The aim of the work presented in this chapter is to develop further the understanding of the behaviour of the two replicators,T1andT2, referred to as theT1–T2network, employing a more complex, dynamic exchange environment of a dynamic covalent library (DCL). The selected environment of a DCL is inspired by the work described181
previously, and is comprised of four aldehydes,AtoD, and four nucleophiles,WtoZ, affording an exchange poolaof 16 condensation products (AW!DZ), which, together
with the unreacted aldehydes and nucleophiles, give a dynamic library of 24 components in total (Figure 4.2).
The nucleophile pool is assembled from three amines,W,XandY, and hydroxy- lamineZ, each tagged with an aryl-fluorine tag, permitting efficient analysis of library samples by19F{1H} NMR spectroscopy. Alternative aryl-CF
3 groups were not em-
ployed in this library as work described181,203previously has shown that the resonances
for library components employing such tags could not be resolved successfully as a result of the low sensitivity of their chemical shifts to changes in their electronic environment. This design allows the resonances for the 24 library components, as well as the cycloadducts formed through irreversible 1,3-dipolar cycloaddition reaction with maleimides, to be distinguished by19F{1H}NMR spectroscopy (Figure 4.3).
aSeveral of the compounds employed in the construction of DCLs have been discussed in the earlier sections of this thesis. For ease of understanding, the numbering of these compounds has been changed in this chapter: aldehydes are labelled fromAtoDand nucleophilesWtoZ. Condensation products of these aldehydes and nucleophiles are represented by the combination of their letters. This notation is carried through to the cycloadducts formed by the reaction of nitrones with maleimides.
Aldehydes
Nucleophiles Exchange Pool
N N H O NH2 F F F F NH2 Cl NH2 NHOH O O O O Cl Cl O2N NC R5 N R1 R5 N+ R4 O– R6 N+ R4 O– R7 N+ R4 O– R8 N+ R4 O– R5 N R2 R6 N R1 R6 N R2 R7 N R1 R7 N R2 R8 N R1 R8 N R2 R7 N R3 R5 N R3 R 8 N R3 R6 N R3 A B C D W X Y Z
Figure 4.2 Aldehyde and nucleophile components employed in the DCL experiments. AldehydesAto Dreact with anilinesWtoYand hydroxylamineZto produce 12 imines and four nitrone exchange pool components. In the library, only the four nitrones possess the reactive site (orange) necessary for 1,3-dipolar cycloaddition reactions with maleimides. Similarly, only four exchange pool components formed by reaction with aldehydeAbear the amidopyridine recognition site (blue). Only componentAZ, however, bears both the recognition and reactive element required for template-directed replication.
ppm -105 -110 -115 -120 -125 -130 F NO2 Br Internal standard ppm -120.5 -121.0 -121.5 ppm -110.0 -110.5 ppm -116.0 -116.5 -117.0 ppm-112.8 -113.0 -113.2 Z W Y T2 T1 trans cycloadducts Y Imines X Azoxy Z Nitrones W Imines BW AW CW DW cis cis cis X Imines CZ DZ BZ AZ CX DXBX AX δF
Figure 4.3 Example partial19F{1H}NMR spectrum (282.4 MHz, CD2Cl2saturated withpTSA mono- hydrate) of a DCL assembled from four aldehydes and four nucleophiles ([A] to [D] = [W] = [Z] = [M1] = [M2] = 10 mM) and 1-bromo-2-fluoro-4-nitrobenzene as internal standard, after seven days at 5 C.
The pool of aldehyde and nucleophile components comprising the library was designed to include also the building blocks necessary for the formation ofT1 and T2replicators. Specifically, aldehydeAwas equipped with a 6-methylamidopyridine recognition unit. Condensation of this aldehyde with hydroxylamineZresults in the formation of nitroneNF, referred to asAZthroughout this chapter—the key building
block for the formation of both replicators. Nitrone AZ is the only component in the library possessing both the recognition site and the reactive site required for the recognition-mediated 1,3-dipolar cycloaddition with maleimides M1 and M2. The template-mediated replication oftrans-T1andtrans-T2, explored inChapter 3, was shown to proceed efficiently and diastereoselectivelyb, relative to the corresponding
recognition-disabled reactions.
When a dynamic pool of components is first assembled from the aldehyde and nucleophile components, there are no condensation products present, and so the library exchange pool can be envisaged as a feeding stock for the formation of nitroneAZas it is removed from the exchange pool over time through irreversible reactions. Presence of Aand Z could enable the recognition nitrone to be produced continuously for a transient period of time—a period limited by the finite amount of library resources and the stability of the different exchange pool components. Overall, the library exchange pool contains four nitrones. In addition to nitroneAZ, equipped with a recognition site necessary for self-replication, three nitrones,BZ,CZ, andDZ, capable of reacting only through the much slower and significantly less diastereoselective bimolecular pathways, are present. Ideally, the library can be directed by addition of recognition-enabledM1 andM2maleimides and their corresponding templates, to synthesise the self-replicating templates preferentially, out of the pool of all of the possible cycloaddition products. Selectivity for one recognition-enabled product over another within the system will be examined and compared to the selectivity determined for these replicators within a simple competition scenario, driven by kinetic selection only (Chapter 3). Moreover, the ability of the two irreversible, kinetically-controlled processes to influence the dynamic library and shift its composition away from its original equilibrium position, towards preferential formation of these self-replicating products will be analysed.
Prior to examining the feasibility of directing the library to form self-replicating templates preferentially, it was imperative to select conditions that would promote reproducible formation of the exchange pool. Even though previous studies in the Philp laboratory have revealed that CDCl3works sufficiently well as a solvent for simple
bOnly thetransdiastereoisomer is capable of taking part in template-directed replication processes in this system, and, thus, unless emphasis on thetransproduct is required, the notation of the cycloadduct products capable of replication will omit thetransnotation (for example,trans-T1will be generally referred to asT1throughout the experimental chapters.
kinetic experiments, it does not yield consistently reproducible results under dynamic covalent exchange conditions as a result of the variable water and acid content. Work within the Philp laboratory has shown that CD2Cl2, as a less hygroscopic solvent,
containing smaller amounts of acidic impurities, is a suitable alternative as a reaction medium. Water and acid were reproducibly introduced to each library by saturating CD2Cl2withpara-toluenesulfonic acid monohydrate (further referred to aspTSA). For
details of this procedure, see experimental section inChapter 9. All experiments in this chapter were conducted at the same temperature as employed throughout the kinetic studies inChapter 3(5 C) in order to permit comparison between results.