Design, synthesis, and biological activity of novel ammonium salts containing sterically hindered phenolic fragment and phosphoryl group

Novel multifunctional ammonium salts was obtained with high antimicrobial, antioxidant and low cytotoxic activity.

Abstract

Here, we present an approach to novel “hybrid” biologically active compounds based on a combination of sterically hindered phenol and ammonium pharmacophores in a single molecule. The novel target ammonium salts were obtained by the reaction of 3-(3,5-di-tert-butyl-4-hydroxyphenyl)-N-(2-(dimethylamino)alkyl)propanamide with aliphatic bromides or by the reaction of phosphorylated methylenequinones with diamines followed by alkylation with organic bromides. A series of twenty-three novel multifunctional ammonium salts that contain a sterically hindered phenolic fragment were assessed for antimicrobial, cytotoxic and antioxidant activity. The compounds exhibited antimicrobial activity against Staphylococcus aureus ATCC 209p, Bacillus cereus ATCC 8035, Escherichia coli CDC F-50, Pseudomonas aeruginosa ATCC 9027, Aspergillus niger BKMF-1119, Trichophyton mentagrophytes var. gypseum 1773, and Candida albicans 855-653 in the concentration range of 442–0.70 μM. The maximum activity of an ammonium salt among all the types of structure was observed in cases in which a decyl radical was present on the onium nitrogen atom. The most active compounds exhibited antioxidant activity at levels of 0.25 and 0.50 mM and did not display cytotoxic properties towards WI-38 (human embryonic lung cells) and Chang liver (human liver cells) cell lines in the concentration range of 0.70–11.3 μM.

1. Introduction

One modern trend in medicinal chemistry comprises the construction of multifunctional drugs. These compounds are characterized by a broad range of pharmacological effects and are capable of interacting with several targets. This becomes possible owing to the presence of several pharmacophore fragments, of which the effects are combined. These preparations possess more predictable pharmacokinetic profiles, and the risk of incompatibility with other preparations is reduced significantly owing to the decrease in the number of drugs prescribed to a patient.

We have chosen the onium fragment as a basic pharmacophore group. It is known that ammonium salts are of interest as physiologically active compounds.1,2 Onium structures are present in many natural and biologically important compounds (betaines, choline, and acetylcholine). The biomedical application of ammonium salts is based on the presence of local anesthetic, anti-inflammatory, and analgesic, as well as antifungal and antibacterial, activities, owing to their ability to be attracted to the negatively charged bacterial membrane;3–5 they are also able to inhibit human leukocyte elastase.6 Over the past two decades there have appeared a large number of reports on the bactericidal activity of ammonium salts against two main causative agents of sexually transmitted diseases, namely, Chlamydia trachomatis and Neisseria gonorrhoeae.7–9 The exact mechanism of the effect of ammonium salts on bacteria was not studied; however, it is known that they neutralize the charge on membranes10 and dissolve bacterial membranes, whereupon a fatal leakage of the cell contents occurs through the opening.11,12

The need to search for new antimicrobial drugs is justified, because microorganisms develop resistance to pharmaceutical drugs available on the market.13 The resistance of pathogenic bacteria to antibiotics has become a serious problem for the modern healthcare system and medicine in society and threatens the vital activities of mankind. The search for new agents to control resistant bacteria is one of the most important areas in the development of medicinal chemistry.14 It should be noted that many bactericidal quaternary ammonium salts are toxic, do not exhibit selectivity in high concentrations and destroy mammalian cell membranes.15,16

A reduction in toxicity can be achieved by incorporating a sterically hindered phenolic fragment into the molecule.17,18 In addition, sterically hindered 2,6-dialkylphenols are biomimetics of the natural antioxidant α-tocopherol (vitamin E) and represent a class of known phenolic antioxidants. They are used to protect fuels, oils, polymeric materials, and food products from oxidative and thermal destruction; high-performance low-toxicity non-steroidal compounds that possess anti-inflammatory,19,20 antiviral,21 antiallergic,22 antimicrobial,23 and UV-protecting activities24 have been found among them.

Derivatives of 3-(3′,5′-di-tert-butyl-4′-hydroxyphenyl)propionic acid (phenozan) (Fig. 1), also known as IKhFANs, are promising drugs for the therapy of Alzheimer's disease and other forms of dementia.25 A choline fragment provides the anticholinesterase activity of the molecule, whereas a long-chain alkyl group enables penetration through the lipid bilayer of the cell membrane. The hydrophobicity of the substituents on the quaternary nitrogen atom in IKhFANs significantly affects their membranotropic characteristics. As the length of the aliphatic substituent and hence the hydrophobicity of the derivative increases, the echinocytogenic, stomatocytogenic, and hemolytic activities of IKhFANs first increase and then, after passing through a maximum, decrease.

Fig. 1. IKhFANs-10.

IKhFANs that contain methyl groups on the nitrogen atom penetrate through the membrane to an insignificant extent and act less effectively in comparison with more hydrophobic homologs that contain octyl, decyl, and dodecyl groups.26

In addition, an increase in antioxidant activity can also be achieved by the introduction of a phosphoryl group into the molecule together with a sterically hindered phenolic fragment. It is known that phosphorus-containing sterically hindered phenols exhibit antiperoxide activity together with antiradical activity owing to the presence of a phosphoryl group.27 A decrease in the promoting effects of mercury and tin compounds was shown during the long-term oxidation of lipids by peroxide in the presence of phosphoryl-containing sterically hindered phenols.28 Functionalized phosphonates are effective inhibitors of various enzymes, including a series of proteases and esterases;29 they are also used as haptens for the synthesis of catalytic antibodies that possess esterase activity.30 In addition, aminophosphonates that contain a sterically hindered phenolic fragment can be used for the prevention and treatment of degenerative joint diseases (osteoarthritis, cartilage loss after injury), abnormal smooth muscle cell proliferation, enhanced thrombosis and restenosis, as well as cardiovascular and neurological diseases.31,32

Various procedures for the synthesis of aminophosphonates that contain a sterically hindered phenolic fragment are described in the literature.31–33 The main drawbacks of these approaches are the high temperatures of the reaction and the presence of catalysts, as well as the low yields of the products. A convenient approach for the synthesis of new derivatives of sterically hindered phenols that contain a phosphoryl fragment comprises the use of phosphorus-containing 2,6-di-tert-butyl-4-methylene-2,5-cyclohexadienones34 in reactions with nucleophiles. Stable phosphorus-containing methylenequinones easily react with amines35–40 and aminoacetals41,42 to give the products of nucleophilic addition in high yields.

The strategy for the construction of “hybrid” ammonium compounds in this paper is based on a series of sequential transformations. In the first stage, structures are formed that contain a terminal dimethylamino group as a result of the reactions of phosphorylated methylenequinones or the methyl ester of 3,5-di-tert-butyl-4-hydroxyphenylpropionic acid with N,N-dimethylethane-1,2-diamine and N,N-dimethylpropane-1,3-diamine. In the second stage, the target hybrid ammonium structures are prepared as a result of the reaction of the terminal dimethylamino group with various organic bromides, such as aliphatic (ethyl, octyl, decyl, dodecyl, and hexadecyl) bromides and benzyl bromide, which differ in hydrophobicity. As a result of these transformations, the corresponding analogs of IKhFANs can be obtained, which contain an amine bond and an aminophosphonate group with a sterically hindered phenolic fragment. It is known that labile covalent bonds, such as ester bonds, are insufficiently stable in aqueous media over a broad range of pH values and biological media and are susceptible to gradual hydrolysis.43 We expect that IKhFAN analogs that contain an amide bond, which is highly stable in biological media, can be of interest in terms of studying their antimicrobial activity.

In this paper, the structure–property relationship for a broad range of synthesized quaternary onium salts that contain a sterically hindered phenolic fragment and a phosphoryl group is analyzed. From this perspective, this study is accordingly divided into two parts. The first part is devoted to the synthesis of sterically hindered phenols that contain an onium fragment, whereas the second part is devoted to the preparation of their phosphorylated analogs.

2. Results and discussion

2.1. Chemistry

In the first stage, we modified methyl 3-(3,5-di-tert-butyl-4-hydroxyphenyl)propanoate 1 with a dimethylalkanediamine fragment (Scheme 1) according to a previously described procedure.44

Scheme 1. Synthesis of amides 2 and 3.

The reaction of compounds 2 and 3 with ethyl, octyl, decyl, dodecyl, and hexadecyl bromides in a 1 : 1 ratio at room temperature in acetonitrile gave the ammonium salts 4a–e and 5a–e (Scheme 2).

Scheme 2. Synthesis of ammonium salts 4a–e and 5a–e.

In the second approach, aminophosphonates with a terminal tertiary amino group were prepared in the first step, which are of interest as by-products of the synthesis of ammonium salts. Previously, we developed a procedure for the synthesis of ammonium salts that was based on the reaction of diethyl [(3,5-di-tert-butyl-4-oxo-2,5-cyclohexadienylidene)methyl]phosphonate with N,N-dimethylethane-1,2-diamine with the subsequent quaternization of the synthesized aminophosphonate.45 In this work, ammonium salts based on methylenequinones 6b that contain a diisopropylphosphonate fragment were synthesized to determine the structure–property relationship. To increase the length of the spacer in the reactions with methylenequinones 6a and b, N,N-dimethylpropane-1,3-diamine was used.

The reactions of methylenequinones 6a and b with N,N-dimethylethane-1,2-diamine and N,N-dimethylpropane-1,3-diamine occur at room temperature to give the products of nucleophilic 1,6-addition 7a and b and 8a and b in high yields (Scheme 3).

Scheme 3. Synthesis of aminophosphonates 7a and b and 8a and b.

The quaternization reactions of aminophosphonates 7a and b and 8a and b with ethyl, decyl and dodecyl bromides, as well as benzyl bromide, were carried out at room temperature to give products 9a and 9b– 16a and 16b in high yields (Scheme 4). Depending on the nature of the organic bromide, the reactions proceeded in acetonitrile (in the case of the aliphatic bromides) or in toluene (in the case of benzyl bromide).

Scheme 4. Synthesis of ammonium salts 9a and b– 16a and b.

2.2. Biological evaluation

2.2.1. Antimicrobial activity

The antimicrobial (bacteriostatic, fungistatic, bactericidal, and fungicidal) activities of the synthesized ammonium salts that contain sterically hindered phenolic fragments 4a–e, 5a–e, and 9a and 9b– 16a and 16b were studied in vitro in the concentration range of 442–0.70 μM. The results are given in Tables 1 and 2.

Table 1. Bacteriostatic and fungistatic activities of ammonium salts 4a–e, 5a–e, and 9a and 9b– 16a and 16b.

Table 2. Bactericidal and fungicidal activities of ammonium salts 4a–e, 5a–e, and 9a and 9b– 16a and 16b.

The test objects were represented by cultures of Gram-positive bacteria, such as Staphylococcus aureus ATCC 209p and Bacillus cereus ATCC 8035, Gram-negative bacteria, such as Escherichia coli CDC F-50 and Pseudomonas aeruginosa ATCC 9027, and fungi, such as Aspergillus niger BKMF-1119, Trichophyton mentagrophytes var. gypseum 1773, and Candida albicans 855-653.

Bacteriostatic and fungistatic activities were investigated using the serial dilution method in liquid nutrient media in accordance with a previously described procedure46 by the determination of the minimum inhibitory concentration (MIC) that caused suppression of the growth and reproduction of the test microorganisms. Bactericidal and fungicidal activities, which cause the death of the microbial cells, were determined using literature procedures.47,48 The tests were performed in duplicate and repeated twice.

The antibacterial activity of compounds 4a–e, 5a–e, and 9a and 9b– 16a and 16b was observed in the concentration range of 442–0.7 μM. Regarding Gram-positive bacteria, compound 12b was most active; it displayed bactericidal activity with respect to S. aureus 209p that exceeded the bactericidal activity of norfloxacin (fluoroquinolone antibiotic) by a factor of 6. Regarding Gram-negative bacteria, the salts 4c, 5c and 12b were most active. According to their bacteriostatic activity, these compounds were superior to chloramphenicol antibiotics by a factor of 14.

The antifungal activity of the objects under study manifested itself in the concentration range of 432–0.9 μM. Compound 5c was found to be the most active; it exhibited fungicidal activity against C. albicans at a concentration of 0.9 μM and was thus superior to the reference drug ketoconazole by a factor of 8.

A large dataset on the antimicrobial activity of the ammonium salts that contain sterically hindered phenolic fragments was obtained, and it was interesting that it revealed some relationships between structural features and activities. It was determined that the substituents on the phosphorus atom and the spacer length did not significantly affect the activities of the salts. An increase in the lipophilic characteristics of the substituent on the quaternary nitrogen atom in the series of ethyl (4a, 5a, 9a, 9b, 10a, 10b), octyl (4b, 5b), benzyl (15a, 15b, 16a, 16b), and decyl resulted in an increase in antimicrobial activity. However, a further increase in the length of the alkyl substituent on the quaternary nitrogen atom from 10 to 12 (4d, 5d, 13a, 14a) and 16 (4e, 5e) carbon atoms did not give rise to the expected increase in the activity of the salts. It should be noted that the maximum activity of an ammonium salt among all the types of structure under study was observed in cases in which a decyl group was present on the onium nitrogen atom (4c, 5c, 11a, 11b, 12b). These data are consistent with previous studies of IKhFAN derivatives regarding the effect of the hydrophobicity of the substituent on the quaternary nitrogen atom on their membranotropic properties.26

Thus, we showed that phosphorylated sterically hindered phenols that contain an ammonium fragment displayed higher activity with respect to Gram-positive bacteria (Staphylococcus aureus ATCC 209p and Bacillus cereus ATCC 8035), whereas analogous phosphorus-free sterically hindered phenols exhibited higher activity with respect to Gram-negative bacteria (Escherichia coli CDC F-50 and Pseudomonas aeruginosa ATCC 9027) and fungi (Aspergillus niger BKMF-1119, Trichophyton mentagrophytes var. gypseum 1773, and Candida albicans 855-653).

2.2.2. Cytotoxicity

An important characteristic in the design of new drugs is their cytotoxic effect with respect to mammalian cells. The cytotoxicity of the ammonium salt derivatives 11a, 11b, and 12b, which exhibited high antimicrobial activity, was determined against WI-38 (human embryonic lung cells) and Chang liver (human liver cells) cell lines. The studies were carried out in the concentration range in which the growth and reproduction of the bacterial and fungal test strains were inhibited. Cytotoxicity was determined by calculating the number of viable WI-38 (human embryonic lung cells) and Chang liver (human liver cells) cells.49

As follows from the results in Fig. 2 and 3, only compound 11a exhibited a cytotoxic effect at its highest concentration (47.0 μM). At lower concentrations (0.70–11.3 μM), compounds 11a, 11b, and 12b did not display cytotoxic effects with respect to the WI-38 and Chang liver cell lines.

Fig. 2. Determination of cytotoxic effects of compounds with respect to WI-38 cells. The concentrations of the compounds were as follows (μM): 11a (2.9; 11.0; 47.0), 11b (0.70; 2.7; 11.3), and 12b (0.70; 2.7; 11.0).

Fig. 3. Determination of cytotoxic effects of compounds with respect to Chang liver cells. The concentrations of the compounds were as follows (μM): 11a (2.9; 11.0; 47.0), 11b (0.70; 2.7; 11.3), and 12b (0.70; 2.7; 11.0).

2.2.3. Antioxidant activity

It is known that antioxidant therapy is indicated in the treatment of a large number of diseases. In this case, antioxidants are able to reduce the toxicity and, in some cases, to enhance the activity of drugs.17 The antiradical properties of the substances were studied using chemiluminescence by a known procedure50,51 with a Lum-100 chemiluminometer (OOO DISoft, Russia).

Upon the introduction of solutions of the standard antioxidant ionol into the reaction mixture, the chemiluminescence intensity decreased, which indicates the interaction of the substance with free radicals (Fig. 4). In this case, with an increase in the ionol concentration, there was a decrease in the chemiluminescence intensity. One example was that at a concentration of 1 mM the chemiluminescence intensity gradually decreased to 24% of the initial value over 10 min (Fig. 4C). Upon the addition of ionol solutions with concentrations of 0.50 and 0.25 mM to the chemiluminescent system, the decrease in the luminescence intensity was drastic, although it only fell to 44% and 64% of the initial value, respectively (Fig. 4B and A). Moreover, there was a slow rise in the chemiluminescence plot upon the introduction of ionol at a concentration of 0.50 mM, which indicates a gradual loss of the ability of the antioxidant to interact with free radicals.

Fig. 4. Chemiluminescence intensity curves for a system that consisted of ABAP and LM in a buffer solution (total volume of 1.000 mL): the area to the left of the arrow represents the time before the addition of the test substances (baseline); the arrow and the fall of the curve to 0 represent the time of the introduction of the substances; and the increases in the chemiluminescence intensity curves, which are below the baseline, correspond to the interaction of the antioxidant with radicals and their partial inactivation. Plots A, B, and C correspond to chemiluminescence intensity curves for various concentrations of substances: A is 0.25 mM, B is 0.50 mM, and C is 1.00 mM.

Upon the introduction of compounds 10a, 11a, and 12a into the reaction mixture at a concentration of 0.25 mM, similar patterns were observed in the chemiluminescence curves (Fig. 4A). The maximum decrease in the chemiluminescence intensity in the case of the three tested compounds reached 44% of the initial value, which was more pronounced in comparison with the effect of ionol on the system (the maximum decrease only reached 64% of the initial value). Upon the introduction of 10a, 11a, and 12a into the system at a concentration of 0.50 mM, the following mechanism of the interaction of these compounds with free radicals was observed (Fig. 4B). The maximum decreases in the chemiluminescence intensity were identical in the case of all three compounds and reached nearly 26% of the initial value, which was more pronounced in comparison with the effect of ionol. In contrast to those for ionol, the chemiluminescence curves that were recorded upon the introduction of the test compounds into the system at concentrations of 0.25 and 0.50 mM continued to fall over the observation period. These results indicate the occurrence of enhanced antioxidant activity in the cases of compounds 10a, 11a, and 12a in comparison with pure ionol. In the case of 12a, the maximum decrease in the chemiluminescence intensity was observed after delays of 400 s at a concentration of 0.25 mM and 500 s at a concentration of 0.50 mM, respectively.

Upon the introduction of the substances into the system at a concentration of 1 mM, the maximum antioxidant activity was observed in the case of compound 11a, because the maximum decrease in the chemiluminescence intensity to 20% of the initial value was observed under its influence (Fig. 4C) directly after its addition to the system. The antioxidant activities of 10a and 12a at a concentration of 1 mM were similar and did not differ from that of ionol at a concentration of 1 mM: the maximum decrease in the chemiluminescence intensity to 26% of the initial value was only observed 600 s after the addition of these compounds to the system (Fig. 4C).

As follows from the results, compounds 10a, 11a, and 12a were able to interact with free radicals and caused a steady decrease in the chemiluminescence intensity of the 2,2′-azobis(2-methylpropionamidine) dihydrochloride (ABAP) + luminol system, which generates free radicals. At low concentrations (0.25 and 0.50 mM), all the substances exhibited enhanced antioxidant activity in comparison with the standard antioxidant ionol. At a concentration of 1 mM, 11a exhibited the highest activity. Compounds 10a and 12a at a concentration of 1 mM acted in a similar way to ionol, with a trend toward a decrease in antioxidant activity. In the case of compound 12a, lower antioxidant activity was observed.

3. Conclusion

IKhFAN analogues that contain an amide bond have been prepared for the first time via the reaction of 3-(3,5-di-tert-butyl-4-hydroxyphenyl)-N-(2-(dimethylamino)alkyl)propanamide with aliphatic bromides. It has been shown that the addition of phosphorylated methylenequinones to N-nucleophiles (N,N-dimethylethane-1,2-diamine and N,N-dimethylpropane-1,3-diamine) results in novel organophosphorus compounds that contain a sterically hindered phenolic fragment. The quaternization of α-aminophosphonates that contain a terminal dimethylamino group with monobromides (ethyl, decyl, and dodecyl bromides, as well as benzyl bromide) afforded previously unknown ammonium salts. The antimicrobial activity of a broad range of sterically hindered phenols that contain phosphorylated and ammonium fragments has been studied. It has been determined that phosphorylated sterically hindered phenols that contain an ammonium fragment exhibited higher activity with respect to Gram-positive bacteria (Staphylococcus aureus ATCC 209p and Bacillus cereus ATCC 8035), whereas similar phosphorus-free sterically hindered phenols exhibited higher activity with respect to Gram-negative bacteria (Escherichia coli CDC F-50 and Pseudomonas aeruginosa ATCC 9027) and fungi (Aspergillus niger BKMF-1119, Trichophyton mentagrophytes var. gypseum 1773, and Candida albicans 855-653). The maximum activity of an ammonium salt among all the types of structure was observed in cases in which a decyl radical was present on the onium nitrogen atom (4c, 5c, 11a, 11b, 12b). Compounds 11a, 11b, and 12b did not display cytotoxic properties towards WI-38 and Chang liver cell lines in the concentration range of 0.70–11.3 μM. Compounds 10a, 11a, and 12b exhibited enhanced antioxidant activity with respect to the standard antioxidant ionol at concentrations of 0.25 and 0.50 mM.

Thus, we have shown that hybrid ammonium salts that contain sterically hindered phenolic and phosphoryl groups are promising classes of compounds for further studies and exhibit high biological activities of various types.

4. Experimental section

4.1. Chemistry

¹³C NMR spectra were recorded using a Bruker Avance 600 instrument with an operating frequency of 150 MHz. ¹H and ³¹P NMR spectra were obtained with a Bruker MSL-400 spectrometer operating at a frequency of 400.13 and 161.94 MHz, respectively. Mass spectra (MALDI-TOF) were obtained with a Bruker Ultraflex III TOF/TOF spectrometer (p-nitroaniline matrix). IR spectra were recorded using a Bruker Vector 22 Fourier spectrometer in the range of 400–4000 cm^–1 on KBr pellets. Elemental analysis was performed with a Carlo Erba EA 1108 instrument.

4.1.1. Compounds 2 and 3

Compounds 2 and 3 were synthesized by a literature procedure.44

4.1.2. General procedure for the synthesis of compounds 4a–e and 5a–e

To a solution of 0.4 mmol of compound 2 or 3 in 4 mL of acetonitrile, 0.03 mmol of the corresponding bromide was added dropwise. The reaction mixture was maintained at room temperature for 2–3 days; the solvent was removed; and the products were washed with hexane and dried.

4.1.2.1. 2-(3-(3,5-Di-tert-butyl-4-hydroxyphenyl)propanamido)-N-ethyl-N,N-dimethylethanaminium bromide (4a)

Yield: 0.17 g (93%), mp: 108–110 °C. IR (cm^–1): 1654 (C C_arom), 3406 (NH), 3641 (OH). ¹H NMR (CDCl₃) δ 1.36 (t, ³J_HH = 7.4 Hz, 3H, N⁺CH₂CH[combining low line]₃), 1.42 (s, 18H, C(CH[combining low line]₃)₃), 2.57 (m, 2H, C_arom–CH[combining low line]₂CH₂), 2.85 (m, 2H, C_arom–CH₂CH[combining low line]₂), 3.25 (s, 6H, N⁺(CH[combining low line]₃)₂), 3.64 (m, 2H, N⁺CH[combining low line]₂CH₃), 3.72–3.75 (m, 4H, N⁺CH[combining low line]₂CH[combining low line]₂), 5.06 (br.s., 1H, OH), 7.00 (s, 2H, H_arom), 8.26 (br.s., NH). ¹³C NMR (CDCl₃) δ 8.4 (N⁺CH₂C[combining low line]H₃), 30.4 (C(C[combining low line]H₃)₃), 31.3 (C_arom–C[combining low line]H₂), 33.7 (NHC[combining low line]H₂), 34.3 (C[combining low line](CH₃)₃), 38.2 (C(O)C[combining low line]H₂), 51.2 (N⁺(C[combining low line]H₃)₂), 60.9 (N⁺C[combining low line]H₂CH₃), 62.1 (NHCH₂C[combining low line]H₂), 124.9 (C[combining low line]H_arom), 131.3 (C[combining low line]_arom–CH₂), 135.9 (C[combining low line]_arom–C(CH₃)₃), 152.0 (C[combining low line]OH), 173.9 (C[combining low line]O). HRMS (MALDI): calcd for C₂₃H₄₁N₂O₂ [M – Br]⁺ 377, found 377. Anal. calcd for C₂₃H₄₁BrN₂O₂ (%): C 60.38; H 9.03; Br 17.47; N 6.12. Found (%): C 60.30; H 9.14; Br 17.41; N 6.04.

4.1.2.2. N-(2-(3-(3,5-Di-tert-butyl-4-hydroxyphenyl)propanamido)ethyl)-N,N-dimethyloctan-1-aminium bromide (4b)

Yield: 0.20 g (95%), mp: 32–34 °C. IR (cm^–1): 1661 (arom), 3411 (NH), 3644 (OH). ¹H NMR (CDCl₃) δ 0.88 (t, ³J_HH = 6.5 Hz, 3H, N⁺(CH₂)₇CH₃), 1.27–1.34 (m, 10H, N⁺CH₂CH₂(CH[combining low line]₂)₅CH₃), 1.43 (s, 18H, C(CH[combining low line]₃)₃), 1.73 (s, 2H, N⁺CH₂CH[combining low line]₂(CH₂)₅CH₃), 2.58 (m, 2H, C_arom–CH₂CH[combining low line]₂), 2.87 (m, 2H, C_arom–CH[combining low line]_{2[combining low line]}CH₂), 3.26 (s, 6H, N⁺(CH[combining low line]₃)₂), 3.48 (m, 2H, N⁺CH[combining low line]_{2[combining low line]}CH₂(CH₂)₅CH₃), 3.77 (s, 4H, NHCH[combining low line]_{2[combining low line]}CH₂), 5.05 (br.s., 1H, OH), 7.01 (s, 2H, H_arom), 8.30 (br.s., NH). ¹³C NMR (CDCl₃) δ 14.01 (N⁺(CH₂)₇C[combining low line]H₃), 22.5, 22.8 (N⁺CH₂C[combining low line]H₂(CH₂)₄C[combining low line]H₂CH₃), 26.2 (N⁺CH₂CH₂C[combining low line]H₂(CH₂)₄CH₃), 28.9 (N⁺(CH₂)₃(C[combining low line]H₂)₂(CH₂)₃), 30.4 (C(C[combining low line]H₃)₃), 31.3 (C[combining low line](CH₃)₃), 31.3 (N⁺(CH₂)₅C[combining low line]H₂CH₂CH₃), 34.0 (NHC[combining low line]H₂), 34.3 (C_arom–C[combining low line]H₂CH₂), 38.3 (C_arom–CH₂C[combining low line]H₂), 51.6 (N⁺(C[combining low line]H₃)₂), 62.9 (NHCH₂C[combining low line]H₂), 66.0 (CH₂N⁺C[combining low line]H₂), 124.9 (C[combining low line]H_arom), 131.3 (C[combining low line]_arom–CH₂), 135.9 (C[combining low line]_arom–C(CH₃)₃), 152.0 (C[combining low line]OH), 174.05 (C[combining low line]O). HRMS (MALDI): calcd for C₂₉H₅₃N₂O₂ [M – Br]⁺ 461, found 461. Anal. calcd for C₂₉H₅₃BrN₂O₂ (%): C 64.31; H 9.86; Br 14.75; N 5.17. Found (%): C 65.60; H 10.49; Br 14.81; N 5.00.

4.1.2.3. N-(2-(3-(3,5-Di-tert-butyl-4-hydroxyphenyl)propanamido)ethyl)-N,N-dimethyldecan-1-aminium bromide (4c)

Yield: 0.20 g (88%), mp: 44–46 °C. IR (cm^–1): 1663 (arom), 3400 (NH), 3645 (OH). ¹H NMR (CD Cl₃) δ 0.89 (t, ³J_HH = 6.7 Hz, 3H, N⁺(CH₂)₉CH[combining low line]₃), 1.26 (br.s., 14H, N⁺CH₂CH₂(CH[combining low line]₂)₇CH₃), 1.43 (s, 18H, C(CH[combining low line]₃)₃), 1.73 (br.s., 2H, N⁺CH₂CH[combining low line]₂(CH₂)₇CH₃), 2.58 (m, 2H, C_arom–CH[combining low line]₂), 2.86 (m, 2H, C_arom–CH₂CH[combining low line]₂), 3.27 (s, 6H, N⁺(CH[combining low line]₃)₂), 3.49 (m, 2H, N⁺CH[combining low line]₂CH₂(CH₂)₇CH₃), 3.76 (s, 4H, NHCH[combining low line]₂CH[combining low line]₂), 5.05 (br.s., 1H, OH), 7.01 (s, 2H, H_arom), 7.79 (br.s., NH[combining low line]). ¹³C NMR (CDCl₃) δ 14.0 (N⁺(CH₂)₉C[combining low line]H₃), 22.6 (N⁺(CH₂)₈C[combining low line]H₂CH₃), 22.8 (N⁺CH₂C[combining low line]H₂CH₂(CH₂)₆CH₃), 26.2 (N⁺CH₂CH₂C[combining low line]H₂(CH₂)₆CH₃), 29.1–29.3 (N⁺(CH₂)₃(C[combining low line]H₂)₄), 30.3 (C(C[combining low line]H₃)₃), 31.3 (C_arom–C[combining low line]H₂CH₂), 31.8 (N⁺CH₂(CH₂)₆C[combining low line]H₂CH₂CH₃), 34.0 (NHC[combining low line]H₂), 34.3 (C[combining low line](CH₃)₃), 38.3 (C_arom–CH₂C[combining low line]H₂), 51.6 (N⁺(C[combining low line]H₃)₂), 62.8 (C[combining low line]H₂N⁺CH₂), 65.95 (CH₂N⁺C[combining low line]H₂), 124.9 (C[combining low line]H_arom), 131.2 (C[combining low line]_arom–CH₂), 135.8 (C[combining low line]_arom–C(CH₃)₃), 152.0 (C[combining low line]OH), 174.0 (C[combining low line]O). HRMS (MALDI): calcd for C₃₁H₅₇N₂O₂ [M – Br]⁺ 489, found 489. Anal. calcd for C₃₁H₅₇BrN₂O₂ (%): C 65.36; H 10.08; Br 14.03; N 4.92. Found (%): C 65.35; H 10.17; Br 13.96; N 4.85.

4.1.2.4. N-(2-(3-(3,5-Di-tert-butyl-4-hydroxyphenyl)propanamido)ethyl)-N,N-dimethyldodecan-1-aminium bromide (4d)

Yield: 0.22 g (92%), mp: 38–40 °C. IR (cm^–1): 1664 (arom), 3395 (NH), 3647 (OH). ¹H NMR (CDCl₃) δ 0.90 (t, ³J_HH = 6.7 Hz, 3H, N⁺(CH₂)₁₁CH[combining low line]₃), 1.27 (br.s., 18H, N⁺CH₂CH₂(CH[combining low line]₂)₉CH₃), 1.44 (s, 18H, C(CH[combining low line]₃)₃), 1.74 (br.s., 2H, N⁺CH₂CH[combining low line]₂), 2.60 (m, 2H, C_arom–CH[combining low line]₂), 2.88 (m, 2H, C_arom–CH[combining low line]₂CH₂), 3.25 (s, 6H, N⁺(C[combining low line]H₃)₂), 3.44–3.48 (m, 2H, N⁺CH[combining low line]₂CH₂(CH₂)₉CH₃), 3.79 (s, 4H, CH[combining low line]₂N⁺CH[combining low line]₂), 5.05 (br.s., 1H, OH), 7.03 (s, 2H, H_arom), 8.35 (br.s., 1H, NH[combining low line]). ¹³C NMR (CDCl₃) δ 14.0 (N⁺(CH₂)₁₁C[combining low line]H₃), 22.6 (N⁺(CH₂)₁₀C[combining low line]H₂CH₃), 22.8 (N⁺CH₂C[combining low line]H₂CH₂), 26.2 (N⁺CH₂CH₂C[combining low line]H₂), 29.3, 29.6 (N⁺(CH₂)₃(C[combining low line]H₂)₇), 30.3 (C(C[combining low line]H₃)₃), 31.9 (N⁺(CH₂)₁₀C[combining low line]H₂), 34.0 (C_arom–C[combining low line]H₂CH₂), 34.3 (C_arom–CH₂C[combining low line]H₂), 38.3 (NHC[combining low line]H₂CH₂), 51.6 (N⁺(C[combining low line]H₃)₂), 62.9 (NHCH₂C[combining low line]H₂), 66.2 (CH₂N⁺C[combining low line]H₂), 125.0 (C[combining low line]H_arom), 131.2 (C[combining low line]_arom–CH₂), 135.8 (C[combining low line]_arom–C(CH₃)₃), 152.0 (C[combining low line]OH), 174.0 (C[combining low line]O). HRMS (MALDI): calcd for C₃₃H₆₁N₂O₂ [M – Br]⁺ 517, found 517. Anal. calcd for C₃₃H₆₁BrN₂O₂ (%): C 66.31; H 10.29; Br 13.37; N 4.69. Found (%): C 66.33; H 10.21; Br 13.42; N 4.54.

4.1.2.5. N-(2-(3-(3,5-Di-tert-butyl-4-hydroxyphenyl)propanamido)ethyl)-N,N-dimethylhexadecan-1-aminium bromide (4e)

Yield: 0.24 g (92%), mp: 32–34 °C. IR (cm^–1): 1652 (arom), 3410 (NH), 3645 (OH). ¹H NMR (CDCl₃) δ 0.88 (t, ³J_HH = 7.13 Hz, 3H, N⁺(CH₂)₁₅CH[combining low line]₃), 1.26–1.30 (m, 26H, N⁺CH₂CH₂(CH[combining low line]₂)₁₃CH₃), 1.42 (s, 18H, C(CH[combining low line]₃)₃), 1.72 (br.s., 2H, N⁺CH₂CH[combining low line]₂(CH₂)₁₃CH₃), 2.58 (m, 2H, C_arom–CH₂CH[combining low line]₂), 2.86 (m, 2H, C_arom–CH[combining low line]₂CH₂), 3.26 (s, 6H, N⁺(CH[combining low line]_{3[combining low line]})₂), 3.48 (m, 2H, N⁺CH[combining low line]₂CH₂(CH₂)₁₃CH₃), 3.77 (s, 4H, NHCH[combining low line]_{2[combining low line]}CH[combining low line]₂N⁺), 5.05 (br.s., 1H, OH), 7.01 (s, 2H, H_arom), 8.29 (br.s., 1H, NH[combining low line]). ¹³C NMR (CDCl₃) δ 14.1 (N⁺(CH₂)₁₅C[combining low line]H₃), 22.7 (N⁺CH₂C[combining low line]H₂(CH₂)₁₃CH₃), 22.7 (N⁺(CH₂)₁₄C[combining low line]H₂CH₃), 26.3 (N⁺(CH₂)₂C[combining low line]H₂(CH₂)₁₂CH₃), 29.4 (N⁺(CH₂)₃(C[combining low line]H₂)₉(CH₂)₂CH₃), 30.4 (C[combining low line](CH₃)₃), 31.4 (C[combining low line](CH₃)₃, N⁺(CH₂)₁₃C[combining low line]H₂CH₂CH₃), 31.9 (NHC[combining low line]H₂CH₂), 34.3 (C_arom–C[combining low line]H₂CH₂), 38.4 (C_arom–CH₂C[combining low line]H₂), 51.6 (N⁺(C[combining low line]H₃)₂), 62.7 (NHCH₂C[combining low line]H₂), 66.0 (CH₂N⁺C[combining low line]H₂), 125.0 (C[combining low line]H_arom), 131.3 (C[combining low line]_arom–CH₂), 135.8 (C[combining low line]_arom–C(CH₃)₃), 152.0 (C[combining low line]OH), 174.0 (C[combining low line]O). HRMS (MALDI): calcd for C₃₇H₆₉N₂O₂ [M – Br]⁺ 573, found 573. Anal. calcd for C₃₇H₆₉BrN₂O₂ (%): C 67.96; H 10.64; Br 12.22; N 4.28. Found (%): C 68.03; H 10.71; Br 12.16; N 4.34.

4.1.2.6. 3-(3-(3,5-Di-tert-butyl-4-hydroxyphenyl)propanamido)-N-ethyl-N,N-dimethylpropan-1-aminium bromide (5a)

Yield: 0.17 g (90%), mp: 46–48 °C. IR (cm^–1): 1652 (C C_arom), 1725 (CO), 3425 (NH), 3641 (OH). ¹H NMR (CDCl₃) δ 1.39–1.40 (m, 21H, N⁺CH₂CH[combining low line]₃, C(CH[combining low line]₃)₃), 2.06–2.09 (m, 2H, NHCH₂CH[combining low line]₂CH₂), 2.61 (m, 2H, C_arom–CH[combining low line]₂CH₂), 2.88 (m, 2H, C_arom–CH₂CH[combining low line]₂), 3.23 (s, 6H, N⁺(CH[combining low line]₃)₂), 3.39 (m, 2H, N⁺CH[combining low line]₂CH₃), 3.52–3.56 (m, 2H, NH(CH₂)₂CH[combining low line]₂), 3.81 (m, 2H, NHCH[combining low line]₂(CH₂)₂), 5.05 (br.s., 1H, OH), 7.03 (s, 2H, H_arom), 8.26 (br.s., NH). ¹³C NMR (CDCl₃) δ 8.5 (N⁺CH₂C[combining low line]H₃), 22.8 (NHCH₂C[combining low line]H₂), 30.4 (C(C[combining low line]H₃)₃), 31.7 (C_arom–C[combining low line]H₂), 34.3 (C[combining low line](CH₃)₃), 36.1 (C_arom–CH₂C[combining low line]H₂), 38.5 (NHC[combining low line]H₂), 50.4 (N⁺(C[combining low line]H₃)₂), 60.1 (N⁺C[combining low line]H₂CH₃), 62.3 (C[combining low line]H₂N⁺CH₂), 125.0 (C[combining low line]H_arom), 131.6 (C[combining low line]_arom–CH₂), 135.8 (C[combining low line]_arom–C(CH₃)₃), 151.9 (C[combining low line]OH), 173.9 (C[combining low line]O). HRMS (MALDI): calcd for C₂₄H₄₃N₂O₂ [M – Br]⁺ 391, found 391. Anal. calcd for C₂₄H₄₃BrN₂O₂ (%): C 61.13; H 9.69; Br 16.95; N 6.42. Found (%): C 61.09; H 9.72; Br 16.87; N 6.53.

4.1.2.7. N-(3-(3-(3,5-Di-tert-butyl-4-hydroxyphenyl)propanamido)propyl)-N,N-dimethyloctan-1-aminium bromide (5b)

Yield: 0.20 g (90%), mp: 30–32 °C. IR (cm^–1): 1660 (arom), 1725 (CO), 3645 (OH). ¹H NMR (CDCl₃) δ 0.87 (t, ³J_HH = 5.59 Hz, 3H, N⁺(CH₂)₇CH[combining low line]₃), 1.26–1.35 (m, 10H, N⁺CH₂CH₂(CH[combining low line]₂)₅CH₃), 1.42 (s, 18H, C(CH[combining low line]₃)₃), 1.72 (br.s., 2H, N⁺CH₂CH[combining low line]₂(CH₂)₅CH₃), 2.08 (br.s., 2H, NHCH₂CH[combining low line]_{2[combining low line]}CH₂), 2.59 (m, 2H, C_arom–CH₂CH[combining low line]₂), 2.86 (m, 2H, C_arom–CH[combining low line]_{2[combining low line]}CH₂), 3.26 (s, 6H, N⁺(CH[combining low line]₃)₂), 3.37–3.39 (m, 4H, CH[combining low line]_{2[combining low line]}N⁺CH[combining low line]_{2[combining low line]}), 3.80 (m, 2H, NHCH[combining low line]_{2[combining low line]}), 5.03 (br.s., 1H, OH), 7.02 (s, 2H, H_arom), 7.80 (br.s., NH). ¹³C NMR (CDCl₃) δ 14.00 (N⁺(CH₂)₇C[combining low line]H₃), 22.5, 22.8 (N⁺CH₂C[combining low line]H₂(CH₂)₄C[combining low line]H₂CH₃), 26.3 (NHCH₂C[combining low line]H₂CH₂), 28.9–29.0 (N⁺CH₂CH₂C[combining low line]H₂(CH₂)₂C[combining low line]H₂CH₃), 30.4 (N⁺(CH₂)₃(C[combining low line]H₂)₂(CH₂)₃), 31.6 (C[combining low line](CH₃)₃), 31.7 (C(C[combining low line]H₃)₃), 34.3 (C_arom–C[combining low line]H₂CH₂), 36.1 (C_arom–CH₂C[combining low line]H₂), 38.6 (NHC[combining low line]H₂), 51.0 (N⁺(C[combining low line]H₃)₂), 63.0 (NHCH₂CH₂C[combining low line]H₂), 64.9 (CH₂N⁺C[combining low line]H₂), 125.0 (C[combining low line]H_arom), 131.6 (C[combining low line]_arom–CH₂), 135.8 (C[combining low line]_arom–C(CH₃)₃), 151.9 (C[combining low line]OH), 174.0 (C[combining low line]O). HRMS (MALDI): calcd for C₃₀H₅₅N₂O₂ [M – Br]⁺ 475, found 475. Anal. calcd for C₃₀H₅₅BrN₂O₂ (%): C 64.84; H 9.98; Br 14.38; N 5.04. Found (%): C 64.80; H 10.03; Br 14.44; N 4.98.

4.1.2.8. N-(3-(3-(3,5-Di-tert-butyl-4-hydroxyphenyl)propanamido)propyl)-N,N-dimethyldecan-1-aminium bromide (5c)

Yield: 0.21 g (90%), mp: 116–118 °C. IR (cm^–1): 1660 (arom), 3400 (NH), 3647 (OH). ¹H NMR (CDCl₃) δ 0.89 (t, ³J_HH = 6.9 Hz, 3H, N⁺(CH₂)₉CH[combining low line]₃), 1.27–1.36 (m, 14H, N⁺(CH[combining low line]₂)₇CH₃), 1.43 (s, 18H, C(CH[combining low line]₃)₃), 1.73 (br.s., 2H, N⁺CH₂CH[combining low line]₂(CH₂)₇CH₃), 2.09 (br.s., 2H, NHCH₂CH[combining low line]₂), 2.60–2.63 (m, 2H, C_arom–CH₂CH[combining low line]₂), 2.86–2.89 (m, 2H, C_arom–CH[combining low line]₂), 3.25 (s, 6H, N⁺(CH[combining low line]₃)₂), 3.24–3.42 (m, 4H, CH[combining low line]₂N⁺CH[combining low line]₂), 3.80–3.84 (m, 2H, NHCH[combining low line]₂), 5.04 (br.s., 1H, OH), 7.03 (s, 2H, H_arom), 7.79 (br.s., NH). ¹³C NMR (CDCl₃) δ 14.0 (N⁺CH₂C[combining low line]H₃), 22.7, 22.6 (C[combining low line]H₂CH₂N⁺C[combining low line]H₂CH₃), 26.2 (N⁺CH₂CH₂C[combining low line]H₂), 29.1 (N⁺CH₂C[combining low line]H₂CH₂), 29.3 (N⁺(CH₂)₃(C[combining low line]H₂)₄), 30.1 (N⁺C[combining low line]H₂CH₂CH₃), 30.9 (C_arom–C[combining low line]H₂), 31.3 (C(C[combining low line]H₃)₃), 34.3 (C[combining low line](CH₃)₃), 36.1 (C_arom–CH₂C[combining low line]H₂), 38.5 (NHC[combining low line]H₂), 50.9 (N⁺(C[combining low line]H₃)₂), 62.9 (C[combining low line]H₂N⁺CH₂), 64.8 (CH₂N⁺C[combining low line]H₂), 124.9 (C[combining low line]H_arom), 131.6 (C[combining low line]_arom–CH₂), 135.8 (C[combining low line]_arom–C(CH₃)₃), 151.9 (C[combining low line]OH), 173.92 (C[combining low line]O). HRMS (MALDI): calcd for C₃₂H₅₉N₂O₂ [M – Br]⁺ 503, found 503. Anal. calcd for C₃₂H₅₉BrN₂O₂ (%): C 65.84; H 10.19; Br 13.69; N 4.80. Found (%): C 65.75; H 10.21; Br 13.61; N 4.75.

4.1.2.9. N-(3-(3-(3,5-Di-tert-butyl-4-hydroxyphenyl)propanamido)propyl)-N,N-dimethyldodecan-1-aminium bromide (5d)

Yield: 0.23 g (94%), mp: 44–46 °C. IR (cm^–1): 1658 (arom), 3404 (NH), 3647 (OH). ¹H NMR (CDCl₃) δ 0.90 (t, ³J_HH = 6.7 Hz, 3H, N⁺(CH₂)₁₁CH[combining low line]₃), 1.28 (br.s., 18H, N⁺CH₂CH₂(CH[combining low line]₂)₉CH₃), 1.44 (s, 18H, C(CH[combining low line]₃)₃), 1.75 (br.s., 2H, N⁺CH₂CH[combining low line]₂(CH₂)₉CH₃), 2.09 (br.s., 2H, NHCH₂CH[combining low line]₂CH₂N⁺), 2.61 (m, 2H, C_arom–CH₂CH[combining low line]₂), 2.87 (m, 2H, C_arom–CH[combining low line]₂), 3.24 (s, 6H, N⁺(C[combining low line]H₃)₂), 3.33–3.40 (m, 4H, CH[combining low line]₂N⁺CH[combining low line]₂), 3.84 (m, 2H, NHCH[combining low line]₂), 5.04 (br.s., 1H, OH), 7.06 (s, 2H, H_arom). ¹³C NMR (CDCl₃) δ 14.0 (N⁺(CH₂)₁₁C[combining low line]H₃), 22.8, 22.7 (C[combining low line]H₂CH₂N⁺(CH₂)₁₀C[combining low line]H₂CH₃), 26.1 (N⁺CH₂C[combining low line]H₂CH₂), 26.2 (N⁺CH₂CH₂C[combining low line]H₂), 29.6, 29.3 (N⁺(CH₂)₃(C[combining low line]H₂)₆), 30.4 (C(C[combining low line]H₃)₃), 31.7 (C_arom–C[combining low line]H₂CH₂), 31.9 (N⁺(CH₂)₉C[combining low line]H₂), 34.3 (C[combining low line](CH₃)₃), 36.1 (C_arom–CH₂C[combining low line]H₂), 38.6 (NHC[combining low line]H₂), 50.9 (N⁺(C[combining low line]H₃)₂), 62.9 (C[combining low line]H₂N⁺CH₂), 64.8 (CH₂N⁺C[combining low line]H₂), 125.0 (C[combining low line]H_arom), 131.6 (C[combining low line]_arom–CH₂), 135.7 (C[combining low line]_arom–C(CH₃)₃), 151.9 (C[combining low line]OH), 173.9 (C[combining low line]O). HRMS (MALDI): calcd for C₃₃H₆₁N₂O₂ [M – Br]⁺ 531, found 531. Anal. calcd for C₃₃H₆₁BrN₂O₂ (%): C 66.75; H 10.38; Br 13.06; N 4.58. Found (%): C 66.77; H 10.31; Br 12.99; N 4.45.

4.1.2.10. N-(2-(3-(3,5-Di-tert-butyl-4-hydroxyphenyl)propanamido)ethyl)-N,N-dimethylhexadecan-1-aminium bromide (5e)

Yield: 0.24 g (90%), mp: 28–30 °C. IR (cm^–1): 1653 (arom), 3408 (NH), 3646 (OH). ¹H NMR (CDCl₃) δ 0.88 (t, ³J_HH = 6.3 Hz, 3H, N⁺(CH₂)₁₅CH[combining low line]₃), 1.25 (br.s., 26H, N⁺CH₂CH₂(CH[combining low line]₂)₁₃CH₃), 1.42 (s, 18H, C(CH[combining low line]₃)₃), 1.72 (br.s., 2H, N⁺CH₂CH[combining low line]₂(CH₂)₁₃CH₃), 2.07 (br.s., 2H, NHCH₂CH[combining low line]₂CH₂N⁺), 2.60 (m, 2H, C_arom–CH₂CH[combining low line]₂), 2.87 (m, 2H, C_arom–CH[combining low line]₂CH₂), 3.24 (s, 6H, N⁺(CH[combining low line]_{3[combining low line]})₂), 3.32–3.39 (m, 4H, CH[combining low line]₂N⁺CH[combining low line]₂), 3.82 (m, 2H, NHCH[combining low line]₂), 5.03 (br.s., 1H, OH), 7.02 (s, 2H, H_arom), 8.29 (br.s., 1H, NH). ¹³C NMR (CDCl₃) δ 14.1 (N⁺(CH₂)₁₅C[combining low line]H₃), 22.6 (N⁺CH₂C[combining low line]H₂(CH₂)₁₃C[combining low line]H₂CH₃), 22.8 (NHCH₂C[combining low line]H₂CH₂), 26.3 (N⁺(CH₂)₂C[combining low line]H₂(CH₂)₁₂CH₃), 29.1 (N⁺(CH₂)₃(C[combining low line]H₂)₉(CH₂)₂CH₃), 29.3 (N⁺(CH₂)₁₃C[combining low line]H₂CH₂CH₃), 30.4 (C(C[combining low line]H₃)₃), 31.9 (C[combining low line](CH₃)₃), 34.3 (C_arom–C[combining low line]H₂CH₂), 36.2 (C_arom–CH₂C[combining low line]H₂), 38.6 (NHC[combining low line]H₂CH₂), 51.0 (N⁺(C[combining low line]H₃)₂), 62.9 (NH(CH₂)₂C[combining low line]H₂), 64.8 (CH₂N⁺C[combining low line]H₂), 125.0 (C[combining low line]H_arom), 131.7 (C[combining low line]_arom–CH₂), 135.8 (C[combining low line]_arom–C(CH₃)₃), 151.9 (C[combining low line]OH), 173.9 (C[combining low line]O). HRMS (MALDI): calcd for C₃₃H₆₁N₂O₂ [M – Br]⁺ 587, found 587. Anal. calcd for C₃₃H₆₁BrN₂O₂ (%): C, 68.34; H, 10.71; Br, 11.96; N, 4.19. Found (%): C, 68.28; H, 10.75; Br, 11.90; N, 4.23.

4.1.3. General procedure for the synthesis of compounds 7a and b and 8a and b

To a solution of 1.12 mmol of the appropriate methylenequinone 6a or b in 3 mL of methylene dichloride, 1.09 mmol of the corresponding amine (N,N-dimethyl-1,2-diaminoethane or N,N-dimethyl-1,3-diaminopropane) was added dropwise. The reaction mixture was maintained at room temperature for 5 h in a dry argon flow; the solvent was removed; and the products were washed with pentane and dried.

4.1.3.1. Diethyl ((3,5-di-tert-butyl-4-hydroxyphenyl)((2-(dimethylamino)ethyl)amino)methyl)phosphonate (7a)

Yield: 0.50 g (100%), mp: 83–85 °C. IR (cm^–1): 1056 (POC), 1236 (PO), 1654 (arom), 3367 (NH), 3612 (OH). ¹H NMR (CDCl₃) δ 1.09 (t, ³J_HH = 7.1 Hz, 3H, CH₃), 1.25 (t, ³J_HH = 7.1 Hz, 3H, CH₃), 1.41 (s, 18H, t-Bu), 2.14 (s, 6H, N(CH₃)₂), 2.23 (s, 1H, NH), 2.36 (m, 2H, NCH₂), 2.57 (m, 2H, NHCH₂), 3.91 (d, ²J_PH = 19.0 Hz, 1H, CH), 3.76–4.05 (m, 4H, OCH₂), 5.15 (br.s., 1H, OH), 7.16 (d, ⁴J_PH = 2.3 Hz, 2H, H_arom). ¹³C NMR (CDCl₃) δ 16.1 (C[combining low line]H₃), 16.2 (C[combining low line]H₃), 16.3 (C[combining low line]H₃), 16.4 (C[combining low line]H₃), 30.3 (C(C[combining low line]H₃)₃), 34.3 (C[combining low line](CH₃)₃), 45.3 (N(CH₃)₂), 45.4 (NHCH₂), 45.6 (NHCH₂), 58.9 (NCH₂), 61.2 (CH, J_PC = 154.1 Hz), 62.3 (OCH₂, J_PC = 6.6 Hz), 62.4 (OCH₂, J_PC = 6.9 Hz), 125.0 (C[combining low line]_aromCH, J_PC = 6.3 Hz), 126.3 (CH_arom, J_PC = 3.5 Hz), 135.8 (C[combining low line]_aromC(CH₃)₃, J_PC = 1.6 Hz), 154.3 (C_aromOH, J_PC = 3.2 Hz). ³¹P NMR (CDCl₃) δ 24.9. HRMS (MALDI): calcd for C₂₃H₄₃N₂O₄P [M]⁺ 443, found 443. Anal. calcd for C₂₃H₄₃N₂O₄P (%): C, 62.42; H, 9.79; N, 6.33; P, 7.00. Found (%): C, 62.48; H, 9.83; N, 6.30; P, 6.95.

4.1.3.2. Diisopropyl ((3,5-di-tert-butyl-4-hydroxyphenyl)((2-(dimethylamino)ethyl)amino)methyl)phosphonate (7b)

Yield: 0.52 g (99%), mp: 82–84 °C. IR (cm^–1): 1049 (POC), 1234 (PO), 1650 (arom), 3362 (NH), 3610 (OH). ¹H NMR (CDCl₃) δ 0.94 (d, ³J_HH = 6.2 Hz, 3H, OCH(CH[combining low line]_{3[combining low line]})₂), 1.22 (d, ³J_HH = 6.2 Hz, 3H, OCH(CH[combining low line]_{3[combining low line]})₂), 1.26 (d, ³J_HH = 6.2 Hz, 3H, OCH(CH[combining low line]_{3[combining low line]})₂), 1.27 (d, ³J_HH = 6.2 Hz, 3H, OCH(CH[combining low line]_{3[combining low line]})₂), 1.42 (s, 18H, t-Bu), 2.20 (s, 6H, N(CH₃)₂), 2.4 (m, 2H, NHCH₂CH[combining low line]₂), 2.6 (m, 2H, NHCH₂), 3.85 (d, ²J_PH = 19.0 Hz, 1H, CH), 4.46 (m, 1H, OCH), 4.66 (m, 1H, OCH), 5.13 (s, 1H, OH), 7.18 (d, ⁴J_PH = 2.1 Hz, 2H, H_arom). ¹³C NMR (CDCl₃) δ 23.3 (C[combining low line]H₃), 23.9 (C[combining low line]H₃), 24.1 (C[combining low line]H₃), 24.3 (C[combining low line]H₃), 30.3 (C(C[combining low line]H₃)₃), 34.3 (C[combining low line](CH₃)₃), 45.3 (N(CH₃)₂), 45.6 (NHCH₂), 45.7 (NHCH₂), 58.9 (NCH₂), 61.7 (CH, J_PC = 155.7 Hz), 70.8 (OCH₂, J_PC = 7.4 Hz), 71.0 (OCH₂, J_PC = 7.1 Hz), 125.3 (C[combining low line]_aromCH, J_PC = 6.4 Hz), 126.7 (CH_arom, J_PC = 2.7 Hz), 135.6 (C[combining low line]_aromC(CH₃)₃, J_PC = 1.8 Hz), 154.3 (C_aromOH, J_PC = 3.0 Hz). ³¹P NMR (CDCl₃) δ 22.9. HRMS (MALDI): calcd for C₂₅H₄₇N₂O₄P [M]⁺ 471, found 471. Anal. calcd for C₂₅H₄₇N₂O₄P (%): C, 63.80; H, 10.07; N, 5.95; P, 6.58. Found (%): C, 63.72; H, 9.99; N, 6.09; P, 6.63.

4.1.3.3. Diethyl ((3,5-di-tert-butyl-4-hydroxyphenyl)((3-(dimethylamino)propyl)amino)methyl)phosphonate (8a)

Yield: 0.49 g (97%), mp: 100–101 °C. IR (cm^–1): 1050 (POC), 1235 (PO), 1656 (arom), 3360 (NH), 3616 (OH). ¹H NMR (CDCl₃) δ 1.21 (t, ³J_HH = 7.06 Hz, 3H, CH₃), 1.27 (t, ³J_HH = 7.06 Hz, 3H, CH₃), 1.43 (s, 18H, t-Bu), 1.64 (m, NHCH₂CH[combining low line]₂CH₂), 2.21 (s, 6H, N(CH₃)₂), 2.24–2.36 (m, 2H, CH₂N), 2.58 (m, 2H, NHCH₂), 3.79 (m, 1H, CH), 3.95 (m, 2H, OCH₂), 4.03 (m, 2H, OCH₂), 5.16 (s, 1H, OH), 7.17 (d, ⁴J_PH = 2.08 Hz, 2H, H_arom). ¹³C NMR (CDCl₃) δ 16.2 (C[combining low line]H₃), 16.3 (C[combining low line]H₃), 16.4 (C[combining low line]H₃), 16.5 (C[combining low line]H₃), 27.8 (NHCH₂CH[combining low line]₂CH₂), 30.3 (C(C[combining low line]H₃)₃), 34.3 (C[combining low line](CH₃)₃), 45.2 (NHCH₂), 45.3 (N(CH₃)₂), 45.5 (NHCH₂), 58.8 (NCH₂), 61.0 (CH, J_PC = 153.3 Hz), 62.5 (OCH₂, J_PC = 6.6 Hz), 62.6 (OCH₂, J_PC = 6.9 Hz), 124.0 (C[combining low line]_aromCH, J_PC = 6.1 Hz), 126.1 (CH_arom, J_PC = 4.2 Hz), 135.7 (C[combining low line]_arom–C(CH₃)₃, J_PC = 2.4 Hz), 154.3 (C_aromOH, J_PC = 3.4 Hz). ³¹P NMR (CDCl₃) δ 24.3. HRMS (MALDI): calcd for C₂₄H₄₅N₂O₄P [M]⁺ 456, found 456. Anal. calcd for C₂₄H₄₅N₂O₄P (%): C, 63.13; H, 9.93; N, 6.14; P, 6.78. Found (%): C, 63.22; H, 9.89; N, 6.33; P, 7.00.

4.1.3.4. Diisopropyl ((3,5-di-tert-butyl-4-hydroxyphenyl)((3-(dimethylamino)propyl)amino)methyl)phosphonate (8b)

Yield: 0.52 g (97%), mp: 84–86 °C. IR (cm^–1): 1055 (POC), 1230 (PO), 1657 (arom), 3366 (NH), 3610 (OH). ¹H NMR (CDCl₃) δ 0.94 (d, ³J_HH = 6.18 Hz, 3H, OCH(CH[combining low line]_{3[combining low line]})₂), 1.21 (d, ³J_HH = 6.18 Hz, 3H, OCH(CH[combining low line]_{3[combining low line]})₂), 1.25 (d, ³J_HH = 6.18 Hz, 3H, OCH(CH[combining low line]_{3[combining low line]})₂), 1.26 (d, ³J_HH = 6.18 Hz, 3H, OCH(CH[combining low line]_{3[combining low line]})₂), 1.42 (s, 18H, t-Bu), 1.63 (m, 2H, NHCH₂CH[combining low line]₂CH₂), 2.20 (s, 6H, N(CH₃)₂), 2.28 (m, 2H, NCH₂), 2.56 (m, 2H, NHCH[combining low line]₂), 3.84 (d, ²J_PH = 19.0 Hz, 1H, CH), 4.45 (m, 1H, OCH), 4.65 (m, 1H, OCH), 5.13 (s, 1H, OH), 7.12 (d, ⁴J_PH = 1.9 Hz, 2H, H_arom). ¹³C NMR (CDCl₃) δ 23.3 (C[combining low line]H₃), 23.9 (C[combining low line]H₃), 24.1 (C[combining low line]H₃), 24.3 (C[combining low line]H₃), 27.9 (NHCH₂C[combining low line]H₂CH₂), 30.3 (C(C[combining low line]H₃)₃), 34.3 (C[combining low line](CH₃)₃), 45.4 (N(CH₃)₂), 46.3 (NHCH₂), 46.4 (NHCH₂), 57.9 (NCH₂), 61.5 (CH, J_PC = 155.2 Hz), 70.8 (OCH₂, J_PC = 7.3 Hz), 71.0 (OCH₂, J_PC = 7.1 Hz), 125.2 (C[combining low line]_aromCH, J_PC = 6.3 Hz), 126.7 (CH_arom, J_PC = 3.5 Hz), 135.6 (C[combining low line]_aromC(CH₃)₃, J_PC = 1.8 Hz), 153.3 (C_aromOH, J_PC = 3.1 Hz). ³¹P NMR (CDCl₃) δ 22.9. HRMS (MALDI): calcd for C₂₆H₄₉N₂O₄P [M]⁺ 483, found 483. Anal. calcd for C₂₆H₄₉N₂O₄P (%): C, 64.43; H, 10.19; N, 5.78; P, 6.39. Found (%): C, 64.42; H, 10.25; N, 5.69; P, 6.34.

4.1.4. General procedure for the synthesis of compounds 9a and 9b– 16a and 16b

To a solution of 0.23 mmol of compound 7a or b or 8a or b in 2 mL of acetonitrile/toluene, 0.3 mmol of the corresponding alkyl bromide was added dropwise. The reaction mixture was maintained at room temperature for 12 h in a dry argon flow. The solvent was removed, and the light-yellow product was washed with diethyl ether and dried.

4.1.4.1. 2-(((3,5-Di-tert-butyl-4-hydroxyphenyl)(diethoxyphosphoryl)methyl)amino)-N-ethyl-N,N-dimethylethan-1-aminium bromide (9a)

Yield: 0.12 g (95%), mp: 92–93 °C. IR (cm^–1): 1024 (POC), 1237 (PO), 1653 (arom), 3634 (OH). ¹H NMR (CD₃OD) δ 1.13 (t, ³J_HH = 6.6 Hz, 3H, OCH₂CH[combining low line]_{3[combining low line]}), 1.31 (t, ³J_HH = 6.8 Hz, 3H, OCH₂CH[combining low line]_{3[combining low line]}), 1.36 (t, ³J_HH = 7.0 Hz, 3H, N⁺CH₂CH[combining low line]_{3[combining low line]}), 1.46 (s, 18H, t-Bu), 2.98–3.07 (m, 2H, NHCH₂), 3.16 (s, 6H, N⁺CH₃), 3.44–3.50 (m, 4H, N⁺CH[combining low line]_{2[combining low line]}, N⁺CH[combining low line]_{2[combining low line]}CH₃), 3.81–4.11 (m, 5H, OCH₂, CH), 7.27 (d, ⁴J_PH = 2.1 Hz, 2H, H_arom). ¹³C NMR (CD₃OD) δ 7.3 (N⁺CH₂C[combining low line]H₃), 7.4 (N⁺CH₂C[combining low line]H₃), 15.4 (C[combining low line]H₃), 15.6 (C[combining low line]H₃), 29.6 (C(C[combining low line]H₃)₃), 34.3 (C[combining low line](CH₃)₃), 41.4 (NHCH₂), 41.5 (NHCH₂), 50.4 (N⁺(CH₃)₂), 59.6 (CH, J_PC = 157.2 Hz), 60.4 (N⁺C[combining low line]H₂CH₃), 61.9 (NCH₂), 62.6 (OCH₂, J_PC = 7.5 Hz), 63.0 (OCH₂, J_PC = 7.2 Hz), 125.1 (C[combining low line]_aromCH, J_PC = 6.4 Hz), 125.4 (CH_arom, J_PC = 2.3 Hz), 138.2 (C[combining low line]_aromC(CH₃)₃, J_PC = 2.0 Hz), 154.1 (C_aromOH, J_PC = 3.1 Hz). ³¹P NMR (CD₃OD) δ 24.2. HRMS (MALDI): calcd for C₂₅H₄₈N₂O₄P [M – Br]⁺ 471, found 471. Anal. calcd for C₂₅H₄₈BrN₂O₄P (%): C, 54.44; H, 8.77; Br, 14.49; N, 5.08; P, 5.62. Found, (%): C, 54.48; H, 8.83; Br, 14.57; N, 5.01; P, 5.53.

4.1.4.2. 2-(((3,5-Di-tert-butyl-4-hydroxyphenyl)(diisopropoxyphosphoryl)methyl)amino)-N-ethyl-N,N-dimethylethan-1-aminium bromide (9b)

Yield: 0.13 g (96%), mp: 109–111 °C. IR (cm^–1): 1026 (POC), 1234 (PO), 1655 (arom), 3621 (OH). ¹H NMR (CD₃OD) δ 0.94 (d, ³J_HH = 6.2 Hz, 3H, OCH(CH[combining low line]_{3[combining low line]})₂), 1.25 (d, ³J_HH = 6.2 Hz, 3H, OCH(CH[combining low line]_{3[combining low line]})₂), 1.30–1.33 (m, 6H, N⁺CH₂CH[combining low line]_{3[combining low line]}, OCH(CH[combining low line]_{3[combining low line]})₂), 1.46 (s, 18H, t-Bu), 2.97–3.06 (m, 2H, NHCH₂), 3.14 (s, 6H, N⁺CH₃), 3.40–3.49 (m, 4H, N⁺CH[combining low line]_{2[combining low line]}, N⁺CH[combining low line]_{2[combining low line]}CH₃), 3.99 (d, ²J_PH = 20.2 Hz, 1H, CH), 4.40 (m, 1H, OCH), 4.67 (m, 1H, OCH), 7.26 (d, ⁴J_PH = 2.0 Hz, 2H, H_arom). ¹³C NMR (CD₃OD) δ 7.4 (N⁺CH₂C[combining low line]H₃), 22.5 (C[combining low line]H₃), 23.1 (C[combining low line]H₃), 23.2 (C[combining low line]H₃), 23.3 (C[combining low line]H₃), 29.5 (C(C[combining low line]H₃)₃), 34.3 (C[combining low line](CH₃)₃), 41.5 (NHCH₂), 41.6 (NHCH₂), 50.4 (N⁺(CH₃)₂), 60.4 (CH, J_PC = 159.0 Hz), 60.4 (N⁺C[combining low line]H₂CH₃), 61.9 (NCH₂), 71.2 (OCH), 72.0 (OCH), 125.4 (C[combining low line]_aromCH), 125.7 (CH_arom), 138.1 (C[combining low line]_aromC(CH₃)₃), 154.1 (C_aromOH). ³¹P NMR (CD₃OD) δ 21.6. HRMS (MALDI): calcd for C₂₇H₅₂N₂O₄P [M – Br]⁺ 499, found 499. Anal. calcd for C₂₇H₅₂BrN₂O₄P (%): C, 55.95; H, 9.04; Br, 13.79; N, 4.83; P, 5.34. Found (%): C, 55.91; H, 9.10; Br, 13.72; N, 4.86; P, 5.31.

4.1.4.3. 3-(((3,5-Di-tert-butyl-4-hydroxyphenyl)(diethoxyphosphoryl)methyl)amino)-N-ethyl-N,N-dimethylpropan-1-aminium bromide (10a)

Yield: 0.12 g (92%), mp: 95–98 °C. IR (cm^–1): 1029 (POC), 1216 (PO), 1624 (arom), 3423 (NH). ¹H NMR (CD₃OD) δ 1.12 (t, ³J_HH = 7.04 Hz, 3H, OCH₂C[combining low line]H[combining low line]_{3[combining low line]}), 1.31 (t, ³J_HH = 7.05 Hz, 3H, OCH₂C[combining low line]H[combining low line]_{3[combining low line]}), 1.36 (t, ³J_HH = 7.07 Hz, 3H, N⁺CH₂CH[combining low line]₃), 1.45 (s, 18H, t-Bu), 1.94 (m, 2H, NHCH₂CH[combining low line]₂CH₂N), 2.68 (m, 2H, NHCH₂), 3.09 (s, 6H, NCH₃), 3.44 (m, 4H, N⁺C[combining low line]H[combining low line]_{2[combining low line]}, N⁺C[combining low line]H[combining low line]_{2[combining low line]}CH₃), 3.80–4.11 (m, 4H, OCH₂), 4.04 (d, ²J_PH = 19.49 Hz, 1H, CH), 7.26 (d, ⁴J_PH = 1.91 Hz, 2H, H_arom). ¹³C NMR (CD₃OD) δ 7.2 (N⁺CH₂C[combining low line]H₃), 15.3 (C[combining low line]H₃), 15.4 (C[combining low line]H₃), 15.5 (C[combining low line]H₃), 15.6 (C[combining low line]H₃), 22.4 (NHCH₂C[combining low line]H₂CH₂N), 29.5 (C(C[combining low line]H₃)₃), 34.3 (C[combining low line](CH₃)₃), 41.1 (NHCH₂), 41.3 (NHCH₂), 49.6 (N⁺(CH₃)₂), 59.5 (N⁺C[combining low line]H₂CH₃), 60.0 (CH, J_PC = 155.2 Hz), 61.9 (NCH₂), 62.7 (OCH₂, J_PC = 7.5 Hz), 63.0 (OCH₂, J_PC = 7.3 Hz), 125.0 (C[combining low line]_aromCH), 125.8 (CH_arom), 138.1 (C[combining low line]_aromC(CH₃)₃), 153.9 (C_aromOH). ³¹P NMR (CD₃OD) δ 24.6. HRMS (MALDI): calcd for C₂₆H₅₀N₂O₄P [M – Br]⁺ 485, found 485. Anal. calcd for C₂₆H₅₀BrN₂O₄P (%): C, 55.22; H, 8.91; N, 4.95; P, 5.48; Br, 14.13. Found (%): C, 55.17; H, 9.02; N, 5.14; P, 5.68; Br, 14.08.

4.1.4.4. 3-(((3,5-Di-tert-butyl-4-hydroxyphenyl)(diisopropoxyphosphoryl)methyl)amino)-N-ethyl-N,N-dimethylpropan-1-aminium bromide (10b)

Yield: 0.13 g (95%), mp: 99–101 °C. IR (cm^–1): 1026 (POC), 1247 (PO), 1655 (arom), 3621 (OH). ¹H NMR (CD₃OD) δ 0.98 (d, ³J_HH = 6.1 Hz, 3H, OCH(CH[combining low line]_{3[combining low line]})₂), 1.26 (d, ³J_HH = 6.1 Hz, 3H, OCH(CH[combining low line]_{3[combining low line]})₂), 1.32 (d, ³J_HH = 6.2 Hz, 3H, OCH(CH[combining low line]_{3[combining low line]})₂), 1.35 (d, ³J_HH = 6.1 Hz, 3H, OCH(CH[combining low line]_{3[combining low line]})₂), 1.38 (t, ³J_HH = 7.4 Hz, 3H, N⁺CH₂CH[combining low line]_{3[combining low line]}), 1.47 (s, 18H, t-Bu), 1.94 (m, 2H, NHCH₂CH[combining low line]₂CH₂N), 2.69 (m, 2H, NHCH₂), 3.01 (s, 6H, N⁺CH₃), 3.34 (m, 2H, N⁺CH[combining low line]_{2[combining low line]}), 3.45 (q, ³J_HH = 7.4 Hz, 2H, N⁺CH[combining low line]_{2[combining low line]}CH₃), 3.95 (d, ²J_PH = 19.8 Hz, 1H, CH), 4.42 (m, 1H, OCH), 4.69 (m, 1H, OCH), 4.78 (br.s., 1H, OH), 7.26 (d, ⁴J_PH = 2.0 Hz, 2H, H_arom). ¹³C NMR (CD₃OD) δ 9.4 (N⁺CH₂C[combining low line]H₃), 25.2 (C[combining low line]H₃, J_PC = 4.7 Hz), 25.3 (C[combining low line]H₃, J_PC = 2.9 Hz), 25.4 (C[combining low line]H₃, J_PC = 3.7 Hz), 24.5 (C[combining low line]H₃, J_PC = 3.8 Hz), 24.6 (NHCH₂C[combining low line]H₂CH₂N), 31.7 (C(C[combining low line]H₃)₃), 36.4 (C[combining low line](CH₃)₃), 46.5 (NHCH₂), 51.7 (N⁺(CH₃)₂), 61.7 (N⁺C[combining low line]H₂CH₃), 62.9 (CH, J_PC = 157.1 Hz), 64.1 (NCH₂), 73.4 (OCH, J_PC = 7.7 Hz), 74.0 (OCH, J_PC = 5.6 Hz), 127.4 (CH_arom, J_PC = 6.7 Hz), 128.4 (C[combining low line]_aromCH, J_PC = 2.1 Hz), 140.2 (C[combining low line]_arom–C(CH₃)₃, J_PC = 1.7 Hz), 156.1 (C_aromOH, J_PC = 3.0 Hz). ³¹P NMR (CD₃OD) δ 22.0. HRMS (MALDI): calcd for C₂₈H₅₄N₂O₄P [M – Br]⁺ 513, found 513. Anal. calcd for C₂₈H₅₄BrN₂O₄P (%): C, 56.65; H, 9.17; Br, 13.46; N, 4.72; P, 5.22. Found (%): C, 56.69; H, 9.13; Br, 13.51; N, 4.70; P, 5.18.

4.1.4.5. N-(2-(((3,5-Di-tert-butyl-4-hydroxyphenyl)(diethoxyphosphoryl)methyl)amino)ethyl)-N,N-dimethyldecan-1-aminium bromide (11a)

Yield: 0.15 g (98%), mp: 48–50 °C. IR (cm^–1): 1031 (POC), 1186 (PO), 1631 (arom), 3203 (NH), 3641 (OH). ¹H NMR (CD₃OD) δ 0.92 (t, ³J_HH = 6.8 Hz, 3H, N⁺CH₂CH₂(CH₂)₇C[combining low line]H[combining low line]_{3[combining low line]}), 1.13 (t, ³J_HH = 7.0 Hz, 3H, OCH₂CH[combining low line]_{3[combining low line]}), 1.31 (t, ³J_HH = 7.0 Hz, 3H, OCH₂CH[combining low line]_{3[combining low line]}), 1.35 (m, 14H, N⁺CH₂CH₂(CH[combining low line]₂)₇CH₃), 1.46 (s, 18H, t-Bu), 1.74 (m, 2H, N⁺CH₂CH[combining low line]_{2[combining low line]}(CH₂)₇CH₃), 3.01 (m, 2H, NHCH[combining low line]₂), 3.14 (s, 3H, N⁺CH₃), 3.15 (s, 3H, N⁺CH₃), 3.40 (m, 4H, NHCH₂CH[combining low line]_{2[combining low line]}N⁺, N⁺CH[combining low line]_{2[combining low line]}CH₂(CH₂)₇CH₃), 3.93 (m, 4H, OCH₂), 4.09 (d, ²J_PH = 19.6 Hz, 1H, CH), 7.26 (d, ⁴J_PH = 2.0 Hz, 2H, H_arom). ¹³C NMR (CD₃OD) δ 13.0 (N⁺CH₂CH₂(CH₂)₆CH₂C[combining low line]H₃), 15.2 (OCH₂C[combining low line]H₃), 15.3 (OCH₂C[combining low line]H₃), 15.4 (OCH₂C[combining low line]H₃), 15.5 (OCH₂C[combining low line]H₃), 22.2 (N⁺CH₂CH₂(CH₂)₆C[combining low line]H₂CH₃), 22.3 (N⁺CH₂CH₂(CH₂)₆C[combining low line]H₂CH₃), 26.0 (N⁺CH₂C[combining low line]H₂(CH₂)₆CH₂CH₃), 28.8 (N⁺CH₂CH₂C[combining low line]H₂(CH₂)₅CH₂CH₃), 28.98 (N⁺CH₂CH₂CH₂(C[combining low line]H₂)₄CH₂CH₂CH₃), 29.2 (N⁺CH₂CH₂CH₂(CH₂)₄C[combining low line]H₂CH₂CH₃), 29.4 (C(C[combining low line]H₃)₃), 31.6 (N⁺CH₂CH₂CH₂(CH₂)₄C[combining low line]H₂CH₂CH₃), 34.3 (C[combining low line](CH₃)₃), 41.5 (NHCH₂), 41.6 (NHCH₂), 50.9 (N⁺(CH₃)₂), 59.8 (CH, J_PC = 156.9 Hz), 62.2 (NCH₂), 62.6 (OCH₂, J_PC = 7.5 Hz), 63.0 (OCH₂, J_PC = 7.2 Hz), 64.9 (N⁺C[combining low line]H₂CH₂CH₂(CH₂)₄CH₂CH₂CH₃), 125.0 (C[combining low line]_aromCH), 125.2 (CH_arom), 138.9 (C[combining low line]_arom–C(CH₃)₃), 154.2 (C_aromOH). ³¹P NMR (CD₃OD) δ 24.2. HRMS (MALDI): calcd for C₃₃H₆₄N₂O₄P [M – Br]⁺ 584, found 584. Anal. calcd for C₃₃H₆₄BrN₂O₄P (%): C 59.71; H 9.72; Br 12.04; N 4.22; P 4.67. Found (%): C 59.76; H 9.77; Br 11.90; N 4.19; P 4.69.

4.1.4.6. N-(2-(((3,5-Di-tert-butyl-4-hydroxyphenyl)(diisopropoxyphosphoryl)methyl)amino)ethyl)-N,N-dimethyldecan-1-aminium bromide (11b)

Yield: 0.15 g (94%), mp: 80–83 °C. IR (cm^–1): 1026 (POC), 1298 (PO), 1660 (arom), 3408 (NH). ¹H NMR (CD₃OD) δ 0.92 (t, ³J_HH = 6.9 Hz, 3H, N⁺CH₂CH₂(CH₂)₇CH[combining low line]₃), 0.96 (d, ³J_HH = 6.2 Hz, 3H, OCH(CH[combining low line]₃)₂), 1.25 (d, ³J_HH = 6.2 Hz, 3H, OCH(CH[combining low line]₃)₂), 1.31 (d, ³J_HH = 6.2 Hz, 3H, OCH(CH[combining low line]₃)₂), 1.32 (m, 14H, N⁺CH₂CH₂(CH[combining low line]₂)₇CH₃), 1.33 (d, ³J_HH = 6.1 Hz, 3H, OCH(CH[combining low line]_{3[combining low line]})₂), 1.46 (s, 18H, t-Bu), 1.73 (m, 2H, N⁺CH₂CH[combining low line]₂(CH₂)₇CH₃), 3.01 (m, 2H, NHCH₂), 3.14 (s, 6H, N⁺CH₃), 3.36 (m, 2H, N⁺CH[combining low line]_{2[combining low line]}CH₂(CH₂)₇CH₃), 3.43 (m, 2H, N⁺CH[combining low line]_{2[combining low line]}), 3.99 (d, ²J_PH = 19.7 Hz, 1H, CH), 4.41 (m, 1H, OCH), 4.66 (m, 1H, OCH), 7.27 (d, ⁴J_PH = 2.0 Hz, 2H, H_arom). ¹³C NMR (CD₃OD) δ 13.0 (N⁺CH₂CH₂(CH₂)₆CH₂C[combining low line]H₃), 22.2 (N⁺CH₂CH₂(CH₂)₆C[combining low line]H₂CH₃), 22.4 (OCH(C[combining low line]H₃)₂), 22.9 (OCH(C[combining low line]H₃)₂), 23.0 (OCH(C[combining low line]H₃)₂), 23.1 (OCH(C[combining low line]H₃)₂), 26.1 (N⁺CH₂C[combining low line]H₂(CH₂)₆CH₂CH₃), 28.8 (N⁺CH₂CH₂C[combining low line]H₂(CH₂)₅CH₂CH₃), 28.9 (N⁺CH₂CH₂CH₂(C[combining low line]H₂)₄CH₂CH₂CH₃), 29.2 (N⁺CH₂CH₂CH₂(CH₂)₄C[combining low line]H₂CH₂CH₃), 29.4 (C(C[combining low line]H₃)₃), 31.6 (N⁺CH₂CH₂CH₂(CH₂)₄C[combining low line]H₂CH₂CH₃), 34.3 (C[combining low line](CH₃)₃), 41.7 (NHCH₂), 50.9 (N⁺(CH₃)₂), 60.5 (CH, J_PC = 159.3 Hz), 62.2 (NCH₂), 64.9 (N⁺C[combining low line]H₂CH₂CH₂(CH₂)₄CH₂CH₂CH₃), 71.2 (OCH, J_PC = 7.8 Hz), 72.1 (OCH, J_PC = 7.6 Hz), 125.3 (C[combining low line]_aromCH, J_PC = 2.4 Hz), 125.6 (CH_arom, J_PC = 6.7 Hz), 138.1 (C[combining low line]_arom–C(CH₃)₃), 154.1 (C_aromOH, J_PC = 3.0 Hz). ³¹P NMR (CD₃OD) δ 22.5. HRMS (MALDI): calcd for C₃₅H₆₈N₂O₄P [M – Br]⁺ 612, found 612. Anal. calcd for C₃₅H₆₈BrN₂O₄P (%): C, 60.77; H, 9.91; Br, 11.55; N, 4.05; P, 4.48. Found (%): C, 60.82; H, 9.97; Br, 11.49; N, 4.09; P, 4.50.

4.1.4.7. N-(3-(((3,5-Di-tert-butyl-4-hydroxyphenyl)(diethoxyphosphoryl)methyl)amino)propyl)-N,N-dimethyldecan-1-aminium bromide (12a)

Yield: 0.14 g (90%), mp: 76–78 °C. IR (cm^–1): 1051 (POC), 1656 (arom), 3394 (NH). ¹H NMR (CD₃OD) δ 0.87 (t, ³J_HH = 6.5 Hz, 3H, N⁺CH₂CH₂(CH₂)₇C[combining low line]H[combining low line]_{3[combining low line]}), 1.06 (t, ³J_HH = 7.00 Hz, 3H, OCH₂CH[combining low line]₃), 1.25–1.33 (m, 17H, N⁺CH₂CH₂(CH[combining low line]₂)₇CH₃, OCH₂CH[combining low line]_{3[combining low line]}), 1.42 (s, 18H, t-Bu), 1.68 (m, 2H, N⁺CH₂CH[combining low line]_{2[combining low line]}(CH₂)₇CH₃), 1.88 (m, 2H, NHCH₂CH[combining low line]_{2[combining low line]}CH₂N⁺), 2.69 (br.t., ³J_HH = 5.3 Hz, 2H, NHCH[combining low line]₂), 3.35 (s, 3H, NCH₃), 3.36 (s, 3H, NCH₃), 3.50–3.60 (m, 4H, N⁺CH[combining low line]_{2[combining low line]}, N⁺CH[combining low line]_{2[combining low line]}CH₂(CH₂)₇CH₃), 3.70 (m, 1H, OCH₂), 3.89 (m, 1H, OCH₂), 4.02 (m, 2H, OCH₂), 3.81 (d, ²J_PH = 19.24 Hz, 1H, CH), 5.21 (s, 1H, OH), 7.12 (s, 2H, H_arom). ¹³C NMR (CD₃OD) δ 14.0 (N⁺CH₂CH₂(CH₂)₆CH₂C[combining low line]H₃), 16.2 (OCH₂C[combining low line]H₃), 16.5 (OCH₂C[combining low line]H₃), 22.6 (N⁺CH₂CH₂(CH₂)₆C[combining low line]H₂CH₃), 22.8 (N⁺CH₂CH₂(CH₂)₆C[combining low line]H₂CH₃), 23.4 (NHCH₂C[combining low line]H₂CH₂N⁺), 26.2 (N⁺CH₂C[combining low line]H₂(CH₂)₆CH₂CH₃), 29.1 (N⁺CH₂CH₂C[combining low line]H₂(CH₂)₅CH₂CH₃), 29.2 (N⁺CH₂CH₂CH₂(C[combining low line]H₂)₄CH₂CH₂CH₃), 29.4 (N⁺CH₂CH₂CH₂(CH₂)₄C[combining low line]H₂CH₂CH₃), 30.3 (C(C[combining low line]H₃)₃), 31.8 (N⁺CH₂CH₂CH₂(CH₂)₄C[combining low line]H₂CH₂CH₃), 34.3 (C[combining low line](CH₃)₃), 44.5 (NHCH₂), 44.6 (NHCH₂), 51.3 (N⁺(CH₃)₂), 60.9 (CH, J_PC = 154.9 Hz), 62.3 (OCH₂, J_PC = 7.4 Hz), 62.5 (NCH₂), 62.9 (OCH₂, J_PC = 7.1 Hz), 64.5 (N⁺C[combining low line]H₂CH₂CH₂(CH₂)₄CH₂CH₂CH₃), 124.9 (CH_arom, J_PC = 6.4 Hz), 125.9 (C[combining low line]_aromCH, J_PC = 3.2 Hz), 138.1 (C[combining low line]_arom–C(CH₃)₃, J_PC = 2.1 Hz), 153.7 (C_aromOH, J_PC = 3.2 Hz). ³¹P NMR (CD₃OD) δ 22.7. HRMS (MALDI): calcd for C₃₄H₆₆N₂O₄P [M – Br]⁺ 597, found 597. Anal. calcd for C₃₄H₆₆BrN₂O₄P (%): C, 60.25; H, 9.82; Br, 11.79; N, 4.13; P, 4.57. Found (%): C, 60.31; H, 9.89; Br, 11.68; N, 4.06; P, 4.51.

4.1.4.8. N-(3-(((3,5-Di-tert-butyl-4-hydroxyphenyl)(diisopropoxyphosphoryl)methyl)amino)propyl)-N,N-dimethyldecan-1-aminium bromide (12b)

Yield: 0.15 g (92%), mp: 38–40 °C. IR (cm^–1): 1031 (POC), 1294 (PO), 1658 (arom), 3400 (NH). ¹H NMR (CD₃OD) δ 0.92 (t, ³J_HH = 6.9 Hz, 3H, N⁺CH₂CH₂(CH₂)₇CH[combining low line]₃), 0.97 (d, ³J_HH = 6.2 Hz, 3H, OCH(CH[combining low line]₃)₂), 1.25 (d, ³J_HH = 6.2 Hz, 3H, OCH(CH[combining low line]₃)₂), 1.30 (d, ³J_HH = 6.2 Hz, 3H, OCH(CH[combining low line]₃)₂), 1.32 (m, 14H, N⁺CH₂CH₂(CH[combining low line]₂)₇CH₃), 1.33 (d, ³J_HH = 6.1 Hz, 3H, OCH(CH[combining low line]_{3[combining low line]})₂), 1.45 (s, 18H, t-Bu), 1.73 (m, 2H, N⁺CH₂CH[combining low line]₂(CH₂)₇CH₃), 1.90 (m, 2H, NHCH₂CH[combining low line]_{2[combining low line]}CH₂N⁺), 2.66 (m, 2H, NHCH[combining low line]₂), 3.06 (s, 3H, NCH₃), 3.07 (s, 3H, NCH₃), 3.28–3.41 (m, 4H, N⁺CH[combining low line]_{2[combining low line]}, N⁺CH[combining low line]_{2[combining low line]}CH₂(CH₂)₇CH₃), 3.91 (d, ²J_PH = 19.6 Hz, 1H, CH), 4.40 (m, 1H, OCH), 4.66 (m, 1H, OCH), 7.23 (d, ⁴J_PH = 2.1 Hz, 2H, H_arom). ³¹P NMR (CD₃OD) δ 24.2. HRMS (MALDI): calcd for C₃₆H₇₀N₂O₄P [M – Br]⁺ 626, found 626. Anal. calcd for C₃₆H₇₀BrN₂O₄P (%): C, 61.26; H, 10.00; Br, 11.32; N, 3.97; P, 4.39. Found (%): C, 61.21; H, 10.11; Br, 11.27; N, 3.94; P, 4.43.

4.1.4.9. N-(2-(((3,5-Di-tert-butyl-4-hydroxyphenyl)(diethoxyphosphoryl)methyl)amino)ethyl)-N,N-dimethyldodecan-1-aminium bromide (13a)

Yield: 0.14 g (88%), mp: 45–47 °C. IR (cm^–1): 1027 (POC), 1176 (PO), 1634 (arom), 3221 (NH), 3637 (OH). ¹H NMR (CD₃OD) δ 0.88 (t, ³J_HH = 6.7 Hz, 3H, N⁺CH₂CH₂(CH₂)₉CH[combining low line]_{3[combining low line]}), 1.07 (t, ³J_HH = 7.05 Hz, 3H, OCH₂CH[combining low line]_{3[combining low line]}), 1.26 (m, 21H, N⁺CH₂CH₂(CH[combining low line]₂)₉CH₃, OCH₂CH[combining low line]_{3[combining low line]}), 1.43 (s, 18H, t-Bu), 1.68 (m, 2H, N⁺CH₂CH[combining low line]_{2[combining low line]}(CH₂)₉CH₃), 3.10 (m, 2H, NHCH[combining low line]₂), 3.41 (s, 6H, NCH₃), 3.42 (s, 6H, NCH₃), 3.58 (m, 2H, N⁺CH[combining low line]_{2[combining low line]}CH₂(CH₂)₉CH₃), 3.69–3.94 (m, 3H, OCH₂, CH), 4.03 (m, 2H, OCH₂), 5.24 (s, 1H, CH), 7.16 (d, ⁴J_PH = 2.03 Hz, 2H, H_arom). ¹³C NMR (CD₃OD) δ 14.1 (N⁺CH₂CH₂(CH₂)₈CH₂C[combining low line]H₃), 16.2 (OCH₂C[combining low line]H₃), 16.3 (OCH₂C[combining low line]H₃), 16.4 (OCH₂C[combining low line]H₃), 16.5 (OCH₂C[combining low line]H₃), 22.6 (N⁺CH₂CH₂(CH₂)₈C[combining low line]H₂CH₃), 22.9 (N⁺CH₂CH₂(CH₂)₈C[combining low line]H₂CH₃), 26.3 (N⁺CH₂C[combining low line]H₂(CH₂)₈CH₂CH₃), 29.2 (N⁺CH₂CH₂C[combining low line]H₂(CH₂)₇CH₂CH₃), 29.3 (N⁺CH₂CH₂CH₂(C[combining low line]H₂)₆CH₂CH₂CH₃), 29.4 (N⁺CH₂CH₂CH₂(C[combining low line]H₂)₆CH₂CH₂CH₃), 29.5 (N⁺CH₂CH₂CH₂(C[combining low line]H₂)₆CH₂CH₂CH₃), 29.6 (N⁺CH₂CH₂CH₂(C[combining low line]H₂)₆CH₂CH₂CH₃), 30.3 (C(C[combining low line]H₃)₃), 31.9 (N⁺CH₂CH₂CH₂(CH₂)₆C[combining low line]H₂CH₂CH₃), 34.3 (C[combining low line](CH₃)₃), 42.6 (NHCH₂), 42.7 (NHCH₂), 51.8 (N⁺(CH₃)₂), 60.6 (CH, J_PC = 157.0 Hz), 62.2 (NCH₂), 62.3 (OCH₂, J_PC = 7.5 Hz), 62.8 (OCH₂, J_PC = 7.2 Hz), 65.3 (N⁺C[combining low line]H₂(CH₂)₁₀CH₃), 125.1 (C[combining low line]_aromCH), 125.2 (CH_arom), 136.2 (C[combining low line]_arom–C(CH₃)₃), 153.9 (C_aromOH). ³¹P NMR (CD₃OD) δ 24.2. HRMS (MALDI): calcd for C₃₅H₆₈N₂O₄P [M – Br]⁺ 612, found 612. Anal. calcd for C₃₅H₆₈BrN₂O₄P (%): C, 60.77; H, 9.91; Br, 11.55; N, 4.05; P, 4.48. Found (%): C, 60.71; H, 9.98; Br, 11.49; N, 4.00; P, 4.52.

4.1.4.10. N-(3-(((3,5-Di-tert-butyl-4-hydroxyphenyl)(diethoxyphosphoryl)methyl)amino)propyl)-N,N-dimethyldodecan-1-aminium bromide (14a)

Yield: 0.15 g (93%), mp: 46–48 °C. IR (cm^–1): 1024 (POC), 1649 (arom), 3398 (NH). ¹H NMR (CD₃OD) δ 0.86 (t, ³J_HH = 6.6 Hz, 3H, N⁺CH₂CH₂(CH₂)₉CH[combining low line]_{3[combining low line]}), 1.05 (t, ³J_HH = 7.0 Hz, 3H, OCH₂CH[combining low line]_{3[combining low line]}), 1.16–1.36 (m, 21H, N⁺CH₂CH₂(CH[combining low line]₂)₉CH₃, OCH₂CH[combining low line]_{3[combining low line]}), 1.41 (s, 18H, t-Bu), 1.68 (m, 2H, N⁺CH₂CH[combining low line]_{2[combining low line]}(CH₂)₉CH₃), 1.88 (m, 2H, NHCH₂CH[combining low line]_{2[combining low line]}CH₂N⁺), 2.68 (t, ³J_HH = 5.9 Hz, 2H, NHCH[combining low line]₂), 3.33 (s, 3H, NCH₃), 3.34 (s, 3H, NCH₃), 3.49–3.59 (m, 4H, N⁺CH[combining low line]_{2[combining low line]}, N⁺CH[combining low line]_{2[combining low line]}CH₂(CH₂)₉CH₃), 3.66–3.72 (m, 1H, OCH₂), 3.85–3.90 (m, 1H, OCH₂), 3.98–4.04 (m, 2H, OCH₂), 3.81 (d, ²J_PH = 19.3 Hz, 1H, CH), 5.20 (s, 1H, CH), 7.12 (s, 2H, H_arom). ¹³C NMR (CD₃OD) δ 14.1 (N⁺CH₂CH₂(CH₂)₈CH₂C[combining low line]H₃), 16.2 (OCH₂C[combining low line]H₃), 16.3 (OCH₂C[combining low line]H₃), 16.5 (OCH₂C[combining low line]H₃), 22.6 (N⁺CH₂CH₂(CH₂)₈C[combining low line]H₂CH₃), 22.8 (N⁺CH₂CH₂(CH₂)₈C[combining low line]H₂CH₃), 23.4 (NHCH₂C[combining low line]H₂CH₂N⁺), 26.2 (N⁺CH₂C[combining low line]H₂(CH₂)₈CH₂CH₃), 29.2 (N⁺CH₂CH₂C[combining low line]H₂(CH₂)₇CH₂CH₃), 29.4 (N⁺CH₂CH₂CH₂(CH₂)₆C[combining low line]H₂CH₂CH₃), 29.3, 29.4, 29.5, 29.6 (N⁺CH₂CH₂CH₂(C[combining low line]H₂)₄CH₂CH₂CH₃), 30.3 (C(C[combining low line]H₃)₃), 34.3 (C[combining low line](CH₃)₃), 44.6 (NHCH₂), 44.7 (NHCH₂), 51.3 (N⁺(CH₃)₂), 60.9 (CH, J_PC = 154.8 Hz), 62.3 (OCH₂, J_PC = 7.4 Hz), 62.4 (NCH₂), 62.9 (OCH₂, J_PC = 7.2 Hz), 64.4 (N⁺C[combining low line]H₂(CH₂)₁₀CH₃), 124.9 (CH_arom, J_PC = 6.1 Hz), 125.9 (C[combining low line]_aromCH), 136.1 (C[combining low line]_arom–C(CH₃)₃), 153.6 (C_aromOH, J_PC = 2.8 Hz). ³¹P NMR (CD₃OD) δ 22.7. HRMS (MALDI): calcd for C₃₆H₇₀N₂O₄P [M – Br]⁺ 626, found 626. Anal. calcd for C₃₆H₇₀BrN₂O₄P (%): C, 61.26; H, 10.00; Br, 11.32; N, 3.97; P, 4.39. Found (%): C, 61.31; H, 10.06; Br, 11.37; N, 3.92; P, 4.30.

4.1.4.11. N-Benzyl-2-(((3,5-di-tert-butyl-4-hydroxyphenyl)(diethoxyphosphoryl)methyl)amino)-N,N-dimethylethan-1-aminium bromide (15a)

Yield: 0.14 g (99%), mp: 100–102 °C. IR (cm^–1): 1030 (POC), 1216 (PO), 1626 (arom), 3418 (NH). ¹H NMR (CD₃OD) δ 1.11 (t, ³J_HH = 7.0 Hz, 3H, OCH₂CH[combining low line]_{3[combining low line]}), 1.28 (t, ³J_HH = 7.0 Hz, 3H, OCH₂CH[combining low line]_{3[combining low line]}), 1.45 (s, 18H, t-Bu), 3.11 (m, 2H, NHCH[combining low line]_{2[combining low line]}), 3.12 (s, 3H, N⁺CH[combining low line]₃), 3.13 (s, 3H, N⁺CH[combining low line]₃), 3.49 (m, 2H, N⁺CH[combining low line]_{2[combining low line]}), 3.79 (m, 1H, OCH[combining low line]_{2[combining low line]}CH₃), 3.92 (m, 1H, OCH[combining low line]_{2[combining low line]}CH₃), 4.08 (m, 2H, OCH[combining low line]_{2[combining low line]}CH₃), 4.11 (d, ²J_PH = 20.0 Hz, 1H, CH), 4.64 (s, 2H, CH[combining low line]₂Ph), 7.27 (d, ⁴J_PH = 1.7 Hz, 2H, H_arom), 7.57 (m, 5H, CH₂P[combining low line]H[combining low line]). ¹³C NMR (CD₃OD) δ 15.2 (OCH₂C[combining low line]H₃), 15.3 (OCH₂C[combining low line]H₃), 15.4 (OCH₂C[combining low line]H₃), 29.4 (C6), 34.3 (C5), 41.6 (C8), 41.7 (C8), 49.8 (C10), 59.7 (C7, J_PC = 157.5 Hz), 62.5 (OCH₂, J_PC = 7.5 Hz), 63.0 (OCH₂, J_PC = 7.3 Hz), 63.2 (C9), 68.8 (C11), 125.0 (C3, J_PC = 6.5 Hz), 125.3 (C4, J_PC = 2.3 Hz), 127.6 (C12), 128.9 (C14), 130.5 (C15), 132.9 (C13), 138.2 (C2, J_PC = 2.2 Hz), 154.2 (C1, J_PC = 3.2 Hz). ³¹P NMR (CD₃OD) δ 24.3. HRMS (MALDI): calcd for C₃₀H₅₀N₂O₄P [M – Br]⁺ 533, found 533. Anal. calcd for C₃₀H₅₀BrN₂O₄P (%): C, 58.72; H, 8.21; Br, 13.02; N, 4.57; P, 5.05. Found (%): C, 58.55; H, 8.74; Br, 12.85; N, 4.24; P, 4.71.

4.1.4.12. N-Benzyl-2-(((3,5-di-tert-butyl-4-hydroxyphenyl)(diisopropoxyphosphoryl)methyl)amino)-N,N-dimethylethan-1-aminium bromide (15b)

Yield: 0.14 g (93%), mp: 151–153 °C. IR (cm^–1): 1029 (POC), 1214 (PO), 1624 (arom), 3425 (NH). ¹H NMR (CD₃OD) δ 0.92 (d, ³J_HH = 6.2 Hz, 3H, OCH(CH[combining low line]_{3[combining low line]})₂), 1.24 (d, ³J_HH = 6.2 Hz, 3H, OCH(CH[combining low line]_{3[combining low line]})₂), 1.28 (d, ³J_HH = 5.9 Hz, 3H, OCH(CH[combining low line]_{3[combining low line]})₂), 1.29 (d, ³J_HH = 5.9 Hz, 3H, OCH(CH[combining low line]_{3[combining low line]})₂), 1.45 (s, 18H, t-Bu), 3.07 (m, 2H, NHCH[combining low line]_{2[combining low line]}), 3.11 (s, 3H, N⁺CH[combining low line]₃), 3.12 (s, 3H, N⁺CH[combining low line]₃), 3.47 (m, 2H, N⁺CH[combining low line]_{2[combining low line]}), 4.02 (d, ²J_PH = 20.4 Hz, 1H, CH), 4.38 (m, 1H, OCH[combining low line](CH₃)₂), 4.63 (s, 1H, CH[combining low line]₂Ph), 4.64 (s, 1H, CH[combining low line]₂Ph), 4.65 (m, 1H, OCH[combining low line](CH₃)₂), 7.26 (d, ⁴J_PH = 2.0 Hz, 2H, H_arom), 7.54 (m, 5H, CH₂P[combining low line]H[combining low line]). ³¹P NMR (CD₃OD) δ 22.7. HRMS (MALDI): calcd for C₃₂H₅₄N₂O₄P [M – Br]⁺ 562, found 562. Anal. calcd for C₃₂H₅₄BrN₂O₄P (%): C, 59.90; H, 8.48; Br, 12.45; N, 4.37; P, 4.83. Found (%): C, 59.95; H, 8.52; Br, 12.41; N, 4.39; P, 4.80.

4.1.4.13. N-Benzyl-3-(((3,5-di-tert-butyl-4-hydroxyphenyl)(diethoxyphosphoryl)methyl)amino)-N,N-dimethylpropan-1-aminium bromide (16a)

Yield: 0.13 g (90%), mp: 97–99 °C. IR (cm^–1): 1027 (POC), 1219 (PO), 1632 (arom), 3401 (NH). ¹H NMR (CD₃OD) δ 1.14 (t, ³J_HH = 7.2 Hz, 3H, OCH₂CH[combining low line]_{3[combining low line]}), 1.31 (t, ³J_HH = 7.1 Hz, 3H, OCH₂CH[combining low line]_{3[combining low line]}), 1.46 (s, 18H, t-Bu), 2.08 (m, 2H, NHCH₂CH[combining low line]₂CH₂N⁺), 2.69 (m, 2H, NHCH[combining low line]_{2[combining low line]}), 3.07 (s, 6H, N⁺CH[combining low line]₃), 3.34 (m, 2H, N⁺CH[combining low line]_{2[combining low line]}), 3.57 (s, 2H, CH[combining low line]₂Ph), 3.86 (m, 1H, OCH[combining low line]_{2[combining low line]}CH₃), 3.95 (m, 1H, OCH[combining low line]_{2[combining low line]}CH₃), 4.08 (m, 2H, OCH[combining low line]_{2[combining low line]}CH₃), 4.06 (d, ²J_PH = 21.4 Hz, 1H, CH), 7.26 (d, ⁴J_PH = 2.2 Hz, 2H, H_arom), 7.53 (t, ³J_HH = 6.7 Hz, 2H, H15), 7.57 (t, ³J_HH = 6.7 Hz, 1H, H16), 7.60 (d, ³J_HH = 6.7 Hz, 2H, H14). ¹³C NMR (CD₃OD) δ 17.6 (OCH₂C[combining low line]H₃), 17.7 (OCH₂C[combining low line]H₃), 24.9 (C9), 31.7 (C6), 36.5 (C5), 46.4 (C8), 51.6 (C11), 62.4 (C7, J_PC = 155.3 Hz), 64.8 (OCH₂, J_PC = 7.2 Hz), 65.0 (C10), 65.3 (OCH₂, J_PC = 10.8 Hz), 69.6 (C12), 127.2 (C3, J_PC = 6.5 Hz), 128.0 (C4, J_PC = 2.6 Hz), 129.8 (C13), 131.3 (C15), 132.8 (C16), 135.0 (C14), 140.4 (C2, J_PC = 1.8 Hz), 156.3 (C1, J_PC = 3.1 Hz). ³¹P NMR (CD₃OD) δ 24.6. HRMS (MALDI): calcd for C₃₁H₅₂N₂O₄P [M – Br]⁺ 547, found 547. Anal. calcd for C₃₁H₅₂BrN₂O₄P (%): C, 59.32; H, 8.35; Br, 12.73; N, 4.46; P, 4.93. Found (%): C, 58.97; H, 8.81; Br, 12.04; N, 4.14; P, 4.21.

4.1.4.14. N-Benzyl-3-(((3,5-di-tert-butyl-4-hydroxyphenyl)(diisopropoxyphosphoryl)methyl)amino)-N,N-dimethylpropan-1-aminium bromide (16b)

Yield: 0.14 g (93%), mp: 146–148 °C. IR (cm^–1): 1033 (POC), 1221 (PO), 1629 (arom), 3416 (NH). ¹H NMR (CD₃OD) δ 0.96 (d, ³J_HH = 6.2 Hz, 3H, OCH(CH[combining low line]_{3[combining low line]})₂), 1.25 (d, ³J_HH = 6.2 Hz, 3H, OCH(CH[combining low line]_{3[combining low line]})₂), 1.29 (d, ³J_HH = 5.8 Hz, 3H, OCH(CH[combining low line]_{3[combining low line]})₂), 1.31 (d, ³J_HH = 5.6 Hz, 3H, OCH(CH[combining low line]_{3[combining low line]})₂), 1.45 (s, 18H, t-Bu), 2.06 (m, 2H, NHCH₂CH[combining low line]₂CH₂N⁺), 2.69 (m, 2H, NHCH[combining low line]_{2[combining low line]}), 3.05 (s, 6H, N⁺CH[combining low line]₃), 3.41 (m, 2H, N⁺CH[combining low line]_{2[combining low line]}), 3.94 (d, ²J_PH = 19.6 Hz, 1H, CH), 4.41 (m, 1H, OCH[combining low line](CH₃)₂), 4.55 (s, 2H, CH[combining low line]₂Ph), 4.67 (m, 1H, OCH[combining low line](CH₃)₂), 7.24 (d, ⁴J_PH = 1.9 Hz, 2H, H_arom), 7.56 (m, 5H, CH₂P[combining low line]H[combining low line]). ¹³C NMR (CD₃OD) δ 22.4 (OCH(C[combining low line]H₃)₂), 22.7 (C9), 23.0 (OCH(C[combining low line]H₃)₂), 23.1 (OCH(C[combining low line]H₃)₂), 23.2 (OCH(C[combining low line]H₃)₂), 29.5 (C6), 34.3 (C5), 44.3 (C8), 49.3 (C11), 60.8 (C7, J_PC = 157.1 Hz), 62.7 (C10), 67.3 (C12), 71.3 (OCH, J_PC = 7.2 Hz), 71.9 (OCH, J_PC = 10.8 Hz), 125.2 (C3, J_PC = 6.7 Hz), 126.2 (C4, J_PC = 2.8 Hz), 127.5 (C13), 129.0 (C15), 130.5 (C16), 132.8 (C14), 138.0 (C2, J_PC = 2.2 Hz), 153.9 (C1, J_PC = 3.1 Hz). ³¹P NMR (CD₃OD) δ 22.9. HRMS (MALDI): calcd for C₃₃H₅₆N₂O₄P [M – Br]⁺ 575, found 575. Anal. calcd for C₃₃H₅₆BrN₂O₄P (%): C, 60.45; H, 8.61; Br, 12.19; N, 4.27; P, 4.72. Found (%): C, 60.50; H, 8.66; Br, 12.14; N, 4.25; P, 4.76.

Conflicts of interest

There are no conflicts to declare.