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Synthesis of inventive biphenyl and azabiphenyl derivatives as potential insecticidal agents against the cotton leafworm, Spodoptera littoralis

Abstract

The emergence of pest resistance of Spodoptera littoralis (order; Lepidoptera, family; Noctuidae) towards the large scale of different classes of insecticides necessitates the development of some new poly-functionalized biphenyl and azabiphenyl with highly anticipated insecticidal bioresponse. Four new biphenyl carboxamidines 4ad and four aza-analogue picolinamidine derivatives 8ad were designed and prepared via the treatment of their corresponding carbonitriles with lithium-bis trimethylsilylamide [LiN(TMS)2], followed by hydrolysis with hydrogen chloride. Furthermore, these compounds were elucidated by spectral data, and their toxicity and insecticidal activity were screened against Spodoptera littoralis. Whereby, toxicological and biochemical aspects of the inventively synthesized biphenyl and azabiphenyl derivatives against the cotton leafworm, Spodoptera littoralis were inspected. As regards the indomitable LC50 and LC90 values, biphenyl and aza-analogues 8d, 8a, 4b, and 8b, revealed the furthermost forceful toxic effects with LC50 values of 113.860, 146.265, 216.624, and 289.879 ppm, respectively. Whereby, their LC90 values are 1235.108, 1679.044, 2656.296, and 3381.256 ppm, respectively, and toxicity index being 22.31%, 17.36%, 11.72%, and 8.76%, respectively, comparing with the already recommended, methomyl insecticide, lannate 90% SP (LC50, 25.396 and LC90, 57.860 and toxicity index, 100%). Additionally, electrochemical parameters via DFT studies were carried out for demonstrating and elucidation of structure–activity relationship (SAR) according to highly motived compounds, descriptors, and the in vivo insecticidal activities.

Graphical Abstract

Peer Review reports

Introduction

Every year, harmful insect pests in agriculture cause considerable losses in crops, and productivity around the world [1,2,3]. As a result of the incidence of pests, especially animal pests, the growth and productivity of crops become at continuous risk. Despite many measures and developments in crop protection, increasing estimates of actual and potential losses according to Food and Agriculture Organization (FAO) are frequently reported [4,5,6]. One of the major causes is increased pest resistance to insecticides, which has gradually spread and affected crop growth and harvest [7,8,9,10]. Over recent decades, the Egyptian cotton leafworm, Spodoptera littoralis, Boisduval (Order; Lepidoptera, Family; Noctuidae) has remained one of the most important and dangerous widespread pests affecting cotton and many important field crops, ornamental plants, vegetables, and weeds in Egypt and many countries over the world [10,11,12]. As it causes severe damage to these host plants and thus negatively affects the quantity and the quality of agricultural production, subsequently, affecting the national economy of these countries, and increasing the food gap around the world [13,14,15,16,17].

As a result of the increased and excessive use of agricultural pesticides to combat this pest, this led to the emergence of pest resistance, as well as the persistence of residues of these pesticides for long periods, which has adverse effects on humans and beneficial non-target organisms as predators parasites, and thus leads to environmental pollution and disruption of the natural balance [18,19,20]. For these reasons, we had to build up some inventive bioactive polyfunctionalized biphenyl isosteres of probable insecticidal effectiveness against S. littoralis under laboratory circumstances, that are safer for the environment, and less toxic to mammals, without forming cross-resistance to other insecticides [21].

Likewise, assessment of the action of the ultimate potent investigated insecticides by the assessment of enzymatic activities as biochemical aspects for instance, Alk-p, Acid-P, total lipids, lipase activity, total protein, and amylase activity, ALT, AST, and Ach-E. On the other hand, nitrogenous heterocyclic molecules have been playing a crucial role as fungicides, herbicides, insecticides, and plant growth regulators [22,23,24,25]. Additionally, compounds containing phenylpyridine derivatives such as halauxifen-methyl, florpyrauxifen-benzyl and boscalid exhibited excellent biological activity against insecticides, fungicides, and herbicides (Fig. 1) [7, 26]. In the same context, the use of halogenated compounds in the development of agrochemical research has significant expansion in the last decade [27, 28]. Encouraged by the aforementioned results, a series of novel biphenylcarboxamidine and their aza-biphenyl analogs substituted with halogens (Cl, F) were designed and synthesized with anticipated pesticidal properties.

Fig. 1
figure 1

Biologically active aza-biphenyl derivatives

Results and discussion

Chemistry

A novel mono cationic biphenyl carboxamidine derivatives 4ad (Scheme 1) were prepared through subsequence steps. Firstly, Suzuki-Miyaura coupling reaction (SMC) of bromobenzonitrile derivatives with substituted phenylboronic acids 2a–c in the presence of tetrakis(triphenylphosphine)palladium(0) (Pd(PPh3)4) as a strong electron-donating and sterically bulky catalyst/ligand afforded biphenylnitriles 3ad in acceptable yield (69–82%) [29]. Secondly, compounds 3ad were converted to the corresponding free bases of biphenyl carboxamidines 4ad, on treatment with LiN(TMS)2 followed by hydrolysis with hydrogen chloride/EtOH solution. Then, carboxamidine derivatives were neutralized with NaOH to yield the corresponding free bases. Finally, the monoamidines hydrochloride salts 4ad were synthesized by the reaction of the free base of monoamidines with a mixture of hydrogen chloride/EtOH solution. It is worthy to mention that the attempts to achieve the optimum condition for compounds 3ad through using different palladium salts palladium(II) carbonate and palladium(II) nitrate (Pd(NO3)2) led to tedious chromatographic purification and did not impart any increase in yields (50-56%). The spectral analyses of compounds 3ad were in accordance with their suggested structures. As IR spectra of all mononitriles 3ad revealed the appearance of the cyano groups in the range of 2225–2231 cm-1. Whereby, mass spectra of compound 3a gave molecular ion peaks m/z at 213.77 (M+) and 215.63 (M+ +2) due to the presence of chlorine isotopes. 1H-NMR spectrum of the biphenylcarbonitrile derivative 3a displayed four doublet signals resonated at δ = 7.54, 7.75, 7.86, and 7.91 ppm with coupling constants of J = 9 Hz due to four aromatic-H’s of benzonitrile ring and four aromatic-H’s of para-chlorophenyl ring, respectively. While in the case of compound 3b, the presence of fluorine atom in the benzonitrile ring gave a molecular ion peak m/z at 231.15 and 233.15. Whereas a molecular ion peak for compound 3c appeared at m/z 215.15. 1H-NMR spectrum of compound 3d showed a characteristic singlet signal at δ = 3.81 ppm corresponding to meta-dimethoxy-H’s. On the other hand, IR spectra of compounds 4ad confirmed the disappearance of nitrile groups while arising new amidine protons corresponding to NH2, +NH2 groups. 1H-NMR spectrum of compound 4a confirmed the presence of amidine protons at δ = 9.31, 9.52 ppm and eight aromatic protons; four of them related to para-chlorophenyl ring at δ = 7.56 and 7.81 ppm with J coupling constant 6.5 Hz, whereas the other four protons of benzamidine ring appeared as multiplet signals at δ = 7.92–7.96 ppm. The 13C-NMR of compound 4a displayed eight signals corresponding to molecular formula C13H11ClN2, and showed a characteristic signal resonated at δ = 165.18 ppm attributed to amidine carbon as showed in supplementary file. In addition, the mass spectrum for chlorobiphenyl amidine 4a displayed molecular ion peaks at (M+, M++2) = 230.82 and 232.46 (44.03, 9.56; chlorine isotopes). The constitution of compound 4b was affirmed through 1H-NMR spectrum which showing two singlet signals corresponding to amidine protons at δ = 9.51 and 9.56 ppm, whereby, the aromatic protons corresponding to para-chlorophenyl and fluorobenzamidine resonate at δ 7.58, 7.75–7.80 and 7.83–7.88 ppm. Whereas, 19F-NMR revealed a singlet signal at −δ112.57 ppm related to one fluorine atom. In addition, the mass spectrum of 4b displayed a molecular ion peak at 248.76 compatible with the proposed structure. In the same context, 1H-NMR spectrum of compound 4c demonstrated two multiplet signals of aromatic hydrogens of para-fluorophenyl ring at δ = 7.33–7.38 and 7.73–7.77 ppm, while the other three aromatic protons of fluorobenzamidine ring appeared at δ = 7.83–7.88, besides, the constitute value of singlet signals of cationic amidine protons at δ = 9.49 and 9.55 ppm. Furthermore, its mass spectrum displayed that the molecular ion peak of compound 4c, compatible with the molecular weight at 232.99 corresponding to its molecular formula C13H11F2N2+.

Scheme 1
scheme 1

Synthesis scheme for the new biphenyl carboxamidine derivatives 4ad

The formation of carboxamidine derivatives 4 may be suggested on the basis of a mechanism that proceeded through the nucleophilic attack of LiN(TMS)2 to nitrile carbon of biphenylcarbonitrile 3 to furnish [1,1ʹ-biphenyl] (bis(trimethylsilyl)amino)methylene)amide 4A as the mechanism involving the addition of lithium amide to the nitrile group, followed by protonation by desilylation reaction using hydrogen chloride led to the attraction of acidic hydrogen by nitrogenous anion to yield intermediate 4B [30, 31]. Then, the chloride anion attacks the most positive silicon atom leading to the concurrent expel of trimethylsilyl chloride molecule (CH3)3SiCl as a volatile liquid. Finally, the previous steps were repeated passing through intermediates 4C and 4D till affording carboxamidines 4ad (Scheme 2).

Scheme 2
scheme 2

The proposed mechanism of the formation of biphenyl carboxamidine 4

On the same manner, treatment of bromopicolinonitrile 5 with substituted-phenylboronic 6ad in refluxing dioxane and in the presence of Pd(PPh3)4 and K2CO3 yielded the corresponding phenylpicolinonitrile derivatives 7ad (Scheme 3). Then, the transformation of phenylpicolinonitriles to phenylpicolinamidine derivatives 8ad (Scheme 3) via the same steps mentioned above for synthesis of biphenyl amidine. Spectral analysis of compounds 7ad and 8ad were in accordance with the suggested structures. The structures of compounds 7ad were supported by IR spectra which revealed the presence of nitrile group at 2227 to 2239 cm−1. 1H-NMR spectrum of compound 7a manifested two doublet signals at δ = 7.61 and 7.88 ppm with the same J = 8.4 Hz for the aromatic protons of the para-chlorophenyl ring, another characteristic doublet signal observed at δ = 8.13 ppm with J = 8.1 Hz, besides, the presence of doublet of doublet signals at 8.36 and a singlet signal at 9.10 corresponding to Ar–H of picolinonitrile ring. Its 13C-NMR spectrum showed ten signals and exhibited a characteristic signal at δ = 117.57 ppm corresponding to the carbonitrile group. The mass spectrum of picolinonitrile 7a gave a molecular ion peak for C12H7ClN2 at m/z = 214.10 (M+, 85.36%) and 216.15 (27.28%) due to chlorine isotopes. In the 1H-NMR spectrum of compound 7c, meta-dimethoxy-H's reverberated as a singlet signal at δ = 3.83 ppm and two singlet signals at δ = 6.62 and 6.95 ppm for the Ar–H of dimethoxyphenyl ring. The 13C-NMR spectrum for compound 7c, revealed eleven carbon signals that corresponded to the elucidated structure and rebounded at δ = 55.48 ppm corresponding to two methoxy groups at meta position and δ = 117.65 ppm for the cyano group. The aromatic protons of picolinonitrile ring were observed as two doublet signals at δ = 8.10 and 8.35 ppm, in addition to a singlet signal that appeared at δ = 9.10 ppm. Moreover, its mass spectrum showed a molecular ion peak at m/z 240.20 (100%), for a molecular formula C14H12N2O2. Conversely, the IR spectra of compounds 8ad confirmed that the nitrile group had vanished, while new bands at 3272–3445 that corresponded to NH2, +NH2, and groups had appeared. The 1H-NMR spectrum of compound 8a exhibited the aromatic protons as two doublet signals at δ = 7.62 and 7.92 ppm with J = 9 Hz for para-chlorophenyl ring, while the aromatic protons of picolinamidine ring reverberated as two doublet and one singlet signals at δ = 8.44, 8.50 and 9.14 ppm, respectively. In addition, two singlet signals at 9.46 (s, 2H, H2N, D2O exchangeable), and 9.66 ppm (s, 2H, NH2+, D2O exchangeable). Whereas, the 13C-NMR spectrum of compound 8a displayed ten signals and revealed the characteristic carbon signal rebounded at δ = 161.58 ppm corresponding to cationic amidine carbon. Its mass spectrum gave the molecular ion at m/z = 231.0 and the base peak at m/z = 63.95. The main characteristic features of 1H-NMR spectrum of 8b showed two singlet signals at δ = 9.51 (s, 2H, NH2 exchangeable with D2O), 9.69 ppm (s, 2H, +NH2 exchangeable with D2O), in addition two doublet signals related to fluorophenyl at δ 7.40 and 7.96 ppm, whereas, aromatic protons of picolinamidine appeared as a multiple signals at δ 8.46–8.47 ppm. 19F-NMR showed a characteristic singlet signal at − δ 112.39 ppm (using TFA as external standard) of fluorine atom. Whereby, its IR spectrum confirmed the disappearance of cyano group while arising a new band at 3411 and 1686 corresponding to NH, C=N, respectively. While, its mass spectrum showed a molecular ion peak at 215.05 which is completely compatible with its molecular weight C12H10FN3. Furthermore, 1H-NMR spectrum for compound 8c exhibited a characteristic singlet signal at δ 3.83 assigned to two methoxy groups, as well as, two singlets at 6.63 and 6.99 ppm for the aromatic protons of dimethoxyphenyl ring. Aromatic protons of picolinamidine ring were found as two doublets at δ = 8.42, 9.13 ppm and one doublet of doublet signal at 8.48 with J = 1.5 and 8 Hz, besides, two singlet signals at δ = 9.45 and 9.65 ppm for amidic protons (H2N, NH2+). A molecular ion peak of compound 8c was noticed as m/z = 257.10 (M+, 39.08%) and while m/z = 241.05 corresponding to its base peak. Also, 13C-NMR spectrum assured the presence of eleven signals, whereas, amidine carbon resonated at δ =161.61 ppm and two methoxy carbons resonated at 55.50 ppm.

Scheme 3
scheme 3

Synthesis of substituted phenylpicolinamidines

Insecticidal activity

Toxicological activity

Toxicity test for Cotton leaf worm (S. littoralis, Order; Lepidoptera, Family; Noctuidae)

The represented data in Table 1 demonstrated the insecticidal efficacy of eight innovatively tested compounds against the 2nd instar larvae of the laboratory strain of the polyphagous pest, cotton leafworm, S. littoralis (Boisd.) at different concentrations. The represented data displayed that the mortality percentages directly increase with the increasing of concentrations and days post-treatment. Consequently, compounds; 8d, 8a, 4b, and 8b were the most potent compounds, where, the mortality percentages of the treated larvae of S. littoralis reached 86.67%, 83.34%, 76.67% and 70.00%, respectively. The total of inspected compounds displayed powerful toxic effects after 7 days (based on LC50 value). Amongst all, compounds 8d, 8a, 4b and 8b exhibit excellent results with LC50’s values 113.860, 146.265, 216.624 and 289.879 ppm, respectively. In the same context, the toxicity indexes are 22.31%, 17.36%, 11.72%, and 8.76%, respectively, compared with the already recommended, methomyl insecticide, lannate 90% SP (LC50, 25.396 & LC90, 57.860 and toxicity index, 100%), according to the toxicity data denoted in Table 2.

Table 1 Mortality% of the 2nd instar larvae of cotton leafworm, S. littoralis after treatment by the newly synthesized compounds compared with Methomyl insecticide, Lannate 90% SP after 7 days of treatment
Table 2 Toxicity bioresponses of the recently synthesized compounds towards the 2nd instar larvae of cotton leafworm, S. littoralis compared with methomyl insecticide, Lannate 90% SP after 7 days post treatment

Biochemical impacts

A. Alkaline phosphatase (Alk-P) and Acid phosphatase (Acid-p) analyses

In Table 3, the data presented that 8d achieved the highest drop in the activity of Alk-P, lower than in the control, it was − 41.99%, followed by 8a, 4b, of which, it was by − 35.81, − 30.63%, respectively, while the nethermost decrease in Alk-P activity was prompted by 8b, by − 26.82% lower than the control sample. Additionally, 8d revealed the maximum reduction in the activity of Acid-P lower than in the control, it was − 85.10%, followed by 8a, 4b, of which, it was by − 81.94, − 78.84%, whereas 8b caused the lowest drop in Acid-P activity, by − 73.96% less than the control sample.

Table 3 The activities of Alk-P and Acid-p in Hemolymph of the 4th Instar Larvae of S. littoralis later 5 days of action with LC50 of 8d, 8a, 4b, and 8b tested compounds
B. Total proteins and total lipids activity’s analyses

Looking at Table 4, it can be detected that all of the examined compounds produced a reduction in total proteins; it ranged from − 3.96 to − 73.97% lower than in the control. The activity of the 8d treated with larvae reached to its lowest level (− 85.07% lower than in the control), and 8b caused the least salient decrease in the total lipids' activity (− 2.86% compared to the control). The results showed that all of the synthesized compounds tested caused a notable reduction in total lipid activity (Table 4).

Table 4 Total proteins and total lipids, activities in the hemolymph of the 4th Instar Larvae of S. littoralis later 5 days of treatment with LC50 of 8d, 8a, 4b, and 8b tested compounds
C. Determination of lipase and amylase activity

Table 5 depicts the results of lipase and amylase activities for the tested compounds, as compound 8d caused a significant increase in the lipase activity; it was 47.56% higher than in the control while the other tested compounds 8a, 4b, and 8b showed a significant decrease in lipase activity; it was by − 70.73, − 70.73 and − 53.66%, respectively, lower than in the control but not significant between each other. Conversely, the obtained results demonstrated that all the investigated compounds caused a notable decrease in the amylase activity (Table 5), the activity of 8b treated larvae fluctuated to its lowest pattern level (− 89.24% lower than in the control), while 8d, 8a and 4b caused remarkable decrease by − 56.06, 65.03 and 81.62%, respectively, lower than in the control.

Table 5 Lipase and amylase activities in Hemolymph of the 4th Instar Larvae of S. littoralis after 5 days of exposure with LC50 of 8d, 8a, 4b, and 8b tested compounds
D. Alanine aminotranferase (ALT) and asparate aminotransferase (AST) activities, analyses

The data showed that all the established compounds displayed a noteworthy accretion in ALT activity (Table 6), and the enzyme activity reached its ultimate value in 8d treated larvae (313.18%). Whereas the enzyme activity was observed to be at the lowermost increase in 8b treated larvae (85.09%). Compounds 8a and 4b have remarkable increases in enzyme activity by 299.00% and 145.56%, respectively, higher than the control. In addition, there was a rise in the activity of asparate aminotransferase (AST) (Table 6). Whereas, compound 8d was the highest potent compound having insecticidal properties, as it displayed a vastly significant enzyme activity exceeding the control sample (330.78%), followed by 8a (187.07), 4b (175.55%) then 8b (118.14%).

Table 6 Changes of ALT and AST activities in Hemolymph of the 4th Instar Larvae of S. littoralis later 5 days of treatment with LC50 of 8d, 8a, 4b, and 8b tested compounds
E. Acetyl cholinesterase enzyme activity analysis

Compound 8d produced a significant highest reduction in the activity of acetyl cholinesterase activity (A-chE) lower than in the control, it was − 65.50%, followed by 8a (− 49.61%) and 4b (− 47.24%) lower than in the control test (Table 7). Whereas, the lowest decrease in A-chE activity was induced by 8b (− 29.96%) compared to the control test.

Table 7 A-chE activity of A-chE in Hemolymph of the 4th Instar Larvae of S. littoralis later 5 days of treatment with LC50 of 8d, 8a, 4b, and 8b tested compounds

Theoretical approaches

Computational calculations were performed using Gaussian 09 program, in the gaseous state, the DFT approach B3LYP as function and 6-311G (d,p) as basis set to investigate chemical reactivity and stability of the geometry optimization preliminary results of expected biological evaluation of the synthesized compounds via studying of different electrochemical parameters such as total energies, spatial distribution of HOMO and LUMO orbitals, energy gap, hardness (η) and global softness (S), which are depicted in Fig. 2, were carried out through using consequent Eqs. (1, 2, 3, 4) [32,33,34,35].

Fig. 2
figure 2

The optimized geometrical structures, spatial distribution of calculated HOMO, LUMO orbitals, and global chemical reactivity descriptors of highly potential tested compounds 8d, 8a, 4b and 8b

$$\Delta E=\left({E}_{HOMO}-{E}_{LUMO}\right)$$
(1)
$$\eta = \frac{1}{2}\left({E}_{HOMO}-{E}_{LUMO}\right)$$
(2)
$$S=\frac{1}{2}\eta$$
(3)
$$\mu = \frac{1}{2}\left({E}_{HOMO}+{E}_{LUMO}\right)$$
(4)

The obtained results showed that highly active compounds in order 8d, 8a, 4b, and 8b having high softness values than other tested compounds. As global chemical reactivity descriptors such as the energy gap, softness, and chemical potential values, are critical theoretical tools for clarifying the chemical reactivity of the synthesized compounds and the biological activity is directly proportional to increasing with their values. Whereby, a molecule that has a high softness and chemical potential values, is called a soft molecule. Soft molecules are more reactive than hard molecules as they have the ability to donate electrons more easily to acceptors than other molecules. Besides, biological activity depends mainly on the ability of the molecule to offer electrons easily to the acceptor. As seen in the highly potent compounds 8d, 8a, 4b, and 8b, there are slight differences in their band gaps, softness, and chemical potential values (Fig. 2). [36, 37]. Additionally, the tested molecules display noticeable chemical reactivity descriptors that facilitate prolonged interactions with the enzymes of cotton leafworms. Subsequently, robust disorders in their biochemical and metabolic processes will be carried out, leading to decrease leafworms, growth rates or reduce in their productivity or cause the death of the targeted worms collectively, according to the above-mentioned results.

Structure activity relationship (SAR)

The main reason for the higher potency of compound 8d than other test molecules might be rationalized due to the presence of pyridine, amidine moieties, and di-substitution of chloro-atoms enhanced the insecticidal activity [38]. Whereas, the other compounds 8a, and 8b containing only one halogenated atom. Whereas, there has been a rise in the number of commercial products containing ‘mixed’ different halogens [28]; in order to explore the essential moiety in insecticidal activity of the synthesized series and aim to investigate the insecticidal activity of molecules that has a mixed or different halogenated atoms chlorine and fluorine atoms we synthesized parent disubstituted halogenated biphenyl compound 4b. However, compound 4b showed lower insecticidal potency than compounds 8d and 8a; and the addition of different halogens did not impart any benefits; this postulate proves that the most essential active moieties in the synthesized compounds are pyridine and amidine moieties.

Experimental

Chemistry

All devices, equipment, materials, and methods are shown and discussed in detail in the ESI.

General methodology of Suzuki coupling methodology for the preparation of biphenyl carbonitriles 3a-d was carried out according to the described method [39]

4ʹ-Chloro-[1,1ʹ-biphenyl]-4-carbonitrile (3a) A pale-yellow solid; yield = 69%, m.p. = 126.5–128 °C, Lit. [40] m.p. = 125–127 ℃, Lit. [41] m.p. = 129–130 ℃; Rf = 0.81, EtOAc/petroleum ether (60–80 °C) (1:4). IR (KBr, νʹ/cm−1): 3067, 3035 (sp2 C–H), 2225 (CN), 1604, 1522, 1481 (C=C). 1H-NMR; δ 7.54 (d, J = 9 Hz, 2H, Ar–H of para-chlorophenyl), 7.75 (d, J = 9 Hz, 2H, Ar–H of benzonitrile), 7.86 (d, J = 9 Hz, 2H, Ar–H of benzonitrile), 7.91 ppm (d, J = 9 Hz, 2H, Ar–H of para-chlorophenyl). MS (EI) (m/e, %) for C13H8ClN; 213.77, 215.63 (M+, 51.71, 16.19%; chlorine isotopes), 120.09 (Base peak, 100%).


4ʹ-Chloro-3-fluoro-[1,1ʹ-biphenyl]-4-carbonitrile (3b) An off-white solid; yield = 70%; m.p. = 174–175 °C, Lit. [42] m.p. = 175–177 ℃; Rf = 0.88, EtOAc/petroleum ether (60–80 °C) (1:4). IR (KBr, νʹ/cm−1): 3086 (sp2 C–H), 2231 (CN), 1618, 1554, 1482 (C=C). MS (EI) (m/e, %) for C13H7ClFN; 231.15, 233.15 (M+, 80.32, 27.18%; chlorine isotopes), 75 (Base peak, 100%).


3,4ʹ-Difluoro-[1,1ʹ-biphenyl]-4-carbonitrile (3c) A white solid; yield = 73%; m.p. = 118–119 °C. Lit. [43]; Rf = 0.91, EtOAc/petroleum ether (60–80 °C) (1:4). IR (KBr, νʹ/cm−1): 3096, 3069 (sp2 C–H), 2231 (CN), 1617, 1596, 1560 (C=C). 1H-NMR; δ 7.33–7.36 (m, 2H, Ar–H of para-fluorophenyl), 7.73 (d, J = 8.0 Hz, 1H, Ar–H of benzonitrile), 7.85–7.90 ppm (m, 3H), 7.97–8.00 (m, 1H, Ar–H of benzonitrile). MS (EI) (m/e, %) for C13H7F2N; 215.15 (M+, Base peak, 100%).


3-Fluoro-3ʹ,5ʹ-dimethoxy-[1,1ʹ-biphenyl]-4-carbonitrile (3d) A pale-yellow solid yield; 82%, m.p. = 114–115 °C; Rf = 0.82, EtOAc/petroleum ether (60–80 °C) (1:4). IR (KBr, νʹ/cm−1): 2953, 2847 (sp3 C–H), 2230 (CN), 1602, 1561(C=C). 1H-NMR; δ 3.81 (s, 6H, meta-dimethoxy-H’s), 6.59 (s, 1H, Ar–H of dimethoxyphenyl), 6.91 (s, 2H, Ar–H of dimethoxyphenyl), 7.76 (dd, J = 8, 1.5 Hz, 1H, Ar–H of fluorobenzonitrile), 7.92 (d, J = 1.5 Hz, 1H, Ar–H of fluorobenzonitrile), 7.96–7.99 ppm (m, 1H, Ar–H of fluorobenzonitrile). MS (EI) (m/e, %) for C15H12FNO2; 257.25 (M+, Base peak, 100%).

Preparation methodology for biphenylcarboxamidine derivatives 4a–d

Biphenylcarbonitrile derivatives 3ad (1.5 mmol) were allowed to react with LiN(TMS)2 (1M solution in THF, 8 mL, 8 mmol) at room temperature with stirring overnight. After that, ethanol-HCl (gas) solution (12 mL, 1.25 M) was added and the reaction mixture was stirred for another 6 h. The resulting mixture was diluted with diethyl ether (Et2O) and the formed solid was filtered off. Then, the resultant biphenylcarboxamidine derivative was neutralized with NaOH (1N) and the formed monoamidine-free base was collected, washed with water. Finally, the target biphenylcarboxamidines hydrochloride salts 4ad were made from their corresponding free bases on treatment with ethanolic-HCl(gas) solution for overnight, the solid formed was filtered off after addition of Et2O.


4ʹ-Chloro-[1,1ʹ-biphenyl]-4-carboxamidine hydrochloride salt (4a) An off white solid; yield = 74%; m.p. = 282–284 °C. IR (KBr, νʹ/cm−1): 3232 (NH), 3057 (sp2 C–H), 1720, 1670, 1608, 1540 (C=N & C=C). 1H-NMR; δ 7.56 (d, J = 6.5 Hz, 2H, Ar–H of para-chlorophenyl), 7.81 (d, J = 6.5 Hz, 2H, Ar–H of para-chlorophenyl), 7.92–7.96 (m, 4H, Ar–H of benzamidine), 9.31 (s, 2H, NH2 exchangeable with D2O), 9.52 ppm (s, 2H, +NH2 exchangeable with D2O). 13C-NMR; δ 127.01 (1C), 127.05 (2C), 128.94 (4C), 129.18 (2C), 133.69 (1C), 137.17 (1C), 143.85 (1C), 165.18 (1C). MS (EI) (m/e, %) for C13H11ClN2; 230.82, 232.46 (M+, 44.03, 9.56%; chlorine isotopes), 219.17 (Base peak, 100%).


4-Chloro-3-fluoro-[1,1-biphenyl]-4-carboxamidine hydrochloride salt (4b) An off white solid; yield = 77%; m.p. = 284–286 °C. IR (KBr, νʹ/cm−1): 3166 (NH), 1673, 1623, 1540 (C=N & C=C). 1H-NMR; δ 7.58 (d, J = 8.0 Hz, 2H, Ar–H of para-chlorophenyl), 7.75–7.80 (m, 2H, Ar–H of fluorobenzamidine), 7.83–7.88 (m, 3H, Ar–H), 9.51 (s, 2H, NH2 exchangeable with D2O), 9.56 ppm (s, 2H, +NH2 exchangeable with D2O). 19F-NMR (DMSO-d6); − δ 112.57 ppm (using TFA as external standard). MS (EI) (m/e, %) for C13H10ClFN2; 248.76 (M+, 14.95%), 250.35 (M+ + 2, 8.23%), 43.22 (Base peak, 100%).


3,4ʹ-Difluoro-[1,1ʹ-biphenyl]-4-carboxamidine hydrochloride salt (4c) An off white solid; yield = 74%; m.p. = 282–284 °C. IR (KBr, νʹ/cm−1): 3250 (NH), 3060 (sp2 C–H), 1680, 1629, 1546 (C=N & C=C). 1H-NMR; δ 7.33–7.38 (m, 2H, Ar–H of para-fluorophenyl), 7.73–7.77 (m, 2H, Ar–H of para-fluorophenyl), 7.83–7.88 (m, 3H, Ar–H of fluorobenzamidine), 9.49 (s, 2H, NH2 exchangeable with D2O), 9.55 ppm (s, 2H, +NH2 exchangeable with D2O). MS (EI) (m/e, %) for C13H10F2N2; 232.99 (M+, 84.42%), 119.53 (Base peak, 100%).


3-Fluoro-3ʹ,5ʹ-dimethoxy-[1,1ʹ-biphenyl]-4-carboxamidine hydrochloride salt (4d) An off white solid; yield = 79%; m.p. = 226–228°C. IR (KBr, νʹ/cm−1): 3381, 3245 (2NH2), 3001 (sp2 C–H), 2841 (sp3 C–H), 1675, 1598, 1460 (C=N & C=C). 1H-NMR; δ 3.81 (s, 6H, meta-dimethoxy-H’s), 6.59 (s, 1H, Ar–H of dimethoxyphenyl), 6.91 (s, 2H, Ar–H of dimethoxyphenyl), 7.73–7.78 (m, 2H, Ar–H of fluorobenzamidine), 7.85–7.88 (d, 1H, J = 10.5 Ar–H of fluorobenzamidine), 9.49 (s, 2H, NH2 exchangeable with D2O), 9.55 ppm (s, 2H, +NH2 exchangeable with D2O). MS (EI) (m/e, %) C15H15FN2O2; 274.95 (M+, 47.95), 167.89 (Base peak, 100%).

General methodology for the preparation of picolinonitrile derivatives 7a–d

Picolinonitrile derivatives 7ad were prepared to adopt the same Suzuki coupling conditions used for the synthesis of biphenyl carbonitriles 3ad, starting with 5-bromopicolinonitrile and the appropriate phenylboronic acid.


5-(4-Chlorophenyl)picolinonitrile (7a) A yellow solid; yield = 66%; m.p. = 144–145 °C; Rf = 0.84, EtOAc/petroleum ether (60–80 °C) (1:4). IR (KBr, νʹ/cm−1): 3055 (sp2 C–H), 2228 (CN), 1653, 1595, 1499 (C=N & C=C). 1H-NMR; δ 7.61 (d, J = 8.4 Hz, 2H, Ar–H of para-chlorophenyl), 7.88 (d, J = 8.4 Hz, 2H, Ar–H of para-chlorophenyl), 8.13 (d, J = 8.1 Hz, 1H, Ar–H of picolinonitrile), 8.36 (dd, J = 8.1, 2.4 Hz, 1H, Ar–H of picolinonitrile), 9.10 ppm (s, 1H, Ar–H of picolinonitrile). 13C-NMR; δ 117.57 (1C), 129.10 (2C), 129.21 (2C), 129.29 (1C), 131.40 (1C), 134.07 (1C), 134.46 (1C), 135.40 (1C), 137.70 (1C), 149.22 (1C). MS (EI) (m/e, %) for C12H7ClN2; 214.10, 216.15 (M+, 85.36, 27.28%; chlorine isotopes), 75.10 (Base peak, 100%).


5-(4-Fluorophenyl)picolinonitrile (7b) A white solid; yield = 64%; m.p. = 146–147 °C, Lit. [44]; Rf = 0.84, EtOAc /petroleum ether (60–80 °C) (1:4). IR (KBr, νʹ/cm−1): 3066 (sp2 C–H), 2231 (CN), 1605, 1561, 1515 (C=N& C=C). 1H-NMR; δ 7.36–7.42 (m, 2H, Ar–H of para-fluorophenyl), 7.88–7.92 (m, 2H, Ar–H of para-fluorophenyl), 8.12 (d, J = 8.1 Hz, 1H, Ar–H of picolinonitrile), 8.34 (dd, J = 8.1, 1.5 Hz, 1H, Ar–H of picolinonitrile), 9.09 ppm (s, 1H, Ar–H of picolinonitrile). MS (EI) (m/e, %) for C12H7FN2; 198.10 (M+, Base peak, 100%).


5-(3,5-Dimethoxyphenyl)picolinonitrile (7c) A buff solid; yield = 75%; m.p. = 140–141 °C; Rf = 0.72, EtOAc /petroleum ether (60–80 °C) (1:4). IR (KBr) νʹ/cm−1: 2965 (sp3 C–H, stretch), 2227 (CN, stretch), 1602, 1460 (C=N & C=C, stretch). 1H-NMR; δ 3.83 (s, 6H, meta-dimethoxy-H’s), 6.62 (s, 1H, Ar–H of dimethoxyphenyl), 6.95 (s, 2H, Ar–H of dimethoxyphenyl), 8.10 (d, J = 7.5 Hz, 1H, Ar–H of picolinonitrile), 8.35 (d, J = 8.1 Hz, 1H, Ar–H of picolinonitrile), 9.10 ppm (s, 1H, Ar–H of picolinonitrile). 13C-NMR; δ 55.48 (2C), 101.24 (1C), 105.43 (2C), 117.65 (1C), 129.01 (1C), 131.32 (1C), 135.61 (1C), 137.25 (1C), 138.86 (1C), 149.48 (1C), 161.13 (2C). MS (EI) (m/e, %) for C14H12N2O2; 240.20 (M+, Base peak, 100%).


5-(3,5-Dichlorophenyl)picolinonitrile (7d) A white solid; yield = 77%; m.p. = 158–160 °C; Rf = 0.87, EtOAc/petroleum ether (60–80 °C) (1:4). IR (KBr, νʹ/cm−1): 3078 (sp2 C–H), 2239 (CN), 1571, 1478, 1426 (C=N & C=C). 1H-NMR; δ 7.74 (s, 1H, meta-dichlorophenyl-H), 7.95 (s, 2H, meta-dichlorophenyl-H’s), 8.15 (d, J = 8.1 Hz, 1H, Ar–H of picolinonitrile), 8.45 (dd, J = 8.1, 2.4 Hz, 1H, Ar–H of picolinonitrile), 9.16 ppm (s, 1H, Ar–H of picolinonitrile). MS (EI) (m/e, %) for C12H6Cl2N2; 248.10 (M+, 59%), 249.05 (12.66%), 251.10 (5.69%): two chlorine isotopes), 99.15 (Base peak, 100%).

General methodology for preparation of picolinamidine derivatives 8a–d

The picolinamidines 8ad were prepared using the same methodology used for formation of monoamidines 4ad, starting with picolinonitriles 7ad.


5-(4-Chlorophenyl)picolinamidine hydrochloride salt (8a) A buff solid; yield = 61%; m.p. = 232–234 °C. IR (KBr, νʹ/cm−1): 3380, 3272 (2NH2), 3061 (sp2 C–H), 1688, 1644, 1588 (C=N & C=C). 1H-NMR; δ 7.62 (d, J = 9 Hz, 2H, Ar–H of para-chlorophenyl), 7.92 (d, J = 9 Hz, 2H, Ar–H of para-chlorophenyl), 8.44 (d, J = 9 Hz, 1H, Ar–H of picolinamidine), 8.50 (d, J = 2.5 Hz, 1H, Ar–H of picolinamidine), 9.14 (s, 1H, Ar–H of picolinamidine), 9.46 (s, 2H, NH2 exchangeable with D2O), 9.66 ppm (s, 2H, +NH2 exchangeable with D2O). 13C-NMR; δ ppm 123.48 (1C), 129.29 (2C), 129.32 (2C), 134.17 (1C), 134.44 (1C), 135.83 (1C), 138.42 (1C), 142.83 (1C), 147.72 (1C), 161.58 (1C). MS (EI) (m/e, %) for C12H10ClN3; 231.00 (M+, 10.95), 63.95 (Base peak, 100%).


5-(4-Fluorophenyl)picolinamidine hydrochloride salt (8b) A buff solid; yield = 64%; m.p. = 228–230 °C. IR (KBr, νʹ/cm−1): 3411 (NH), 3052 (sp2 C–H), 1686, 1596, 1535 (C=N & C=C). 1H-NMR; δ 7.40 (d, J = 8.5 Hz, 2H, Ar–H of ortho-fluorophenyl), 7.96 (d, J = 8.5 Hz, 2H, Ar–H of meta-fluorophenyl), 8.46–8.47 (m, 2H, Ar–H of picolinamidine), 9.12 (s, 1H, Ar–H of picolinamidine), 9.51 (s, 2H, NH2 exchangeable with D2O), 9.69 ppm (s, 2H, +NH2 exchangeable with D2O). 19F-NMR (DMSO-d6); − δ 112.39 ppm (using TFA as external standard). MS (EI) (m/e, %) for C12H10FN3; 215.05 (M+, 24.54%), 199 (M+ + 1−NH3, Base Peak, 100%).


5-(3ʹ,5ʹ-Dimethoxyphenyl)picolinamidine hydrochloride salt (8c) A buff solid; yield = 72%; m.p. = 230–232 °C. IR (KBr, ν\/cm−1): 3445, 3375 (2NH2), 3142, 3045 (sp2 C–H), 2838 (sp3 C–H), 1689, 1599, 1535 (C=N & C=C). 1H-NMR; δ 3.83 (s, 6H, meta-dimethoxy-H’s), 6.63 (s, 1H, Ar–H of dimethoxyphenyl), 6.99 (s, 2H, Ar–H of dimethoxyphenyl), 8.42 (d, J = 8 Hz, 1H, Ar–H of picolinamidine), 8.48 (dd, J = 8, 1.5 Hz, 1H, Ar–H of picolinamidine), 9.13 (d, J = 1.5 Hz, 1H, Ar–H of picolinamidine), 9.45 (s, 2H, NH2 exchangeable with D2O), 9.65 ppm (s, 2H, +NH2 exchangeable with D2O). 13C-NMR; δ 55.50 (2C), 101.05 (1C), 105.57 (2C), 123.36 (1C), 136.02 (1C), 137.32 (1C), 139.55 (1C), 142.74 (1C), 147.93 (1C), 161.16 (2C), 161.61 (1C). MS (EI) (m/e, %) for C14H15N3O2; 257.10 (M+, 39.08), 241.05 (M+ + 1-NH3, Base peak, 100%).


5-(3ʹ,5ʹ-Dichlorophenyl)picolinamidine hydrochloride salt (8d) A buff solid; yield = 70%; m.p. = 286–288 °C. IR (KBr, νʹ/cm−1): 3354 (2NH2), 3053 (sp2 C–H), 1690, 1656, 1581 (C=N & C=C). 1H-NMR; δ 7.76 (s, 1H, Ar–H of 3,5-dichlorophenyl), 8.01 (s, 2H, Ar–H of 3,5-dichloroyphenyl), 8.43 (d, J = 8 Hz, 1H, Ar–H of picolinamidine), 8.57 (d, J = 8 Hz, 1H, Ar–H of picolinamidine), 9.20 (s, 1H, Ar–H of picolinamidine), 9.45 (s, 2H, NH2 exchangeable with D2O), 9.66 ppm (s, 2H, +NH2 exchangeable with D2O). 13C-NMR; δ 123.37 (1C), 126.26 (2C), 128.71 (1C), 135.03 (1C), 136.54 (2C), 136.90 (1C), 138.88 (1C), 143.56 (1C), 148.12 (1C), 161.43 (1C). MS (EI) (m/e, %) for C12H9Cl2N3; 265.32, 266.94 (M + , 5.50; 2.73; two chlorine isotopes), 56.79 (Base peak, 100%).

Toxicity bioassays

Laboratory bioassay

Cotton leaf worm (S. littoralis, Family; Lepidoptera)

Insecticidal efficacy of the newly synthesized compounds against the 2nd instar larvae of S. littoralis (Boisd.) was carried out under laboratory conditions. Eggs of S. littoralis were acquired from Cotton Leafworm Research Department, Plant Protection Research Institute, Agricultural Research Center, Dokki, Giza, Egypt, and incubated under well-ordered conditions of 25 ± 1 °C and 70 ± 5% RH and kept away from any chemical contamination till the time of treatment to get a susceptible and homogenous strain [24, 25].

Pesticides

(E,Z)-methyl-n-{[(methylamino)carbonyl]oxy}ethanimidothioate which is commercially available under the trade name of lannate 90% soluble powder (SP) (Fig. 3) was purchased from the Central Agricultural Pesticides Laboratory (CAPL) in Dokki, Giza, Egypt.

Fig. 3
figure 3

The chemical structures of recommended, methomyl insecticide, lannate 90% SP

Toxicological studies

The experiments were approved using the leaf dip technique as designated [24, 25]. Six concentrations of each compound (25, 50, 100, 200, 400, and 800 ppm) were formulated as emulsions in DMF, and 0.1% Triton X-100 was used as a surfactant. The emulsions were freshly used after preparation. For larvicidal achievement, fresh castor bean leaves were dipped in the prepared concentrations of each tested compound for 10 s. The treated leaves were left in the shade to dry before being accessible to the larvae. The larvae were allowed to feed on the treated leaves for 48 h and then changed to untreated leaves. Three replicates of 10 larvae each were used for each concentration in addition to the control. Control (check) tests were carried out using the same technique without the tested compound. Larval mortality counts were calculated for 7 days after the exposure period. Mortality was corrected according to Abbott’s formula, and then subjected to probit analysis. The toxicity lines (LC-p lines) were drawn on log concentration–probit paper and statistically analyzed according to Finney’s method, to obtain the LC50 and LC90 values of different tested compounds so as to determine the utmost operative one. As well, the efficacy of the examined compounds was assessed by comparing the tested compounds with the most effective compound using the following equation [24, 25]:

$$\mathrm{Toxicity \, index }=\frac{{\mathrm{LC}}_{50} \, \mathrm{ of \, the \, utmost \, effective \, compound}}{{\mathrm{LC}}_{50} \, \mathrm{ of \, the \, tested \, compound}}X 100$$
Biochemical aspects

Enzymatic activities were assessed in this study using the laboratory strain of 4th instar larvae of S. littoralis (Boisd.) after treatment with the tested synthetic biphenyl compounds. At the LC50 value of an aqueous emulsion of each insecticide, castor bean leaves were dipped in for 30 s, then left to dry in shade at r.t for 30 min before being offered to the 4th instar larvae of S. littoralis. For 48 h the larvae were nurtured on the treated leaves, and then transferred to feed on freshly untreated leaves for 3 days. From approximately 50 larvae, the haemolymph was attained by removing one of the prolegs with forceps; gentle pressure was applied on the larvae with the fingers and extracting the haemolymph with a syringe. The haemolymph was collected in test tubes and stowed in a refrigerator until the determination of the enzyme’s activities [24, 25].

Determination of enzyme activities

Alkaline phosphatase (ALK-P) activity was measured according to the reported method [45]. Whereby, acid phosphatase (Acid-p) activity was determined by Fabiny-Byrd &. Ertingshausen. Also, the activity of acetylcholine esterase (AchE) was determined according to the described method. The activities of serum esterases including alanine aminotranferase (ALT) and asparate aminotransferase (AST) enzymes were estimated calorimetrically. Total proteins were estimated by Bradford’s method. Total lipids, lipase, and amylase activities were evaluated according to the reported methods [24, 25].

Statistical analysis

All biological aspects were analyzed using one-way ANOVA by SPSS 13.0 (SPSS, 2004). Duncan’s Multiple Range Test (DMRT) was used to determine the probability level to compare the differences among some parameter means (P < 0.05) by the Costat system for Windows, Version 6.311, Berkeley, CA, USA, Costat program [46].

Conclusion

In the current work, new two series of halogenated biphenyl and azaphenyl derivatives have been synthesized via the Suzuki coupling reaction. The effect of halogenated azaphenyl substituted on the development of agrochemical fields via investigating their insecticidal activity and plant growth regulators has been studied. In addition, biochemical aspects and enzyme activities were studied. Consequently, the results of this study will provide a new avenue direction for the further structural optimization of halogenated phenyl pyridine analogs as insecticidal. In this study, the calculated chemical quantum descriptors showed excellent agreement with the experimental data displaying that compounds 8d, 8a, and 4b as promising potential candidates against the cotton leafworm, S. littoralis.

Availability of data and materials

All data and analysis during this study are available in this article and its Additional file 1.

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Acknowledgements

The authors are indebted to Mansoura University for all support and the facilities provided.

Funding

Open access funding provided by The Science, Technology & Innovation Funding Authority (STDF) in cooperation with The Egyptian Knowledge Bank (EKB).

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Authors and Affiliations

Authors

Contributions

EG: conceptualization, methodology of organic synthesis, software, investigation, writing—original draft. HA : methodology of organic synthesis, formal analysis. MI: Conceptualization, Formal analysis, supervision and editing review and AF: supervision. MS conceptualization, software, investigation, biological aspects experiments data, writing—original draft. All authors reviewed the manuscript.

Corresponding author

Correspondence to Eslam A. Ghaith.

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Ethics approval and consent to participate

All experiments and methods were performed in accordance with relevant guidelines approved by the Committee of Research Ethics in Mansoura University, Egypt with code MU-ACUC (Sc. MS. 23.04.21).

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Not applicable.

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The authors declare that they have no competing interests.

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Supplementary Information

Additional file 1.

Figure S1: IR spectrum of compound 3a. Figure S2: 1H-NMR spectrum of compound 3a. Figure S3: Mass spectrum of compound 3a. Figure S4: IR Spectrum of compound 3b. Figure S5: Mass spectrum of compound 3b. Figure S6: 1H-NMR spectrum of compound 3c. Figure S7: Mass spectrum of compound 3c. Figure S8: IR spectrum of compound 3d. Figure S9: 1H-NMR spectrum of compound 3d. Figure S10: Mass spectrum of compound 3d. Figure S11: IR spectrum of compound 4a. Figure S12: 1H-NMR spectrum of compound 4a. Figure S13: 1H-NMR (D2O) spectrum of compound 4a. Figure S14: 13C-NMR spectrum of compound 4a. Figure S15: Mass spectrum of compound 4a. Figure S16: IR spectrum of compound 4b. Figure S17: 1H-NMR spectrum of compound 4b. Figure S18: 1H-NMR (D2O) spectrum of compound 4b. Figure S19: 19F-NMR spectrum of compound 4b. Figure S20: Mass spectrum of compound 4b. Figure S21: IR spectrum of compound 4c. Figure S22: 1H-NMR spectrum of compound 4c. Figure S23: 1H-NMR (D2O) spectrum of compound 4c. Figure S24: Mass spectrum of compound 4c. Figure S25: IR spectrum of compound 4d. Figure S26: 1H-NMR spectrum of compound 4d. Figure S27: 1H-NMR (D2O) spectrum of compound 4d. Figure S28: Mass spectrum of compound 4d. Figure S29: IR spectrum of compound 7a. Figure S30: 1H-NMR spectrum of compound 7a. Figure S31: 13C-NMR spectrum of compound 7a. Figure S32: Mass spectrum of compound 7a. Figure S33: IR spectrum of compound 7b. Figure S34: 1H-NMR spectrum of compound 7b. Figure S35: Mass spectrum of compound 7b. Figure S36: IR spectrum of compound 7c. Figure S37: 1H-NMR spectrum of compound 7c. Figure S38: 13C-NMR spectrum of compound 7c. Figure S39: Mass spectrum of compound 7c. Figure S40: IR spectrum of compound 7d. Figure S41: 1H-NMR spectrum of compound 7d. Figure S42: Mass spectrum of compound 7d. Figure S43: IR spectrum of compound 8a. Figure S44: 1H-NMR spectrum of compound 8a. Figure S45: 1H-NMR (D2O) spectrum of compound 8a. Figure S46: 13C-NMR spectrum of compound 8a. Figure S47: Mass spectrum of compound 8a. Figure S48: IR spectrum compound 8b. Figure S49: 1H-NMR spectrum of compound 8b. Figure S50: 1H-NMR (D2O) spectrum of compound 8b. Figure S51: 19F-NMR spectrum of compound 8b. Figure S52: Mass spectrum of compound 8b. Figure S53: IR spectrum of compound 8c. Figure S54:1H-NMR spectrum of compound 8c. Figure S55: 1H-NMR spectrum of (D2O) compound 8c. Figure S56: 13C-NMR spectrum of compound 8c. Figure S57: Mass spectrum of compound 8c. Figure S58: IR spectrum of compound 8d. Figure S59: 1H-NMR spectrum of compound 8d. Figure S60: 1H-NMR (D2O) spectrum of compound 8d. Figure S61: The 13C-NMR spectrum of compound 8d. Figure S62: Mass spectrum of compound 8d.

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Ghaith, E.A., Ali, H.A., Ismail, M.A. et al. Synthesis of inventive biphenyl and azabiphenyl derivatives as potential insecticidal agents against the cotton leafworm, Spodoptera littoralis. BMC Chemistry 17, 144 (2023). https://doi.org/10.1186/s13065-023-01050-w

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