Self-immolative comb-polymers: multiple-release of side-reporters by a single stimulus event.

Chemists have developed several sophisticated strategies in order to achieve amplification of molecular signals. Self-immolative molecular systems are molecules that disintegrate into their building blocks through domino-like reactions upon a single triggering stimulus. We and others have previously reported on self-immolative dendritic molecules that amplify a single triggering reaction at the focal point into release of multiple peripheral reporter groups. However, the number of groups that can be incorporated on a dendrimer periphery is limited due to steric hindrance and higher dendrimer generation requires additional synthetic steps. In order to overcome such disadvantages, we recently introduced a novel kind of linear “smart” polymer: These polymers respond to external stimuli by undergoing head-to-tail disassembly through a self-immolative fragmentation once the head-trigger is activated. Disassembly of this type of polymer to release monomers with strong fluorescence signal was demonstrated in context of a molecular sensor with large signal-to-noise ratio. Here, we report synthesis of the next generation of self-immolative polymers, which represent a significant step forward. Appropriate incorporation of side reporters (R) on each monomer and a trigger at the head-monomer generated a self-immolative comb-polymer with releasable side reporters. (Figure 1) Removal of the trigger initiated polymer disassembly along the backbone into its building block, followed by spontaneous release of the reporters from each monomer. Self-immolative comb-polymers can be designed based on building blocks such as 1 (Scheme 1). This molecule can undergo double-elimination reactions to release its two reporters. The disassembly is initiated by cleavage of the trigger to unmask amine 2. The latter spontaneously undergoes 1,6elimination to release a reporter (R) and azaquinone methide 3. This reactive intermediate is rapidly trapped by an available nucleophile to form amine 4. Additional 1,6-elimination, this time at the vinylogous ortho-benzyl position, releases a second reporter unit (R) and compound 5, which subsequently reacts with additional nucleophile to form amine 6. The azaquinone–methide rearrangement can take place either through an ortho-benzyl or through a vinylogous ortho-benzyl position. Our preference to use for a vinylogous ortho-benzyl substituent is based on the synthetic strategy presented in the Supporting Information. We designed self-immolative comb-polymer 7 based on 1 (Scheme 2). The polymeric backbone is constructed of polyurethane. 4-Nitroaniline was used as a reporter molecule