Protonated proton sponges cations

FIGURE 4. Possible types of IHB potential energy profiles in proton sponge cations... 

Theoretical calculations of an [H3N H- NH3]+ system have shown that when the N - N distance is 2.75 A, the potential curve has two minima with a barrier of 10.9 klrnol with a decrease in the distance to ca 2.50 A, the barrier disappears. As seen in Table 5, the minimal N N distance for proton sponge cations is 2.54-2.55 A, i.e. none of the compounds has a symmetrical barrier-free H-bond. Indeed, in 80% of cases, the X-ray studies on salts of proton sponge 1 have revealed an asymmetric hydrogen bridge with the distances N—H and N - H in the ranges 0.84-1.27 A and 1.42-1.86 A, respectively. It is believed that such strong variations are due to the influence of the anion, either by an electric field effect or by structural changes in the crystal lattice. 

Once internalized, the essential step for the polyplex is to escape rapidly the endosomal vesicle in order to release the nucleic acid in the cytosol and prevent its lysosomal degradation. As the endosomal and lysosomal pH presents values between 4.5 and 6.5 and therefore differs from the neutral pH of 7.4 in other biological compartments [58], some polycations containing protonable residues like PEI facilitate this step by the proton sponge effect [59, 60]. As not all cationic polymers display this attribute, another effective method for enhanced endosomal polyplex release is incorporation of specific endosomal membrane disrupting or pore-forming domains, such as lytic lipid moieties or endosomolytic peptides. 

Recently, there has been research activity in the area of chiral proton sponges, in particular, those containing nitrogens with pairs of different substituents. The molecular asymmetry of such sponges, especially well pronounced in the cationic forms, arises as a result of the arrangement of bulkier functions at opposite sides of the naphthalene ring plane. Synthesis of these compounds, e.g. 5248, 5333 and 5449, is also achieved via alkylation of the corresponding A,A -dialkyl- or A,A,A -trialkyl-l,8-diaminonaphthalenes (Scheme 3). 

An interesting situation occurs in the dication of the doubly protonated proton sponge 35 2H+ and in the zwitterion of 4,5-dihydroxy-l,8-bis(dimethylamino)naphthalene (111). The asymmetry of both hydrogen bridges in these systems is clearly controlled by electrostatic factors in order to obtain maximal separation of the two positively charged centres in 35 2H+ and, in reverse, to gain an attraction between the cationic and anionic centres in 111. 

There are very specific changes of the hydrogen bridge geometry in the cations of 2,7-disubstituted proton sponges. The measurements of such systems were performed for five salts with cations 44 H+, 101-II1,102 H+, 105 H+ and 112 H+. The ortfio-substituents in these cations display a distinct steric pressure on the adjacent A-methyl groups, pushing... 

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