with 2,4,6-trimethylbenzoic acid.
Pollington, S.D. et al J.Org.Chem 1991, 56, 1313; Raner, KD. et al J.Org.Chem. 1992, 57, 6231
☺Nonpolar solvents (xylene, toluene, CCl4, hydrocarbons)
Berlan, J.; et al Tetrahedron Lett. 1991, 32, 2363-6.
☺Without solvent
The absorption of the microwave radiation would be limited only to the reactive species. The possibility of specific effects will be optimal from the time you will not be modulated or prevented by the solvents. They may be carried out according to three methods:
☺Reactions between reagents in quasi-equivalent amounts, requiring at least one in liquid phase in heterogeneus medium being the reaction in the interface; ☺Conditions of solid-liquid phase catalysis, in the case of anionic reactions using liquid electrophile as reactant as well as organic phase and a catalytic amount of tetraalkyl ammonium salts as transfer agent and☺Reactions using reagents adsorbed on solid mineral supports (aluminas, silicas, clays) in anhydrous medium.
“Acid” supports: Molecular sieves (3Å, 4Å, 5Å, 13X), sílice(SiO2), activated or calcined alumina(Al2O3), ion-exchange resins (amberlite: 15, 16, IR120, IRC50 y CG-50), natural clays such as montmorillonite: K-10 y KSF, synthetic ones (Clay-Hg, Claysil, Clayzin y NiCl2-K10) and chlorides of iron or zinc supported on silica gel, acids on molecular sieves and superacid solid of sulfates achieved by treating silica with sulfuric acid . “Alkaline” supports:: Hyflo Super Cel (pH= 8,5-9), zeolita(Na+)(pH=9-10), basic alumina, ion-exchange resins (amberlite: A21, A26, A27, IRA68, CG420), Florisil (pH= 8,5-9), salts supported on alumina (KF, t-BuOK, KOH, K2CO3), salts supportes on silica (NBu4F).“Neutral” mineral supports: sands, celite.
D. Bogdal, et al Tetrahedron, 2003, 59:649; M. Lukasiewicz, et al Adv. Synth. Catal. 2003, 345:1269.
The effect of MW is also related to the nature of the reactions (ionic or nonionic), the type of reactants, the transition state (polar or nonpolar), and also with the experimental conditions. Also we saw that depends on the presence/absence of solvent.
Effects according to reaction mechanisms
Relative stability of a polar TS when compared with GS (polar mechanism)
Perreux, L et al Tetrahedron 2001, 57:9199-9223.
Effect according to TS position along the reaction coordinate
(a)Small G early TS small change in the polarity TS/GS weak specific MW effect;
(b)Large G late TS major change in the polarity TS/GS significant MW effect.
In conclusion, "systems that react slower tend to show a more important MW effect that those who react faster".
Isopolar transition state reactions
P N3O
OEt
EtO
+ R1 R2
P NO
OEt
EtON
N
R1(R2)R2(R1)
Cycloaddition of azidomethyldiethylphosphonate with acetylenes and enamines leading to alkyltriazoles without solvent:
Bimolecular reactions between neutral reactants to charged products
Typical reactions are amine or phosphine alkylation or addition to a carbonyl group:
Synthesis of phosphonium salts Nucleophilic substitutions of benzyl chloride as electrophile with Ph3P as nucleophile carried out with accurate control of the power and temperature using a monomode reactor.
Anionic bimolecular reactions involving neutral electrophiles These reactions comprise nucleophilic SN2 substitutions, −elimination and nucleophilic additions to carbonyl compounds or activated double bonds, etc.
Specific MW effects connected to polarity enhancement should depend on the structure of reactive ion pairs in the GS if: a) tight ion pairs (between two hard ions); b) loose ion pairs (between soft ions).
Pearson Theory Hard Soft Acid Base (HSAB) Theory
Soft Base: donor atom is of high polarizability, low electronegativity, easily oxidized, and associated with empty, low-lying orbitals;Hard Base: donor atom is of low polarizability, high electronegativity, hard to oxidize, and associated with empty orbitals of high energy and hence inaccessible;Soft Acid: the acceptor atom is of low positive charge, large size, and has several easily excited outer electrons;Hard Acid: acceptor atom is of high positive charge, small size, and does not have easily excited outer electrons.
Anionic SN2 reactions involving charge localized anions. In this case, the anion being hard and with a high charge density, the reactions are concerned with tight ion pairs. During the course of the reaction, ionic dissociatin is increased and hence polarity is enhanced from the GS towards the TS. Specific MW effects should be expected.
Ejemplo: Reacción de Krapcho.
Anionic SN2 reactions involving charge delocalized anions. Weak or non-existent MW effects are expected for these reactions as the GS and TS exhibit rather similar polarities since they both involve loose ion pairs.
Alkylation of potassium benzoate.
Unimolecular reactions
When ionization (SN1 o E1) or intramolecular addition (cyclisations) processes are concerned, a MW effect could be viewed as resulting from a polarity increase from GS to TS due to development of dipolar intermediates.
Effects on selectivities When competitive reactions are involved, the GS is common for both processes. The mechanism occurring via the more polar TS could therefore be favoured under MW radiation:
The more polar TS1 is more stabilized by dipole-dipole interactions with the electric field and therefore more prone to MW effects.
Concerning the absence of MW effects
The absence of a MW effect can result from at least three different origins:
1.Similar polarity of TS when compared to the GS. 2.Very early TS along the reaction coordinates which
cannot allow the development of polarity between the GS and TS (reactant-like).
3.Too high temperature level, which may produce good yields in short reaction times under conventional heating.