A patent was issued 3 days ago that describes the PTC N-alkylation of imidazole with dichloroethane shown in the diagram. The desired product requires reaction at only one end of the alkylating agent. It is reasonable to assume that the inventors used a very large excess of dichloroethane (34.5 equiv!) as solvent to maximize the probability that the imidazolide anion (formed from imidazole and base) will collide with a dichloroethane molecule rather than a 2-chloroethyl imidazole molecule. Before discussing combining high dilution with the strengths of PTC, let’s talk about the reaction conditions chosen.
The reaction is a solid-liquid PTC system with no added water. In fact, during the workup, the solids were filtered off for separation from the product and consisted of the excess base and KCl byproduct.
Also during workup, the organic phase was washed with water twice, maybe not necessarily to remove residual salts, but probably to begin to separate the tetrabutylammonium salt from the product before purification by chromatography. Tetrabutylammonium salts have a very high affinity for dichloroethane and is quite hard to separate from this solvent by just water washing as I explicitly published in 1998 (http://phasetransfer.com/catsep.pdf). The yield after chromatography was only 41.7%. Since quats have a high affinity to chromatography materials (such as silica), the column undoubtedly removed the phase-transfer catalyst.
I am not totally sure but I think that imidazole is also soluble in dichloroethane. If so, then high dilution is likely even more of a requirement to achieve selectivity of displacement of only one chlorine atom.
It turns out that phase-transfer catalysis provides the opportunity to simulate high dilution in certain systems.
If we assume that the N-alkylation under PTC conditions occurs in the bulk organic phase and not at the interface, then we can control the amount of reactive imidazolide anion in the organic reaction phase by setting the catalyst loading. Let’s say that we use 2 mole% quat, then we can only have no more than 2 mole% imidazolide anion in the reaction phase in the form of [Q+Im-]. If we choose a nonpolar solvent in which imidazole is not very soluble and if we minimize interfacial reaction between imidazolide anion and alkylating agents in the organic phase, then we can create an effective dilution of 100:1 at the outset of the reaction by using 2 mole% quat and 2 equiv of alkylating agent, even though the entire reactor actually contains 1 equiv imidazole and 2 equiv of alkylating agent. The ratio of chloroethylimidazole to dichloroethane will still increase as the reaction progresses, but the ratio of quat imidazolide to alkylating agent IN THE REACTION PHASE will still remain lower throughout the reaction profile than if not using a quat. This improves selectivity.
By the way, the pKa of imidazole is 14.5. Since the pKa of water is 15.7, then when mixing NaOH and imidazole, about 90% of the imidazole will be deprotonated in the imidazolide anion form. So, in order to minimize undesired contact between the imidazolide anion (present to a large extent) and the alkylating agent, we should work at an intermediate rpm and avoid over-agitation.
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