DABCO solvent effects

The Bayhs-Hillman reaction of optically pure azetidine-2,3-diones [235, 236] with methyl vinyl ketone in the presence of l,4-diazabicyclo[2.2.2]octane (DABCO) in acetonitrile at -20°C for 1 h have been reported to give functionalized allylic alcohols, having the p-lactam scaffold, in good yields (80%) and complete diastereoselectivity [237]. In terms of achieving good yields with a reasonable rate of reaction, 50 mol% of DABCO seemed to be the catalyst amount of choice for this reaction. No significant solvent effect was observed in the overall yield (Scheme 108). 

The role of solvent effects in quaternization is one of the first physical organic studies and this is due to Menschutkin (1879LA334). It shows an increase in relative rate from 1 to 742 on going from benzene to benzyl alcohol, which suggests no simple explanation. Typical ranges of solvent-dependent rate ratios are 15,700/1 (nitromethane/cyclohexane) in the alkylation of triethylamine by methyl iodide (68BSF2678), 1660/1 [dimethylsulfoxide (DMSO)/carbon tetrachloride] in the reaction of l,4-diazabicyclo[2,2,2]-octane (DABCO) (5) with (2-bromoethyl)benzene (75JA7433) (Scheme 5),... 

Second, the most repeatedly determined value of kq Is that of l,4-dlazablcyclo(2.2.2)octane (, DABCO). In 1968, Ouannes and Wilson (145) discovered that 2, is a powerful Inhibitor of I02 reactions In solution and then demonstrated that It also quenches IO2 In the gas phase. In contrast to jS, does not react chemically with i02, either In gas phase or In solution [kq > 100 X kf (82)]. Structural reasons for this behavior will be explained later. The published values of kq (DABCO) are scattered and show no evident solvent effect. Formerly, very small solvent effects were reported, though with limited amount of data (68, 72, 146). 

The solvent and temperature effects for the Michael addition of amidoxime 7 to DMAD were probed because the reaction itself occurs without any other catalysts. As shown in Table 6.2, the reaction gave a high ratio of 8E in strongly aprotic polar solvents such as DMF and DMSO (entry 1 and 2). 8E was also found as the major product in MeCN (entry 3), dichloromethane (entry 4), and xylenes (entry 5). To our delight, the desired 8Z was obtained as the major component in methanol (entry 6). The stereoselectivity of 8Z versus 8E was better at low temperature (entry 7). A similar result was observed when the reaction was run in THF or dichlo-roethane in the presence of a catalytic amount of DABCO (entries 9 and 10). 

Enantioselective hydrogenation of 2,3-butanedione and 3,4-hexanedione has been studied over cinchonidine - Pt/Al203 catalyst system in the presence or absence of achiral tertiary amines (quinuclidine, DABCO) using solvents such as toluene and ethanol. Kinetic results confirmed that (i) added achiral tertiary amines increase both the reaction rate and the enantioselectivity, (ii) both substrates have a strong poisoning effect, (iii) an accurate purification of the substrates is needed to get adequate kinetic data. The observed poisoning effect is attributed to the oligomers formed from diketones. 

In a different study, based on the reaction rate data collected in aprotic solvents, the Morita-Baylis-Hillman reaction has been found to be second order in aldehyde and first order in DABCO and acrylate. On the basis of these data, a new mechanism has been proposed, involving a hemiacetal intermediate (110). The proposed mechanism is further supported by two different kinetic isotope effect experiments.145... 

Separation of relatively pure para-cresol from mixed cresols using an organic solvent and thereafter formation of a solid crystalline complex with the solvent has been reported. Piperazine and DABCO (diazabicyclo-octane) have been found to be very effective as extracting agents in this process of separation. There is very little effect of m-cresol in this process. The values of separation factor approach infinity as 100% p-cresol-base complex is crystallized. The yield of p-cresol was impressive with some aliphatic polar solvents, but... 

The conclusion that most amine quenching occurs at the pre-equilibrium limit and therefore rate constants will depend, in part, on the equilibrium constant for exciplex formation, which in turn depends on the amine electron-donating ability, raises the possibility of an alternative mechanism. Here formation of the exciplex would simply facilitate the electronic to vibrational energy transfer discussed for solvent quenching where kA (cf. Eq. (21)) replaces fcisc in Eq. (34). This would be much more effective than solvent quenching where interaction simply involves encounter complexation. That such a mechanism does not operate is demonstrated in Figure 6 which shows a plot [82] of the first-order constant for decay of 02( Ag) luminescence in benzene as a function of DABCO and DABCO-2HI2 [83], There is clearly no isotope effect and the mechanism of Eq. (31) appears very firmly established. A similar conclusion has been drawn from recent work [84] which shows that, as expected, hydrazines also quench 02(1Ag) via the same mechanism. The hydrazine 4 is a particularly efficient quencher with kq values in benzene and acetonitrile about twice those of strychnine. 

A related reaction known as Baylis-Hillman reaction, which also has a large negative activation volume, was found to be greatly accelerated in water, compared with usual organic solvents. The first step is the conjugate addition of a tertiary amine (l,4-diazabicyclo[2.2.2]octane DABCO) to acrylonitrile (Scheme 2) which is fast in water. The second step, which is rate-determining, is accelerated via a process wherein the hydrophobic effect could be involved. Other structured solvents also enhance the Baylis-Hillman reaction, but to a small extent [75]. 

In some cases such reactions have been reported not to be effective with commercial sodium amide. The use of NaNH2 with l,4-diazabicyclo[2.2.2]octane (DABCO) increases the activity of commercially available NaNH2 avoiding the preparation of this reagent in liquid ammonia followed by evaporation of this solvent (ref. 109). 

Azirines. Azirines (2) are formed from vinyl azides (1) when the azides are refluxed in toluene in the presence of a tertiary amine. DABCO is particularly effective N,N-diethylaniline is the least effective amine. Yields are higher than those obtained by thermolysis in aprotic solvents. 

A comparative study has been made of DMAP, DABCO and imidazole as catalysts in the MBH reaction of methyl acrylate or acrylonitrile with aromatic aldehydes (Scheme 2.47). Using neat activated alkenes, where there is no hydrogen bonding or additives effects, DMAP and DABCO present similar catalytic activity at 76 °C in the reaction with i-nitrobenzaldehyde, and DMAP could be an option for DABCO. On the other hand, DABCO is better than DMAP when less reactive electrophiles are used. Imidazole, which exhibits catalytic activity in water media, does not show catalytic activity under solvent-free conditions. Rapid conversion using DMAP and DABCO at low temperature (at — 5 °C) was observed, presumably due to an entropy controlled... 

Kumar et al. have studied the salt effect on the MBH reaction, that is, salt solutions of water and water-like structured solvents, such as formamide and N-methylformamide, were shown to accelerate the MBH reaction in the presence of DABCO. Ethylene glycol, another structured solvent, and its salt solutions fail to make any impact on the reaction rates. The salts that are conventionally defined as salting-out or -in do not behave in a similar fashion when employed in the MBH reactions, an observation supported by solubility measurements. It seems that the cation, anion and the nature of the solvent and the reactants together ascertain whether a salt will enhance or retard the MBH reaction. ... 

Additional investigations by Keay and coworkers [57] provide insight into the effects of various solvents and bases on Pd-BE JAP-catalysed polycyclizations to form tetracyclic products 95a and 95e. These studies showed that the use of dioxane as solvent or PMP as base promotes formation of the undesired tricyclic product, because both reagents can serve as hydride donors. Further experiments showed that l,4-diazabicyclo[2.2.2]octane (DABCO), which is an ineffective hydride donor because of its bridged structure, can be substituted for PMP to reduce formation of by-product 96 without significant loss of enantioselectivity. Likewise, the use of toluene rather than dioxane as the solvent maximizes conversion to the desired tetrayclic products. 

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