Green Technologies for Manufacturing of Neonicotinoids

Green chemistry utilizes a set of 12 principles that reduces or eliminates the use or generation of hazardous substances in the design, manufacture and application of chemical products.24

The design of greener processes is also under consideration in the manufacture of neonicotinoid insecticides and their intermediates. This can be exemplified in case of the two N-nitro-guanidines dinotefuran and clothianidin.

4.3.2.1 Dinotefuran - (R,S)-3-(Hydroxymethyl)-tetrahydrofuran Intermediate

From a green chemistry standpoint, the introduction of a formyl group in 7,12-dioxaspiro[5,6]dodec-9-ene (4) by rhodium-catalyzed hydroformylation using syngas (RhHCO(TPP)3; CO/H2; 130 bar; 100 °C; toluene) and its reduction has

(ii)

D

R1 R2

Phytotonic effects (i)

R

N E

(formation of 6-CNA, 2-CTA)

(iii)

Libh4 Reduction

cat.: RhHCO(TPP)3

cat.: RhHCO(TPP)3

Scheme 4.1 Synthesis of 3-hydroxymethyl)-tetrahydrofuran: pathway (A) by reduction of diethyl 2-carboethoxysuccinate (2), and (B) by rhodium-catalyzed hydroformylation of 7,12-dioxaspiro[5,6]dodec-9-ene (4) using syngas. *mixture of (R)- and (S)-enantiomers (adapted from Potluri et al., 2005).25

been proposed as a useful alternative and environmentally friendly preparation process (via intermediates 5 and 6; yields are Z 90%) for the dinotefuran intermediate (R,S)-3-(hydroxymethyl)-tetrahydrofuran (1; scheme 4.1B).25

Previous synthesis of the intermediate (1) involved LiBH4 reduction of diethyl 2-ethoxycarbonylsuccinate (2), followed by cyclocondensation of the resulting 2-hydroxymethylbutane-1,4-diol (3) using para-toluenesulfonic acid (PTSA; see scheme 4.1a). This method did have some disadvantages, however, such as:

(1) The difficult separation of the triol (3) from aqueous solution during workup because of its very high water solubility;

(2) The large quantities of LiBH4 required to reduce the three ester groups of (2), forming large quantities of salts; and

(3) The separation of PTSA from the reaction mixture, before isolation of (1) by solvent extraction or distillation.

4.3.2.2 Clothianidin - O-Methyl-N-nitroisourea Intermediate

Recently, O-methyl-N-nitroisourea (8) was described as a key building block for the synthesis of N-[(2-chloro-5-thiazolyl)methyl]-N0-nitro-carbaminic acid methyl ester (9), which can be easily transformed into clothianidin by treatment with N-methylamine (see scheme 4.2).26

It was found that an organic solvent was not essential for either reaction step. Both, the replacement of the amino group in (8) and that of the methoxy group in (9) could be carried out in water as a very safe solvent under cleavage of ammonia or methanol.27

Twenty years ago, at the beginning of the neonicotinoid chemistry, the methylthio group in N-[(2-chloro-5-thiazolyl)methyl]-N0-nitro-carbamimi-dothioic acid methyl ester (7) was the preferred leaving group for coupling with the 5-aminomethyl-2-chloro-1,3-thiazole (CTM-NH2) intermediate, resulting in clothianidin and methyl mercaptan waste, respectively.28

Scheme 4.2 Syntheses of clothianidin: pathway (A) by replacement of the methylthio group in N'-[(2-chloro-5-thiazolyl)methyl]-N-nitro-carbamimidothioic acid methyl ester (7) by methylamine, and pathway (B) by replacement of the amino group in O-methyl-N-nitro-isourea (8) by 5-aminomethyl-2-chloro-1,3-thiazole (CTM-NH2) and following replacement of the methoxy group in (9) by methylamine in water (adapted from patent applications).

Scheme 4.2 Syntheses of clothianidin: pathway (A) by replacement of the methylthio group in N'-[(2-chloro-5-thiazolyl)methyl]-N-nitro-carbamimidothioic acid methyl ester (7) by methylamine, and pathway (B) by replacement of the amino group in O-methyl-N-nitro-isourea (8) by 5-aminomethyl-2-chloro-1,3-thiazole (CTM-NH2) and following replacement of the methoxy group in (9) by methylamine in water (adapted from patent applications).

4.3.3 Physico-Chemical Properties of Neonicotinoids

The physico-chemical properties of the five- and six-membered ring systems and non-cyclic neonicotinoids played an important role in their successful development as modern insecticides for sustainable agriculture.

In this context, photostability is a significant factor in their agricultural field performance. As described earlier,29-31 the energy gap for the different functional groups [ = X-Y] from the ground state to the single state increased in the order [ = CH-NO2] o [ = N-NO2] o [ = N-CN].

For technical application methods for neonicotinoids in the field, such as for soil drench, seed treatment or foliar application (see section 4.5), their uptake, good translaminar (see section 4.5.1) and acropetal distribution in plants is crucial for their insecticidal activity against numerous sucking pests. Therefore, not only the bioisosteric fragments (CPM vs CTM substituents or pharmacophore moieties [-N-C(E) = X-Y]) but also the whole molecular shape, including the resulting water solubility, has to be considered.32 As so-called "push-pull" olefins, neonicotinoids can form conjugated coplanar electron-donating and electron-accepting groups. In comparison with other non-polar insecticide classes, the polar, non-volatile neonicotinoids have greater water solubilities (e.g. in case of nitenpyram: 840 g l-1 at pH 7) and lower logPOW values (e.g. dinotefuran: -0.644 at 25 °C) (see Table 4.2).

From these observations, the following conclusions can be drawn:

(1) Generally, non-cyclic neonicotinoids are less lipophilic than the corresponding five- and six-membered ring systems;

Table 4.2 Physico-chemical properties of (5')-(—)-nicotine and neonicotinoid insecticides.

Compounds

Color and physical state

Melting point ("C)

Density (gml 1 at 20 °C)

Solubility in water (gT1 at 20 °C)

LogPow (at 25 °C)

(S)-(-)-Nicotine

247"

1.01

miscible

1.2

Neonicotinoids:

[A] Ring systems

Imidacloprid

colorless crystals

144

1.54

0.61

0.57*

Thiacloprid

yellow crystalline powder

136

1.46

0.185

1.26''

Thiamethoxam

slightly creamy crystalline powder

139.1

1.57

4.1

-0.13

[B] Non-cyclic compounds:

Nitenpyram

pale-yellow crystals

83-84

1.40rf

840e

-0.64

Acetamiprid

colorless

98.9

1.330

4.20f

0.8

Clothianidin

clear colorless solid powder

176.8

1.61

0.327

0.7

Dinotefuran

white crystalline solid

94.6-101.5

1.33

54.3 ±1.3

0.644

"boiling point.

"boiling point.

(2) Water solubility is influenced by the functional group [ = X-Y] within the pharmacophore moiety [-N-(C(E)) = X-Y] and increases in the order [ = N-NO2] < [ = N-CN] < [ = CH-NO2]; and

(3) Regarding E, the lipophilicity increases in the order NH<O<C<S.

According to Briggs et al.,33 somewhat more lipophilic neonicotinoid insecticides should be favorable for seed treatment application (see section 4.5.1), because their root uptake and translocation is more effective than in the case of more hydrophilic compounds (see Figure 4.3).

Due to their higher lipophilicity, thiacloprid and clothianidin show the highest root uptake, whereas nitenpyram and dinotefuran are considered to be more xylem mobile than the other neonicotinoids.

4.3.3.1 Penetration and Translocation of Neonicotinoids

For good leaf coverage in foliar applications, absorption of the ai (active ingredient) through the leaf cuticle and its movement within the leaves from the upper to the lower surface (translaminar) and towards the tip of the leaf (acropetal) is essential for optimal control.

The good penetration, translaminar distribution and xylem mobility of neonicotinoid insecticides in plants can be demonstrated for example by the

Figure 4.3 Systemicity of commercial neonicotinoid insecticides. Relationship between the translocation of neonicotinoids to barley shoots following uptake by the roots (expressed as the Transpiration Stream Concentration Factor), and the octan-1-ol/water partition coefficients (log Kow). Due to their higher lipophilicity thiacloprid and clothianidin show the best root uptake, whereas nitenpyram and dinotefuran are more xylem mobile than the other neonicotinoids. (Diagram and experimental data taken and adapted from Briggs et al., 1982).33

Ucav Swarm

Figure 4.3 Systemicity of commercial neonicotinoid insecticides. Relationship between the translocation of neonicotinoids to barley shoots following uptake by the roots (expressed as the Transpiration Stream Concentration Factor), and the octan-1-ol/water partition coefficients (log Kow). Due to their higher lipophilicity thiacloprid and clothianidin show the best root uptake, whereas nitenpyram and dinotefuran are more xylem mobile than the other neonicotinoids. (Diagram and experimental data taken and adapted from Briggs et al., 1982).33

physico-chemical behavior of thiacloprid in cabbage, which is comparable to imidacloprid.34

The amounts of thiacloprid stripped off from cabbage leaf application sites were 23% and 17% at one day and seven days after application, respectively. Levels in the true leaf increased from 63% to 77% as measured one day and seven days after application, respectively. These results demonstrate that thiacloprid is readily taken up by cabbage leaves, thus providing good systemic control of leaf-sucking pests. The visualization of the translocation pattern of 14C-labelled thiacloprid equivalents by phosphor imaging technology revealed xylem mobility, i.e. translocation of the neonicotinoid in the upwards direction, even one day after application to cabbage leaves (see Figure 4.4a). This xylem mobility is further highlighted in Figure 4.4b, which shows an excellent distribution of thiacloprid in cucumber leaves after spray application.

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