Intrinsic and Extrinsic Control of the pK_a of Thiol Guests inside Yoctoliter Containers

Abstract

Despite decades of research, there are still many open questions surrounding the mechanisms by which enzymes catalyze reactions. Understanding all the noncovalent forces involved has the potential to allow de novo catalysis design, and as a step toward this, understanding how to control the charge state of ionizable groups represents a powerful yet straightforward approach to probing complex systems. Here we utilize supramolecular capsules assembled via the hydrophobic effect to encapsulate guests and control their acidity. We find that the greatest influence on the acidity of bound guests is the location of the acidic group within the yoctoliter space. However, the nature of the electrostatic field generated by the (remote) charged solubilizing groups also plays a significant role in acidity, as does counterion complexation to the outer surfaces of the capsules. Taken together, these results suggest new ways by which to affect reactions in confined spaces.

Electrostatic Potential Field Effects on Amine Macrocyclizations within Yoctoliter Spaces: Supramolecular Electron Withdrawing/Donating Groups

“…We have shown that bound thiol guests are more acidic inside 1 2 , by up to 2.5 p K a units (it transpires that guest motif has a much larger effect on p K a ). 41 We have also observed that rates of macrocyclization of α,ω-thio-alkane halides inside 1 2 are almost 4 orders of magnitude faster than inside 2 2 . 42 These findings also showed that the stabilization of the transition states (TS) for cyclization was greater than that of thiolate stabilization, suggesting a rather complex mechanism by which these capsules affect chemical reactivity.…”

“…Although it was not possible to observe the 1 H NMR signal for a −NH 2 or −NH 3 + group of the bound guest, and therefore not possible to use 1 H NMR spectroscopy to determine ammonium p K a values, we can use the previously determined p K a values for thiols within 1 2 , and 2 2 as a guide. 41 This data suggests that the p K a of a bound ammonium can range from 6 to 12; the amine would be a weak base inside 1 2 , and a relatively strong base inside 2 2 . That trace protonation of the guest inside 2 2 is a possibility that was suggested by a small change in the guest binding region of the 1 H NMR spectrum of the complex when an additional 50 equiv of NaOD was added.…”

A Volumetric Analysis of the 1H NMR Chemical Shielding in Supramolecular Systems

“…. π interactions [36], and of binding modes inside relatively small (of "yoctoliter" volume) capsules [37]. In such investigations, a possibility should be considered that fairly different position(s) of the ligand might be compatible with an experimental value of the complexation shift.…”

Creating Dynamic Nanospaces in Solution by Cationic Cages as Multirole Catalytic Platform for Unconventional C(sp)−H Activation Beyond Enzyme Mimics

“…[4,8,9] Meanwhile,t he supramolecular forces inherent in electrostatic interactions,h ydrogen binding,hydrophobic effect, etc., are also crucial in modulating the reactivity and selectivity of enzymes. [10][11][12][13][14] Aprominent way is to modify acidity-basicity of functional residuals or hosted substrates,w hich facilitates abstraction of proton and stabilization of favored charge-state, [15,16] paving the way for nucleophilic,e lectrophilic or acid/base enzymatic reactions intrinsic in the state of protonation. [17,18] In these regards,m uch effort has been devoted to the design and assembly of supramolecular cages with varied sizes,s hapes,c avities and active-sites for supramolecular catalysis,a ccomplishing reaction acceleration, intermediate stabilization, and special chemical selectivity on the basis of supramolecular confinement effect enforced by the cagedefined nanospace and geometry.…”