Recently our group reported that water soluble, fluorescent squaraine dyes with two appended polyethylene glycol (PEG) chains are rapidly threaded by a tetralactam macrocycle to give a highly stable complex. The macrocyle threading kinetics are remarkably insensitive to the length of the PEG chains. Indeed, there is no decrease in threading rates when the PEG chains are extended by hundreds or thousands of atoms, but the threading kinetics are greatly affected by the steric size of the second N-substituent attached to each squaraine termini. Simply shrinking the X group by two carbons from an N-propyl group to an N-methyl group increases the rate of macrocycle threading by a factor of 5 million. This study has systematically evaluated the dependency of this steric barrier on its location along the PEG. A series of squaraine analogues were prepared with an amino acid unit either attached to the end of the PEG chain or inserted in the middle. The rates of threading were measured using standard mixing and stopped-flow methods. As expected the size of the amino acid side chain affected the rate of macrocycle threading, with slower threading observed with larger side chains. Interestingly the location of the amino acid was also found to be an important factor. When a large amino acid such as phenylalanine was located at the end of the PEG chain there was hardly any change in threading rate, but a large decrease in threading rate was observed when the phenylalanine was moved to the middle of the PEG chain. These effects were further modulated by structural changes in the size of the macrocycle cavity. Taken together, the results provide a clear set of molecular design rules that allow fine tuning of the squaraine/macrocycle threading kinetics and allow fabrication of new classes of fluorescent imaging probes by controlled self-assembly.

Location of the steric speed bump controls squaraine threading by tretralcation macrocycle

253rd National Meeting (2017)

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