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AZ9RBAYCAN KIMYA JURNALI № 2 2017
UDC 547.541.521.621
SYNTHESIS OF DERIVATIVES OF N-OXYPHENYLSULPHANYLIDS AND
THEIR PROPERTIES
S.A.Mammadov, N.P.Ladokhina, S.I.Mammadova, L.S.Aliyeva, Sh.K.Kazimzade
A.Guliyev Institute of Chemistry of Additives, NAS of Azerbaijan
aki05@mail.ru Received 12.01.2016
Reaction of arylsulphochlorides with 2- and 4-hydroxyl-substituted anilines was studied. It established a direct dependence of reaction from changes in the structure and composition of the starting reagents, particularly of an aromatic amine. The reactivity of the synthesized sulphanilides was studied. It was found that despite the content of the aromatic fragment of OH- or OCH3-groups with chloroacetonytrile in the presence of an alkali the 1,4-benzoxazin is formed. However, when, the content of metoxy groups at the 4-position aniline reaction with acetonitrile and butyl iodide lead to N-alkylation of nitrogen sul-phamide. The studies of synthesized compounds have shown that they have high biocidal and fungicidal properties depending on their structure.
Keywords: arylsulphochloride, sulphanilide, chloroacetonitrile, bactericide, fungicide.
Introduction
Sulphamides containing functionally substituted amino groups attract attention of researchers thanks to their valuable properties providing their application as broad-spectrum medical preparations, herbicides, pesticides, bactericides, additives for lubricating oils and lubricants. They easily transform to multifunctional compounds. The methods of producing these compounds depending on their structure, composition and nature of functional groups and their position in aromatic nucleus of sulphochloride and amine are various. Experiments prove that functional groups in aromatic amine have a stronger impact on the course of the reaction than groups in sulphochloride of aromatic fragment. The reaction of arylsulphochlorides with or-thophenylenediamine leads to disulphamides [1], but monosulphamide is obtained in the presence of functional groups in one of amine groups [2].
It was established that [3, 4] directionality and yield of end products during the reaction of halogen, CN, NO2, CF3, SO2H, C(O)H, SO3 and other substituted sulphochlorides with aniline containing benzyl, OH, NR2, CN, NH2, CF3 and other groups differ from the nature and position of these functional groups. Some functional groups facilitate, but others brake the course of the reaction.
Reaction of arylculphochlorides with aniline containing fluorine in meta- and orthopositions and 2-oxyehyl group in nitrogen re-
duces the yield of sulphanilide which Is related to the decrease of reactivity of amine [5].
The presence of pyridyl-, pyridazine-, im-idazolyl-, thiazolyl- and other heterocyclic fragments do not brake the combination reaction of sulphochloride group [6]. However, the following functional groups: halogens, -NO2, -CN, alkoxy-, alkoxycarbonyl- and others considerably influence on sulphamidation reaction [7].
It was established that [8], the presence of amino-, hydroxyl- and thioalkyls, OH-, alkoxy- and carboxygroups in aniline the reaction with sulphochlorides requires special approach to techniques.
Experimental part
Spectra PMR of some synthesized sulphamides were recorded on spectrophotometer "Tesla-467" with operating frequency of 90 MHz, IR-spectra - on device "Nicolet IS-10".
N-2-oxyalkylarylsulphanilides (I, II). 0.1 mol of arylsulphochloride and 0.12 mol of 2-oxyaniline was added into the mixture at room temperature and while mixing 0.12 mol of 27% NaOH solution was added. The mixture was heated up to 60-700C 1.5-2 hours, and then it was cooled. The product was extracted with benzene, washed out with water till neutral reaction and dried. Hexane was added into benzene solution. In case of deposition the solution was filtered and crystallized from benzene and
hexane mixture or from ethanol.
N-2-metoxy- or 4-metoxyalkylarylsulph-anilides (III-V). 0.1 mol of arylsulphochloride and 0.12 mol of 2- or 4-metoxyaniline were dissolved in 25 - 30 ml of pyridine. The mixture was heated 8-10 hours. Then it was distilled with water till full deposition of crystals. Obtained crystals were dissolved in benzene, dried and crystals were deposited by adding hexane.
1-Arylsulphonyl-5-amino-2,3-benzoxa-zine (I, VII). General technique. 0.02 mol of 2-oxy- or 2-metoxyphenylarylsulphanilide and 0.03 mol of NaOH were dissolved in 20 ml of ethanol, heated up to 40-500C, then 0.02 mol of chloracetonitrile was added. Reaction mass was boiled 2-3 hours, cooled and 20 ml of water was added. Obtained deposit was filtered, dried and crystallized from ethanol.
In spectrum PMR of 1-(4-methylphenyl-sulphonyl)-5-amino-2,3-benzoxazine methyl protons of tolyl appear in the shape of triplet in the region of 1.6 ppm protons of aminogroups of benzoxazine in the form of duplet are in the region of 6.3 ppm, but protons of 1,4- and 1,2-sub-stituted aromatic fragments are in 7.5 and 8.0 ppm correspondingly. Proton of benzoxazine appears in the form of singlet in the region 8.45 ppm integral intensity conforms to the amount of protons.
N-Alkyl- or acetonitrile-4-oxymethyl-arylsulphamides (VIII-XI). General technique. 0.02 mol of benzene- or 4-methylbenzenesul-phamide and 0.02 mol of chloracetonitrile or bu-
tyl or hexylbromide were dissolved in 30 mol of benzene. After dissolution 0.03 mol of 27% aqueous solution NaOH was added. The mixture was boiled for 3-3.5 hours, then cooled, 20 mol of hexane was added. Crystals were filtered, washed with water, dried and crystallized from the mixture of benzene and hexane.
Physico-chemical properties of compound I-XI are given in Table 1.
Table 1. Physico-chemical properties of arylsulphanilides and their converted products (I-XI)_
Cipher of compounds T3 3 £ ^ Tmelt5 °C Chemical formula found 0/ calculated
N S
I 88.2 88-90 (benzene+hexane) C12HuNO3S 5.86 5.64 12.95 12.85
II 84.9 107-109 C13H13NO3S 5.73 5.34 12.49 12.17
III 85.4 131-132 (benzene+hexane) CMH15NO3S 5.24 5.45 11.32 11.60
IV 87.8 169-170 (benzene+hexane) C13H13NO3S 5.44 5.34 12.48 12.18
V 89.9 192-195 (ethanol) C14H15NO3S 5.21 5.06 11.89 11.57
VI 69.9 199-201 C14H12N2O3S 10.18 9.76 11.61 11.12
Results and discussions
According to literature data the structure and composition of aromatic amines and sulpho-chlorides essentially influence on reaction and output of sulphanilides. In this regard we studied the influence of functional groups in aniline fragment in 2- and 4-positions on their reaction with arylsulphochlorides:
i / \ UM / \ 3 NaOH
R-\\ //-SOCl +HM\ //"R -NacT
R
R2
R1=R3=H, R2=OH (I); R1=CH3, R2=OH, R3=H (II); R1=CH3, R2=OCH3, R3=H (III); R1=R2=H, R3=OCH3 (IV); R1=CH3, R2=H, R3=OCH3 (V).
Study of sulphamidation showed that functional groups in 4-position have a weak impact on the reaction and high yield of compounds IV and V is provided even at short-term heating. However, when functional groups in aniline are in 2-position, the reaction requires
severer conditions: long-term heating (8-10 hours) with pyridine.
We studied reactivity of N-2-oxy- and N-2-metoxyphenylsulphanilides. When N-2-oxyphe-nylbenzenesulphanilide (I) with chloracetonitrile interacts, benzoxazine-1,4 is formed:
R
SON—
H OH
ClCHCN
R=H (VI); R=CH3 (VII).
NH
When using N-2-oxymethylphenylsulphani-lide compound for such reaction we obtain similar compound physico-chemical properties of which conform to the compound VI. During the reaction with alkali hydrolysis of alkoxy groups till hy-droxyl group occurs, and then benzoaxine-1,4 is formed.
During the reaction 4-metoxyphenylene-benzene- or 4-tolylsulphamide with chloraceto-nitrile and butyliodide, N-alkyl-4-oxymethyl-phenylalkylbenzenesulphamides are formed with lower yield, which is related to the effect of aromatic fragment:
H R2
R1=H, R2=CH2CN (VIII); R1=CH3, R2=CH2CN (IX); R1=H, R2=C4H9 (X); R1=H, R2=CôHi3 (XI).
0.7
I [II IV VII VIII XI Fig.l. Antimicrobial activity of compounds: 1 - bacteria, 2 - fungi.
To expand the dependence of biological activity on chemical structure we studied bio-cide properties of synthesized derivatives of sulphamides (I-XI).
Studies of antimicrobial and fungicide properties (Figure 1) showed that oxyohenyl fragments featuring sulphamides (compound I) are more effective than their oxymethyl deriva-
tives (compound III). Besides, fungicide properties of compounds (I-III) are considerably higher than their antimicrobial properties. Bio-cide concentration of compounds I-III, providing full suppression of bacteria is found to be 0.45-0.6 mol/H0-3, but for fungi it is 0.250.35 mol/l-10-3. Unlike compounds (I-III) heterocyclic compounds (VI and VII) and N-butyl-derivatives (X) by antimicrobial and antifungal actions are close to each other. Biocide concentration of the compounds (VII, VIII and XI) for bacteria is found to be 0.35-0.38 mol/l-10- , but for fungi it is 0.45-0.46 mol/H0-3.
Estimation of fungicide and bactericide properties of compounds for existing All-Union State Standard does not allow us to give clear quantitative evaluation of biocides by their activity. In many cases antimicrobial effect can be disguised by low transport speed of molecules to blocking receptors which allows us to detect penetration into location zone of inhibiting receptors of microorganism. Due to this for more detailed characteristics of biocide properties of synthesized compounds (I-XI) we used modern Hansh method [9].
This method is based upon the assumption of correlation between factors which determine biochemical activity and physico-chemical parameters of substances. Liquid phase can be a standard model for estimation of interaction of active molecules with lipid biophases of bacteria and fungi. For biological action of antimicrobial preparations on aerobic culture we used variety of initial adsorption velocity of oxygen used by cultures in test experiment with and without bio-cides in nutrient medium:
Wo2 without biocide - Wo2with biocide = a.
Rate of biological effect (Kp / h) is defined by formula:
a/AC = Kp / h,
where A - is possible that bioactive compound will reach bioreceptor within a preset time period, C - extra-cellular molar concentration of compound.
The product A-C was named "effective concentration". Value A is related to parameter of hydrophobic nature of compounds. The experimental data of synthesized compounds are shown in Table 2.
Dependence of biological activity speed on effective concentration with mixture of bacteria (Figure 2) showed that sulphamides containing acetonitrile (compound VIII) and ben-zoxazine fragments (compound XI) have high antibacterial and fungicide activity. In these compounds even at concentration of 1.3-1.4 mol/l biological activity speed is lower than in compounds (I-IV) which confirms their fast penetration into intracellular space of microorganisms and blocking vital centers.
It should be stated that effectiveness of compounds (I-IV), however, is higher than in industrial biocide "Sulphaxide".
As Figure 3 shows, fungicide properties of sulphamides are higher than in "Sulphaxide".
Table 2. Antimicrobial properties of some derivatives of N-oxyphenylsulphanilide by Hansh technique
S e Ö o Bacteria mixture Fungi mixture
Biocides and compounds C, mol/l îtribution coeffici of octanol-water, lg Ps Hydrophobic parameter, 5 Steric factor, A Concentration of iocides in nutritiv medium, C, mol/l Active concentrati of biocide, AC, mol/l f o (D ^ s ¿ o ö ^H fp 5? 2 g" 5X S so Rate of biological action, Kp/h f o s > o S3 ~ ti e l a M ° sb o Rate of biological action, Kp/h
Q b ff Hi Ab Ab
Without biocide - - - - - 1.360 - 0.969 -
Sulfaxide 3.98 1.17 0.2010 18.6 3.74 0.763 0.708 0.416 0.148
It It n 27.0 5.61 0.398 0.574 0.256 0.128
1 3.34 0.92 0.1429 7.49 1.07 0.53 0.68 0.195 0.138
I 3 n It It 12.51 1.79 0.47 0.60 0.16 0.122
5 n n n 25.15 3.59 0.15 0.42 0.081 0.091
1 3.68 0.88 0.1495 7.91 1.15 0.65 0.62 0.156 0.122
III 3 n It It 13.22 1.91 0.34 0.54 0.109 0.108
5 n n n 25.56 3.86 0.11 0.38 0.070 0.070
1 3.24 1.45 0.1377 8.28 1.14 0.59 0.68 0.17 0.131
IV 3 It It It 13.81 1.90 0.250 0.61 0.14 0.123
5 n n n 27.78 3.83 0.20 0.43 0.094 0.09
1 3.28 1.520 0.147 9.09 1.340 0.62 0.55 0.051 0.10
VII 3 It It It 15.18 2.23 0.36 0.45 0.041 0.082
5 n n n 30.50 4.48 0.32 0.23 0.05 0.038
1 3.68 1.88 0.1475 9.09 1.34 0.66 0.52 0.08 0.064
VIII 3 n It It 15.18 2.24 0.42 0.42 0.076 0.06
5 n n n 23.27 3.98 0.134 0.55 0.167 0.071
1 4.08 1.81 0.1396 10.46 1.46 0.76 0.42 0.088 0.060
XI 3 a H H 17.46 2.44 0.51 0.35 0.07 0.052
5 H H H 35.10 4.90 0.43 0.19 0.055 0.036
Sulphaxide
1 2 3 4 5
Effective concentration, A C, mol/1
Fig.2. Dependence of biological action rate on effective concentration in the presence of bacteria mixture.
-5
L ^
d о
al
о
'Eg "o
t+Ч
О
<D
=1 Рн
Sulphaxide
0.1Ф 0.130.120.11 0.1 • 0.090.080.070.06т
о.о;
0.04
1 2 3 4 5
Effective concentration, AC, mol/l
Fig.3. Dependence of biological action rate on effective concentration in the presence of fungi mixture.
The increase of antifungal effect is similar to bactericide effect: compounds (VIII) and (XI) are more effective, than compounds (I-IV).
In its biological effect synthesized sul-phamide containing benzoxazine fragment (compound VII) differs from other sulphamides by the fact that its dependence of biological activity speed on effective concentration is much less than (tangent of angle is 150). This indicates its high penetration speed into intracellu-lar space of microorganisms.
The conclusion seems to be that derivatives of synthesized sulphamides have high antimicrobial properties and effectiveness of their action surpasses biocides applied in industry. Mechanism of bactericide action of these compounds involves inhibitory effect on formation of cellular wall of microorganisms, protein de-naturation, and disruption of permeability of cytoplasmic membrane by inhibition of vital bacteria of fragments.
References
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5. Pat. 7132546 USA. Derivatives of aniline or their salts and obtaining of inhibitors of cytokine/ Isihava S.K., Yarnimato K., Okada T. 2006.
6. Pat. 7326812 USA. Arylsulphonamidobenzene compounds / Amgen Inc., Ziao Xion Y., Kayser F. 2008.
7. Pat. 19930075 Germany. New amino-amidinosul-phonamides as antiviral means / Bayer A.G., Bende W., Eckenberg P. 2001.
8. Pat. 7207816 USA. Sulphamide compounds /Allison B., Phuong V.K. 2007.
9. Quantitative Structure-Activity Relation Ships: Fundamental and Application of the Hansh Analysis "Practical Stutters for Medicinal Chemistry. An Integrating Approach for Developing Countries". Course IUPAC. Educational and methodological materials on GSAR and medical chemistry. December 2006. P. 54.
N-2-OKSiFENiLSULFANiLiDLЭRlN TORЭMЭLЭRlNiN SiNTEZi УЭ ONLARIN XASSЭLЭRi
S.Э.Mэmmэdov, N.P.Ladoxina, L§.Hйseynov, S.LMэmmэdova, §.K.Kazlmzadэ
Arilsulfoxloridlэrlэ 2- уэ 4-oksiэvэzo1unmu§ апШп1эг1э reaksiya бyrэnilmi§dir. Миэууэп edilmi§dir Ы, reaksiyanin istiqamэti УЭ maddэ сшт1 i1kin maddэ1эrin, xиsusэn dэ аготаЛ amin1эrin quru1u§undan дох asl1ldlr. Sintez о1ипти§ su1fani1id1эrin reaksiyaya girmэk qabi1iyyэti бyrэni1mi§dir. Aydm o1mu§dur ki, aromatik fraqment 2-vэziyyэtdэ ОН- УЭ ОСН3 o1duqda x1orasetonitrШэ reaksiyadan benzoksazin-1,4 a1шlr. Ani1indэ 4-vэziyyэtdэ metoksiqrup o1duqda x1orasetomtri1 УЭ buti1yodid1э si1famid azotunda a1ki11э§mэ reaksiyasl gedir. Sintez o1unmu§ su1famid1эrin smaq1aп quru1u§dan asl1l o1araq оп^ПП yиksэk keyfiyyэt1i antimikrob УЭ fungisid xassэ1эrэ ma1ik o1duq1aп mиэyyэn
Адаг sбzlэr: arilsulfoxlorid, sulfanШd, xlorasetonitril, bakterisid, fungisid.
СИНТЕЗ ПРОИЗВОДНЫХ ^ОКСИФЕНИЛСУЛЬФАНИЛИДОВ И ИХ СВОЙСТВА С.А.Мамедов, Н.П.Ладохина, С.И.Мамедова, Л.С.Алиева, Ш.К.Кязимзаде
Изучена реакция арилсульфохлоридов с 2- и 4-оксизамещенными анилинами. Установлена прямая зависимость протекания реакции от изменения структуры и состава исходных реагентов, в частности, от ароматического амина. Исследована реакционная способность синтезированных сульфанилидов. Найдено, что, несмотря на содержание в ароматическом фрагменте ОН- или ОСН3-групп, в реакциях с хлорацетонитрилом в присутствии щелочи образуется бензоксазин-1,4. Однако при содержании метоксигрупп в 4-положении анилина эти реакции с ацето-нитрилом и бутилйодидом приводят к М-алкилированию сульфамидного азота. Показано, что синтезированные соединений обладают высокими биоцидной и фунгицидной активностями в зависимости от их структуры.
Ключевые слова: арилсульфохлорид, сульфанилид, хлорацетонитрил, бактерицид, фунгицид.
