Preparation of DCLs

Fig. 97. Preparation of DCl from heavy water and benzoyl chloride. /) Condensation trap A) reflux condenser m) open arm manometer r) reaction flask t) dropping fimnel with capillary stem.

The thermodynamically controlled amide exchange may be catalyzed by amido-alumtnum complexes in organic solvents however, the relatively high temperatures required (90-120 °C) represent a limitation for its use in DCLs of receptors [42, 43]. Alternatively, enzymeotalyzed transimination has been reported. Thioester exchange and amide exchange have not yet been explored for the preparation of DCLs of potential receptors. 

Scheme 3.2 Acetal exchange and related exchange processes explored for the preparation of DCLs.

AUcyne metathesis has not been explored extensively for the preparation of DCLs [90] however, the development of new complexes that allow alkyne metathesis of highly functionalized substrates under mild conditions should stimulate a more widespread use of this reaction [6, 91]. 

Disulfane is usually made from a sulfane mixture known as crude sulfane oil while various methods are available for the preparation of the higher sulfanes. Deuterated sulfanes may be prepared by isotopic exchange with DCl [17]. 

The DCLS QA Program evolved as a result of participation and input from all levels of personnel from the outset. The QA program in the Bureau of Chemistry was the first to be developed at DCLS, and serves as the prototype for QA programs in the other Bureaus, although each Bureau is expected to address its own unique functions in the preparation of a QA plan. 

It should be noted that at some sacrifice of high specific activity, the total yield of DCl can be increased by increasing the quantity of sodium chloride used in the synthesis. Since the quantity of D2SO4 prepared is about 0.250 mol, the stoichiometric quantity of sodium chloride which can be used is about 14.6 grams. However, practical limitations of solubility and handling make the use of more than 2 to 3 g. of the salt impractical. 

V. Aqueous solutions of heavy hydrochloric acid are prepared by condensation of DCl in DgO. 

In summary, careful design of the building blocks and the experiments, and a crihcal and prepared mind when interpreting the results, are essential before the correct conclusions can be drawn from the often complex response of DCLs to molecular recognition events. 

Key to the success of a DCC approach towards the development of synthetic receptors is the reversible chemistry involved in the preparation of the libraries. There is a long list of requirements for the reversible reaction to be used [6). In order to develop new receptors from DCLs two requirements are crucial, (i) The exchange should be active in a reasonable timescale under appropriate reaction conditions. This determines the time that is necessary for the DCL to respond to the addition of a template molecule. Appropriate reaction conditions are those that are compatible with the structure of building blocks and template, and in particular with the recognition groups involved in the intermolecular interactions that drive... 

The exact structure of the building blocks used in the preparation of a DCL will depend on the desired characteristics for the receptor that is needed. Such characteristics will dictate potential recognition groups to be included, which will need to be compatible with the reversible chemistry and reaction conditions used. Most of the receptors discovered to date using the DCC approach have been built from building blocks inspired by previously known receptors. 

Figure 3.5 Preparation of a DCL from different starting points to demonstrate that equilibrium has been reached.

The conceptual simplicity of DCC gave it a jumpstart in terms of research groups involved. Having mastered the skill to use noncovalent and dynamic covalent bonds at will, researchers found DCC the obvious area for the application of supramolecular systems. In fact, the examples shown in the previous section are evidence of this potential. However, an evaluation of the literature over the past 15 years leads to some interesting observations. First, the number of DCLs that have displayed spectacular amplifications are rather limited. Second, apart from some exceptions (see later), nearly all DCLs are rather small (<25 components), especially in comparison to the huge covalent libraries prepared in the conventional manner. These are indicators that the application of DCC may not be as straightforward and general as it appears. In this section we discnss some of these critical issnes. 

The 0,N-dideuterated enol was formed by hydrolysis of the O-trimethylsilyl ether 123 (R = TMS) (in 80% [D6]DMSO/20% D2O with 5. lO " M DCl). N-Methylindoxyl (formed by hydrolysis of its acetate) exists in the solid state as a mixture of the enol and the keto tautomers (34% enol/66% keto). The NMR spectrum of freshly prepared solution in DMSO demonstrated signals of both enol and keto forms. However, at equilibrium (reached in 18 h at RT) the ratio of enol to ketone depends strongly on the polarity of the solvent used thus, in [Dg]DMSO the tautomeric mixture contains 92% enol, while in CDCI3 the keto form predominates (97%). A solution with 100% enol could be generated by hydrolysis of its O-trimethylsilyl ether [conditions 80% [Dfi]DMSO/20% D2O with 5 10" M DCl at 32°C (86TL3275 87PAC1577 88TL250)]. 

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