Communication Preparation of Benzalkonium Salts Differing in the Length of a Side Alkyl Chain

Benzalkonium salts are widely used as disinfectants, biocides and detergents,among a variety of other applications. The cationic surface-activity of these salts determines their potential to act as a biocide on both target and non-target organisms. In this study, a quick synthesis of a complete set of the benzalkonium salts differing in the length of an alkylating chain (from C(2) to C(20)) is described. Moreover, their (1)H-NMR, HPLC-MS, TLC and HPLC analysis were recorded.


Introduction
Quaternary compounds, including the benzalkonium salts, constitute an economically important class of industrial chemicals that are widely distributed among a diverse array of products and users from an industrial to the household sector.Because of their strong cationic surface activity, quaternary compounds are used primarily as disinfectants, biocides, and detergents, but also as anti-electrostatics, and as phase transfer catalysts [1].
Very important features of benzalkonium salts are their bactericidal and antimicrobial properties.The antimicrobial activity depends on a changing length of the side n-alkyl chain.It is well known that the C 12 -homolog is most effective against yeast and fungi, the C 14 -homologue against gram-positive bacteria and C 16 -homolog against gram-negative bacteria [2].For these reasons they are widely used as preservatives for ophthalmic, nasal and parenteral products.They are also used as topical antiseptics and disinfectants for medical equipment [3][4][5][6].
These compounds are not generally used as single components, but rather as mixtures composed of two or three benzalkonium members differing only in the length of the alkyl chains [7][8].Such mixtures are produced on a large-scale in industry.However, a targeted synthesis of pure individuals could be of interest because of the above-mentioned specificity of each salt against different pathogens.Preparation of these compounds has been described previously [9][10][11][12], but a general synthesis applicable to the whole series of benzalkonium salts is lacking.The synthesis of long chain derivatives (C 8 -C 20 ) was described earlier by our group [13].To provide a synthetic route to such compounds, the preparation of the whole set of these compounds (C 2 -C 20 ) is now shown.A new set of the short chain benzalkonium salts was developed and the preparation of the long chain benzalkonium salts was improved.

Results and Discussion
The N-benzyl-N,N-dimethylalkyl bromides 3-12 were prepared by the general method shown in Scheme 1.

Scheme 1. Preparation of benzalkonium salts.
Yields of all reactions, together with the melting points of the prepared salts, are shown in Table 1.Thin-Layer Chromatography (TLC) retention factors and High Pressure Liquid Chromatography (HPLC) retention times for of all the salts are also listed in this table.The yields achieved in this study were superior to those obtained earlier for C 8 -C 20 derivatives [13].Moreover, the C 2 -C 6 derivatives were added to complete the whole C 2 -C 20 set.Yields achieved for those compounds were also adequate.We have to point out that use of our method (mixture of the pure compounds) might conceivably replace the synthetic "all in one" mixtures now used in industry.For example, Ajatine ® (a C 12 analogue used as disinfectant) is generally a mixture of the parent substances (N-benzyl-N,N-dimethylamine, C 12 alkylating chain and solvent) and a reaction product (the appropriate monoquaternary salt).Our pure products (without parent substances) could be used in more sophisticated applications, where potential adverse effects of the parent substances would no longer be a factor.
There are several articles which deal with HPLC analysis of benzalkonium derivatives [14][15][16].None of these, however, describe HPLC analysis of the whole benzalkonium set.In this study, our previously developed HPLC method was modified for a determination of each benzalkonium salt with an aim of distinguishing them [17].Such a method could be applicable not only for the benzalkonium salts but also for other long chain quaternary compounds.For quick laboratory analysis of prepared benzalkonium salts, a TLC method was also developed to distinguish each benzalkonium salt.Such a method could be of interest in the laboratories not equipped by special expensive equipment (HPLC).

Conclusions
A quick and easy method for the preparation of pure benzalkonium salts in adequate yields was described.Their purities were analyzed by 1 H-NMR, HPLC-MS, TLC and HPLC techniques.

Table 1 .
Yields, melting points, retention factors and retention times of prepared bezalkonium salts.