Proton Sponge Research Articles

Synthesis and Selected Transformations of New 2‐Aminopyridine Derivatives Based on Furan‐2(5H)‐ones

AbstractCompounds with γ‐lactone fragments, as well as derivatives of 2‐aminopyridines and 2‐aminopyridons, are biologically active, and some of them are used as drugs. The condensed combination of γ‐lactones with 2‐aminopyridones, such as the natural alkaloid cerpegin, has a wider spectrum of biological activities. Here we combined γ‐lactone and 2‐aminopyridine derivatives into one molecule via a single bond. A series of such compounds were synthesized in high yields through the transformations of unsaturated furan‐2(5H)‐ones. Interestingly, only two of the obtained compounds underwent intermolecular cyclization and led to new isoquinoline derivatives with skeletons similar to the “proton sponges”.

Targeted Doxorubicin-Loaded Dendronized Gold Nanoparticles.

Dendronized nanoparticles, also called nanoparticle-cored dendrimers, combine the advantages of nanoparticles and dendrimers. These very stable and polyvalent nanoparticles can be used for diverse applications. One such application is drug delivery, because the dendrons can enhance the density of the payload. In this report, we describe the design of multifunctional gold nanoparticles (AuNPs) coated with poly(propylene imine) (PPI) dendrons that contain both prostate cancer active targeting and chemotherapeutic drugs. The PPI dendron is a good candidate for the design of drug delivery vehicles because of its ability to induce a proton sponge effect that will enhance lysosomal escape and intracellular therapeutic delivery. The chemotherapeutic drug used is doxorubicin (DOX), and it was linked to the dendron through a hydrazone acid-sensitive bond. Subsequent acidification of the AuNP system to a pH of 4-5 resulted in the release of 140 DOX drugs per nanoparticles. In addition, the PPI dendron was conjugated via "click" chemistry to an EphA2-targeting antibody fragment that has been shown to target prostate cancer cells. In vitro cell viability assays revealed an IC50 of 0.9 nM for the targeted DOX-bearing AuNPs after 48 h incubation with PC3 cells. These results are very promising upon optimization of the system.

Codelivery of Que and BCL-2 siRNA with Lipid-Copolymer Hybrid Nanocomplexes for Efficient Tumor Regression.

The efficacy of chemotherapy is often reduced due to the chemotherapy resistance of tumor cells, which is usually caused by abnormal gene overexpression. Herein, multifunctional nanocomplexes (Que/siBCL2@BioMICs) were developed to deliver quercetin (Que) and BCL-2 siRNA (siBCL2) to synergistically inhibit tumor growth. The nanocomplexes were composed of an amphiphilic triblock copolymer of poly(ethylene glycol) methyl ether methacrylate-poly[2-(dimethylamino) ethyl acrylate]-polycaprolactone (PEGMA-PDMAEA-PCL) and 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-poly(ethylene glycol)-biotin (DSPE-PEG-biotin). Que was encapsulated into the cores through hydrophobic interactions, while negatively charged siBCL2 was loaded through electrostatic interactions. The nanocomplexes could effectively facilitate cellular uptake via biotin-mediated active targeting and cytosolic release of cargos by the "proton sponge effect" of PDMAEA. Que/siBCL2@BioMICs achieved enhanced cytotoxicity and anti-metastasis activity due to a synergistic effect of Que and siBCL2 in vitro. More importantly, superior anti-tumor efficacy was observed in orthotopic 4T1 tumor-bearing mice with reduced primary tumor burden and lung metastatic nodules, while no obvious side effects to major organs were observed. In conclusion, the biotin-targeted nanocomplexes with chemotherapeutic and nucleotide agent entrapment provide a promising strategy for efficient triple-negative breast cancer (TNBC) therapy.

Tailoring a local acid-like microenvironment for efficient neutral hydrogen evolution

Electrochemical hydrogen evolution reaction in neutral media is listed as the most difficult challenges of energy catalysis due to the sluggish kinetics. Herein, the Ir-HxWO3 catalyst is readily synthesized and exhibits enhanced performance for neutral hydrogen evolution reaction. HxWO3 support is functioned as proton sponge to create a local acid-like microenvironment around Ir metal sites by spontaneous injection of protons to WO3, as evidenced by spectroscopy and electrochemical analysis. Rationalize revitalized lattice-hydrogen species located in the interface are coupled with Had atoms on metallic Ir surfaces via thermodynamically favorable Volmer-Tafel steps, and thereby a fast kinetics. Elaborated Ir-HxWO3 demonstrates acid-like activity with a low overpotential of 20 mV at 10 mA cm−2 and low Tafel slope of 28 mV dec−1, which are even comparable to those in acidic environment. The concept exemplified in this work offer the possibilities for tailoring local reaction microenvironment to regulate catalytic activity and pathway.

Blended Block Polycation Micelles Enhance Antisense Oligonucleotide Delivery.

Nucleic acid-based medicines and vaccines are becoming an important part of our therapeutic toolbox. One key genetic medicine is antisense oligonucleotides (ASOs), which are short single-stranded nucleic acids that downregulate protein production by binding to mRNA. However, ASOs cannot enter the cell without a delivery vehicle. Diblock polymers containing cationic and hydrophobic blocks self-assemble into micelles that have shown improved delivery compared to linear nonmicelle variants. Yet synthetic and characterization bottlenecks have hindered rapid screening and optimization. In this study, we aim to develop a method to increase throughput and discovery of new micelle systems by mixing diblock polymers together to rapidly form new micelle formulations. We synthesized diblocks containing an n-butyl acrylate block chain extended with cationic moieties amino ethyl acrylamide (A), dimethyl amino ethyl acrylamide (D), or morpholino ethyl acrylamide (M). These diblocks were then self-assembled into homomicelles (A100, D100, and M100)), mixed micelles comprising 2 homomicelles (MixR%+R'%), and blended diblock micelles comprising 2 diblocks blended into one micelle (BldR%R'%) and tested for ASO delivery. Interestingly, we observed that mixing or blending M with A (BldA50M50 and MixA50+M50) did not improve transfection efficiency compared to A100; however, when M was mixed with D, there was a significant increase in transfection efficacy for the mixed micelle MixD50+M50 compared to D100. We further examined mixed and blended D systems at different ratios. We observed a large increase in transfection and minimal change in toxicity when M was mixed with D at a low percentage of D incorporation in mixed diblock micelles (i.e., BldD20M80) compared to D100 and MixD20+M80. To understand the cellular mechanisms that may result in these differences, we added proton pump inhibitor Bafilomycin-A1 (Baf-A1) to the transfection experiments. Formulations that contain D decreased in performance in the presence of Baf-A1, indicating that micelles with D rely on the proton sponge effect for endosomal escape more than micelles with A. This result supports our conclusion that M is able to modulate transfection of D, but not with A. This research shows that polymer blending in a manner similar to that of lipids can significantly boost transfection efficiency and is a facile way to increase throughput of testing, optimization, and successful formulation identification for polymeric nucleic acid delivery systems.

Predicting a New Δ-Proton Sponge-Base of 4,12-Dihydrogen-4,8,12-triazatriangulene through Proton Affinity, Aromatic Stabilization Energy, and Aromatic Magnetism.

Herein, we report designing a new Δ (delta-shaped) proton sponge base of 4,12-dihydrogen-4,8,12-triazatriangulene (compound 1) and calculating its proton affinity (PA), aromatic stabilization, natural bond orbital (NBO), electron density ρ(r), Laplacian of electron density ∇2 ρ(r), (2D-3D) multidimensional off-nucleus magnetic shielding (σzz (r) and σiso (r)), and scanning nucleus-independent chemical shift (NICSzz and NICS). Density functional theory (DFT) at B3LYP/6-311+G(d,p), ωB97XD/6-311+G(d,p), and PW91/def2TZVP were used to compute the magnetic shielding variables. In addition, relevant bases like pyridine, quinoline, and acridine were also studied and compared. The protonation of compound 1 yields a highly symmetric carbocation of three Hückel benzenic rings. Comparing our findings of the studied molecules showed that compound 1 precedes others in PA, aromatic isomerization stabilization energy, and basicity. Therefore, the basicity may be enhanced when a conjugate acid gains higher aromatic features than its unprotonated base. Both multidimensional σzz (r) and σiso (r) off-nucleus magnetic shieldings outperformed electron-based techniques and can visually monitor changes in aromaticity that occur by protonation. The B3LYP/6-311+G(d,p), ωB97XD/6-311+G(d,p), and PW91/def2TZVP levels showed no significant differences in detailing isochemical shielding surfaces.

Hyperbranched Polymer-Based Vaccines for Cancer Immunotherapy.

Recently, several immunotherapeutic strategies are extensively studied and entered clinical investigation, suggesting their potential to lead a new generation of cancer therapy. Particularly, a cancer vaccine that combines tumor-associated antigens and immune adjuvants with a nanocarrier holds huge promise for inducing specific antitumor immune responses. Hyperbranched polymers, such as dendrimers and branched polyethylenimine (PEI) possessing abundant positively charged amine groups and inherent proton sponge effect are ideal carriers of antigens. Much effort is devoted to design dendrimer/branched PEI-based cancer vaccines. Herein, the recent advances in the design of dendrimer/branched PEI-based cancer vaccines for immunotherapy are reviewed. The future perspectives with regard to the development of dendrimer/branched PEI-based cancer vaccines are also briefly discussed.

8-Bromo-4,5-bis(dimethylamino)quinoline: Synthesis, protonation, and the first structural studies of quinoline “proton sponge” as a base

Synthesized 8-bromo-4,5-bis(dimethylamino)quinoline is the simplest and at the same time the first representative of quinoline “proton sponges”, existing as a base in a crystalline form, and not as an oil. This allowed to perform the XRD study both for the title compound and its salt with HBF4. The results obtained revealed a significant conjugation of the cyclic nitrogen atom with peri-NMe2 groups, which initiates a noticeable planarization of the latter and lengthening the distance between them. As a result, the mono-protonated salts of the title quinoline, either in solid or in solution, exist completely in the quinolinium form. To compare the effect of peri-NMe2 groups on the stability of naphthalene and quinoline proton sponges, the structural index of their aromaticity was calculated for the first time.

Preparation of an amphiphilic peptide (P13) with proton sponge effect and analysis of its antitumor activity

In order to prevent drugs from being captured and degraded by the acidic environment of organelles, such as lysosomes, after entering cells, this study designed and synthesized a novel carrier amphiphilic polypeptide (DGRHHHLLLAAAA), designated P13, for use as a tumor-targeting drug delivery vehicle. The P13 peptide was synthesized by the solid phase synthesis method, and its self-assembly behavior and drug-loading capacity in aqueous solution were studied and characterized in vitro. Doxorubicin (DOX) was loaded by dialysis method, and P13 and DOX were mixed at a mass ratio of 6:1 to form regular rounded globules. The acid–base buffering capacity of P13 was investigated determined by acid–base titration. The results revealed that P13 had excellent acid–base buffering capacity, a critical micelle concentration value of about 0.000 21 g l−1, and the particle size of P13-Dox nanospheres was 167 nm. The drug encapsulation efficiency and drug loading capacity of micelles were 20.40 ± 1.21% and 21.25 ± 2.79%, respectively. At the concentration of 50 μg ml−1 of P13-DOX , the inhibition rate was 73.35%. The results of the in vivo antitumor activity assay in mice showed that P13-DOX also exhibited excellent inhibitory effect on tumor growth, compared with the tumor weight of 1.1 g in the control group, the tumor weight in the P13-DOX-treated group was only 0.26 g. Additionally, the results of hematoxylin and eosin staining of the organs showed that P13-DOX had no damaging effect on normal tissues. The novel amphiphilic peptide P13 with proton sponge effect designed and prepared in this study is expected to be a promising tumor-targeting drug carrier with excellent application potential.

Rough Nanovaccines Boost Antitumor Immunity Through the Enhancement of Vaccination Cascade and Immunogenic Cell Death Induction.

Nanovaccines have attracted intense interests for efficient antigen delivery and tumor-specific immunity. It is challenging to develop a more efficient and personalized nanovaccine to maximize all steps of the vaccination cascade by exploiting the intrinsic properties of nanoparticles. Here, biodegradable nanohybrids (MP) composed of manganese oxide nanoparticles and cationic polymers are synthesized to load a model antigen ovalbumin to form MPO nanovaccines. More interestingly, MPO could serve as autologous nanovaccines for personalized tumor treatment taking advantage of in situ released tumor-associated antigens induced by immunogenic cell death (ICD). The intrinsic properties of MP nanohybrids including morphology, size, surface charge, chemical, and immunoregulatory functions are fully exploited to enhance of all steps of the cascade and induce ICD. MP nanohybrids are designed to efficiently encapsulate antigens by cationic polymers, drain to lymph nodes by appropriate size, be internalized by dendritic cells (DCs) by rough morphology, induce DCmaturation through cGAS-STING pathway, and enhance lysosomal escape and antigen cross-presentation through the "proton sponge effect". The MPO nanovaccines are found to efficiently accumulate in lymph nodes and elicit robust specific T-cell immune responses to inhibit the occurrence of ovalbumin-expressing B16-OVA melanoma. Furthermore, MPO demonstrate great potential to serve as personalized cancer vaccines through the generation of autologous antigen depot through ICD induction, activation of potent antitumor immunity, and reversal of immunosuppression. This work provides a facile strategy for the construction of personalized nanovaccines by exploiting the intrinsic properties of nanohybrids.

α-Amino acid-assisted autoxidation of naphthalene proton sponge affording 1,4-naphthoquinone nitrogen derivatives

1,8-Bis(dimethylamino)naphthalene (naphthalene proton sponge) equipped at position 4 with N-terminal α-amino acid residues undergoes unprecedented easy autoxidation in basic medium forming 5-dimethylamino-1,4-naphthoquinone along with minor amounts of its derivatives. The new reaction is of interest against the background of wide distribution of 1,4-naphthoquinones in nature, their high biological significance and extremely limited information on nitrogen compounds of this series.

Simultaneous Formation of Isomeric and Polycyclic Proton Sponges Derived from 1,8‐Diaminonaphthalenes and Xylylene Dibromides

AbstractThe interaction of 1,8‐diaminonaphthalene with o‐xylylene dibromide leads to two topologically relevant isomeric products, 1,8‐di(isoindolin‐2‐yl)naphthalene (reported previously), and its structural isomer with the bridgehead nitrogens in a bicyclic system (reported for the first time). This is the first case of isolating two heterocyclic analogs of 1,8‐bis(dimethylamino)naphthalene (proton sponge or DMAN) in one reaction. Both isomers are formed in parallel reactions and are not interconverted upon acid treatment. The first representative of heterocyclic “amide proton sponges”, which is still able to participate in intramolecular protonation due to the amide nitrogen atom, was synthesized by direct oxidation of the corresponding isoindoline derivative. Using p‐xylylene dibromide as a bridging bielectrophile, a macroheterocyclization was effectively realized to construct the first paracyclophane extended by two DMAN subunits. Mostly driven by the proximity effect, the molecular structure, unusual protonation trends and reactivity of peri‐diaminonaphthalenes N‐linked with o‐ and p‐xylylene fragments are also discussed.

Recent progress and applications of poly(beta amino esters)-based biomaterials.

Poly(beta-amino esters, PBAEs) are a promising class of cationic polymers synthesized from diacrylates and amines via Michael addition. Recently, PBAEs have been widely developed for drug delivery, immunotherapy, gene therapy, antibacterial, tissue engineering and other applications due to their convenient synthesis, good bio-compatibility and degradation properties. Herein, we mainly summarize the recent progress in the PBAEs synthesis and their applications. The amine groups of PBAEs could be protonated in low pH environment, exhibiting proton sponge and pH-sensitive abilities. Furthermore, the positive PBAEs can interact with negative genes via electrostatic interactions for efficient delivery of nucleic acids. Moreover, positive PBAEs could also directly kill bacteria by disrupting their membranes at high doses. Finally, PBAEs can augment the immune responses, and improve the bioactivity of hydrogels in tissue engineering.

Application of Cell Penetrating Peptides as a Promising Drug Carrier to Combat Viral Infections.

Novel effective drugs or therapeutic vaccines have been already developed to eradicate viral infections. Some non-viral carriers have been used for effective drug delivery to a target cell or tissue. Among them, cell penetrating peptides (CPPs) attracted a special interest to enhance drug delivery into the cells with low toxicity. They were also applied to transfer peptide/protein-based and nucleic acids-based therapeutic vaccines against viral infections. CPPs-conjugated drugs or vaccines were investigated in several viral infections including poliovirus, Ebola, coronavirus, herpes simplex virus, human immunodeficiency virus, hepatitis B virus, hepatitis C virus, Japanese encephalitis virus, and influenza A virus. Some studies showed that the uptake of CPPs or CPPs-conjugated drugs can be performed through both non-endocytic and endocytic pathways. Despite high potential of CPPs for cargo delivery, there are some serious drawbacks such as non-tissue-specificity, instability, and suboptimal pharmacokinetics features that limit their clinical applications. At present, some solutions are utilized to improve the CPPs properties such as conjugation of CPPs with targeting moieties, the use of fusogenic lipids, generation of the proton sponge effect, etc. Up to now, no CPP or composition containing CPPs has been approved by the Food and Drug Administration (FDA) due to the lack of sufficient in vivo studies on stability, immunological assays, toxicity, and endosomal escape of CPPs. In this review, we briefly describe the properties, uptake mechanisms, advantages and disadvantages, and improvement of intracellular delivery, and bioavailability of cell penetrating peptides. Moreover, we focus on their application as an effective drug carrier to combat viral infections.

Multifunctional Dendritic Au@SPP@DOX Nanoparticles Integrating Chemotherapy and Low-Dose Radiotherapy for Enhanced Anticancer Activity.

Combined chemoradiotherapy can improve antitumor efficiency and reduce the side effects of monotherapy. In this study, we aimed to construct dendritic peptide-based multifunctional nanoparticles (Au@SPP@DOX) for a prolonged circulation time, enhanced cellular uptake, and targeted cancer therapy. Amphiphilic micelle PEG-polylysine-SA (SPP) is composed of polylysine combined with hydrophilic poly(ethylene glycol) (PEG) and hydrophobic stearic acid (SA). Doxorubicin (DOX) is loaded via the hydrophilic-hydrophobic interaction of SPP, and gold nanoparticles (AuNPs) are loaded via the electrostatic interaction with SPP. Au@SPP@DOX showed good biocompatibility and could be successfully accumulated at tumor sites through the enhanced permeability and retention (EPR) effect. Then, lysosomes could be ruptured due to the proton sponge effect. DOX became protonated in response to tumor extracellular acidity and was then released from SPP. Under the action of low-dose radiation, Au@SPP@DOX could promote the production of reactive oxygen species (ROS), increase mitochondrial dysfunction, block cell division, and ultimately promote tumor cell apoptosis to achieve a better antitumor effect. This study highlighted the benefit of chemoradiotherapy and suggested that Au@SPP@DOX might serve as a high-efficiency codelivery system for cancer combination therapy in the future.

Unraveling the Nature of Hydrogen Bonds of "Proton Sponges" Based on Car-Parrinello and Metadynamics Approaches.

The nature of intra- and intermolecular non-covalent interactions was studied in four naphthalene derivatives commonly referred to as "proton sponges". Special attention was paid to an intramolecular hydrogen bond present in the protonated form of the compounds. The unsubstituted "proton sponge" served as a reference structure to study the substituent influence on the hydrogen bond (HB) properties. We selected three compounds substituted by methoxy, amino, and nitro groups. The presence of the substituents either retained the parent symmetry or rendered the compounds asymmetric. In order to reveal the non-covalent interaction properties, the Hirshfeld surface (HS) was computed for the crystal structures of the studied compounds. Next, quantum-chemical simulations were performed in vacuo and in the crystalline phase. Car-Parrinello molecular dynamics (CPMD), Path Integral Molecular Dynamics (PIMD), and metadynamics were employed to investigate the time-evolution changes of metric parameters and free energy profile in both phases. Additionally, for selected snapshots obtained from the CPMD trajectories, non-covalent interactions and electronic structure were studied. Quantum theory of atoms in molecules (QTAIM) and the Density Overlap Regions Indicator (DORI) were applied for this purpose. It was found based on Hirshfeld surfaces that, besides intramolecular hydrogen bonds, other non-covalent interactions are present and have a strong impact on the crystal structure organization. The CPMD results obtained in both phases showed frequent proton transfer phenomena. The proton was strongly delocalized in the applied time-scale and temperature, especially in the PIMD framework. The use of metadynamics allowed for tracing the free energy profiles and confirming that the hydrogen bonds present in "proton sponges" are Low-Barrier Hydrogen Bonds (LBHBs). The electronic and topological analysis quantitatively described the temperature dependence and time-evolution changes of the electronic structure. The covalency of the hydrogen bonds was estimated based on QTAIM analysis. It was found that strong hydrogen bonds show greater covalency, which is additionally determined by the proton position in the hydrogen bridge.

PH-sensitive nano-polyelectrolyte complexes with arthritic macrophage-targeting delivery of triptolide

Since pro-inflammatory macrophages take on a critical significance in the pathophysiology of rheumatoid arthritis (RA), the therapeutics to affect macrophages may receive distinct anti-RA effects. However, the therapeutic outcomes are still significantly impeded, which is primarily due to the insufficient drug delivery at the arthritic site. In this study, the macrophage-targeting and pH stimuli-responsive nano-polyelectrolyte complexes were designed for the efficient targeted delivery of triptolide (TP/PNPs) on the arthritic site. The anionic and cationic amphiphilic copolymers, i.e., hyaluronic acid-g-vitamin E succinate (HA-VE) and the quaternized poly (β-amino ester) (QPBAE-C18), were prepared and then characterized. The result indicated that TP/PNPs with the uniform particle size of ∼ 175 nm exhibited the high drug loading capacity and storage stability based on the polymeric charge interaction, in which DLC and DEE of TP/PNPs were obtained as 11.27 ± 0.44 % and 95.23 ± 2.34 %, respectively. Mediated by the “ELVIS” effect of NPs, CD44 receptor-mediated macrophage targeting, and pH-sensitive endo/lysosomal escape under the “proton sponge” effect, TP/PNPs exhibited the enhanced cellular internalization and cytotoxicity while mitigating the inflammation of LPS-activated RAW 264.7 cells. Even after 96-hour after administration, PNPs were preferentially accumulated in the inflammatory joints in a long term. It is noteworthy that after treatment for 14 days with 100 μg/kg of TP, TP/PNPs significantly facilitated arthritic symptom remission, protected cartilage, and mitigated inflammation of antigen-induced arthritis (AIA) rats, whereas the systematic side-effects of TP were reduced. In this study, an effective drug delivery strategy was proposed for the treatment of RA.

Pyridine-extended proton sponge enabling high-performance membrane for flow batteries

The development of high-performance and low-cost membrane is of significance towards vanadium flow battery (VFB). The membrane usually suffer from a trade-off challenge between conductivity and selectivity especially in long-term operation of flow battery. Herein, using a proton sponge drived by the proton absorption capacity of extended pyridine groups, a highly ion-selective membrane is fabricated. During acid-assisted doping behaviors, transport nanochannels with highly proton-selective conductivity are constructed based on well-defined nanophase separation structure. The protonated nanochannels display effectively acidic absorption during hydration process for enabling fast proton conduction (a low area resistance of 0.33 Ω cm2) and repelling vanadium ion (a low vanadium ion permeability of 3.04 × 10−10 cm2 s−1). Consequently, prepared membrane with proton sponge exhibits remarkable performance of high energy efficiency of 85.5%, together with excellent chemical durability over 1000 charge-discharge cycles (more than 1100 h) at 120 mA cm−2 in VFB application. These notable properties make prepared membrane as a potential alternative used in large-scale energy storage systems.

The metal-mediated coupling of the diselenaundecaborate anion [Se2B9H10

The diselenaundecaborate anion, [Se2B9H10]− (1), is isolated in 49 % yield from the one-pot reaction of nido-B10H14, Proton Sponge and selenium in thf. In solution, 1 exhibits a fluxional interchange between symmetry-equivalent positions of its two selenium atoms and open-face ‘bridging’ hydrogen atom that cannot be frozen out on the NMR timescale. This is however resolved by solid-state boron-11 NMR spectroscopy, which shows the spectrum expected from a DFT/GIAO calculation. The treatment of two equivalents of 1 with HgCl2 in dichloromethane affords the conjoined binary cluster anion [(Se2B9H10)(SeB9H11)]− (2), in which the ‘bridging’ selenium atom in 1 links to an {arachno-SeB9H11} moiety. This metal-mediated linking of selenaborane clusters potentially opens a gateway to new macropolyhedral heteroborane assemblies.

Organometallic Synthesis of 2,3,6,7-Tetrasubstituted 1,8-Bis(dimethylamino)naphthalenes for Investigation of the Double Buttressing Effect in Proton Sponges.

The lithiation of 2,7-disubstituted derivatives of 1,8-bis(dimethylamino)naphthalene (DMAN, proton sponge) bearing potentially ortho-directing OMe, NMe2, and SMe groups was studied. It has been shown that OMe groups facilitate selective dual β-lithiation of the naphthalene moiety while the 2(7)-NMe2 groups allow only monolithiation presumably due to the decreased acidity of the ring C-H bonds and conformational immobilization after coordination to the lithium atom. In contrast, the SMe groups provided no ring lithiation and underwent deprotonation of their methyl fragment. The first representatives of previously unknown 2,3,6,7-tetrasubstituted DMANs have been synthesized in good yield after treatment of 2,7-dimethoxy-3,6-dilithio DMAN with the appropriate electrophiles (MeI, Me2S2, Me3SiCl, DMF, etc.). Because the exceedingly high basicity of 2,7-dimethoxy DMAN is commonly attributed to the so-called "buttressing effect" (BE), the availability of 2,3,6,7-tetrasubstituted species provided the first opportunity to study the double BE version. Using X-ray diffraction and basicity measurements, we showed that due to the high conformational mobility of the methoxy groups, the most striking manifestations of double BE are the strong planarization of peri-NMe2 groups and a significant decrease in basicity, while the length and the other properties of the intramolecular NHN hydrogen bond in the corresponding protonated species undergo minor changes.