Mechanochemical Synthesis of Fluorinated Imines

A number of imines, including 12 new compounds, previously not reported in the literature, derived from variously fluorinated benzaldehydes and different anilines or chiral benzylamines were synthesized by a solvent-free mechanochemical method, which was based on the manual grinding of equimolar amounts of the substrates at the room temperature. In a very short reaction time of only 15 min, the method produced the expected products with good-to-excellent yields. The yields were comparable or significantly higher than those reported in the literature for the imines synthesized by other methods. Importantly, the conditions used for the reactions with aniline derivatives also resulted in the high yields of imines obtained from chiral benzylamines, and can be extended to the synthesis with other similar amines. Structures of all imines were confirmed by NMR spectroscopy: 1H, 13C and 19F. For four compounds, X-ray structures were also obtained. The synthetic approach presented in this paper contributes to the prevention of environmental pollution and can be easily extended for larger-scale syntheses. The mechanochemical solvent-free method provides a convenient strategy particularly useful for the preparation of fluorinated imines being versatile intermediates or starting material in the synthesis of drugs and other fine chemicals.


Introduction
Imines, also called Schiff's bases, are an important group of chemicals widely used in organic synthesis both as intermediates and starting materials. The high reactivity of imines results from the presence of the multifunctional C = N bond in their structure, which is able to undergo a wide spectrum of chemical transformations, including reduction, condensation, cyclisation, cycloaddition, nucleophilic addition as well as multicomponent reactions, leading to the formation of various biologically and chemically relevant products. As ligands readily complexing the metals of the d and f blocks, imines are also valuable reagents in coordination chemistry [1][2][3][4][5]. The diversity of compounds containing the azomethine unit shows that the synthetic potential of imines both as substrates and intermediates is indeed great.
Due to its ability to undergo interactions with a wide range of biological targets, the imine function is an essential pharmacophore in nitrogen-containing bioactive compounds [6][7][8][9][10]. There are many different pharmacophores. Among them, one of the most important is fluorine [11]. Fluorination seems to be a standard strategy for modulating the properties of chemical compounds and plays an important role in providing therapeutic agents [12,13]. The pharmacological potential of fluorinated compounds results from the fact that the replacement of hydrogen atoms with fluorine ones does not often violate the molecule conformation; however, due to the fluorine electron-withdrawing inductive effect, may significantly change the chemical and biological properties of the parental molecules [14,15]. This may, in turn, influence interactions with biological targets as well as the metabolism of drugs.
The synthetic method was based on the manual grinding of equimolar amounts of the reagents and was used for the substrates being in a solid state (aldehydes: 3, 4 and amines: a, c, d, e, i, Table 1) as well as in a liquid state (compounds: 1, 2, b, f, g, h, Table 1). In order to study the scope of the reaction, activated amines, having electron-donating groups, as well as deactivated amines, containing electron-withdrawing substituents, were used (Table 1). The reagents were ground for 15 min. This time was selected as suitable for all types of substrates used in our studies. For activated amines, 10 min was sufficient. However, this was not enough in the case of deactivated amines. Prolonged grinding (20 min) did not result in a better yield. Therefore, in order to standardize the reaction time and to develop the most general method possible, we chose 15 min, bearing in mind that fine tuning of the reaction conditions is very likely for each individual combination of substrates.
The products were obtained in good-to-excellent yields (68-99%, Table 1) with three outliers, 2b, 3b and 3i, whose yields were, respectively, 58%, 56% and 45% only. To improve the yield, the synthesis with an auxiliary additive (K2CO3) was attempted in the case of 2b. However, any yield benefits were observed; therefore, no more reactions were performed this way. Most of the 36 crude products did not contain substrates, indicating their full conversion. These imines were directly subjected to structural studies. In the 1 H, The synthetic method was based on the manual grinding of equimolar amounts the reagents and was used for the substrates being in a solid state (aldehydes: 3, 4 a amines: a, c, d, e, i, Table 1) as well as in a liquid state (compounds: 1, 2, b, f, g, h, Table  In order to study the scope of the reaction, activated amines, having electron-donati groups, as well as deactivated amines, containing electron-withdrawing substituen were used (Table 1). The reagents were ground for 15 min. This time was selected suitable for all types of substrates used in our studies. For activated amines, 10 min w sufficient. However, this was not enough in the case of deactivated amines. Prolong grinding (20 min) did not result in a better yield. Therefore, in order to standardize t reaction time and to develop the most general method possible, we chose 15 min, beari in mind that fine tuning of the reaction conditions is very likely for each individu combination of substrates.
The products were obtained in good-to-excellent yields (68-99%, Table 1) with thr outliers, 2b, 3b and 3i, whose yields were, respectively, 58%, 56% and 45% only. To i prove the yield, the synthesis with an auxiliary additive (K2CO3) was attempted in t case of 2b. However, any yield benefits were observed; therefore, no more reactions we performed this way. Most of the 36 crude products did not contain substrates, indicati their full conversion. These imines were directly subjected to structural studies. In the 1 1f 87% * The synthetic method was based on the manual grinding of equimolar amounts of the reagents and was used for the substrates being in a solid state (aldehydes: 3, 4 and amines: a, c, d, e, i, Table 1) as well as in a liquid state (compounds: 1, 2, b, f, g, h, Table 1). In order to study the scope of the reaction, activated amines, having electron-donating groups, as well as deactivated amines, containing electron-withdrawing substituents, were used (Table 1). The reagents were ground for 15 min. This time was selected as suitable for all types of substrates used in our studies. For activated amines, 10 min was sufficient. However, this was not enough in the case of deactivated amines. Prolonged grinding (20 min) did not result in a better yield. Therefore, in order to standardize the reaction time and to develop the most general method possible, we chose 15 min, bearing in mind that fine tuning of the reaction conditions is very likely for each individual combination of substrates.
The products were obtained in good-to-excellent yields (68-99%, Table 1) with three outliers, 2b, 3b and 3i, whose yields were, respectively, 58%, 56% and 45% only. To improve the yield, the synthesis with an auxiliary additive (K2CO3) was attempted in the case of 2b. However, any yield benefits were observed; therefore, no more reactions were performed this way. Most of the 36 crude products did not contain substrates, indicating their full conversion. These imines were directly subjected to structural studies. In the 1 H, The synthetic method was based on the manual grinding of equimolar amounts of the reagents and was used for the substrates being in a solid state (aldehydes: 3, 4 and amines: a, c, d, e, i, Table 1) as well as in a liquid state (compounds: 1, 2, b, f, g, h, Table 1). In order to study the scope of the reaction, activated amines, having electron-donating groups, as well as deactivated amines, containing electron-withdrawing substituents, were used (Table 1). The reagents were ground for 15 min. This time was selected as suitable for all types of substrates used in our studies. For activated amines, 10 min was sufficient. However, this was not enough in the case of deactivated amines. Prolonged grinding (20 min) did not result in a better yield. Therefore, in order to standardize the reaction time and to develop the most general method possible, we chose 15 min, bearing in mind that fine tuning of the reaction conditions is very likely for each individual combination of substrates.
The products were obtained in good-to-excellent yields (68-99%, Table 1) with three outliers, 2b, 3b and 3i, whose yields were, respectively, 58%, 56% and 45% only. To improve the yield, the synthesis with an auxiliary additive (K2CO3) was attempted in the case of 2b. However, any yield benefits were observed; therefore, no more reactions were performed this way. Most of the 36 crude products did not contain substrates, indicating their full conversion. These imines were directly subjected to structural studies. In the 1 H, The synthetic method was based on the manual grinding of equimolar amounts of the reagents and was used for the substrates being in a solid state (aldehydes: 3, 4 and amines: a, c, d, e, i, Table 1) as well as in a liquid state (compounds: 1, 2, b, f, g, h, Table 1). In order to study the scope of the reaction, activated amines, having electron-donating groups, as well as deactivated amines, containing electron-withdrawing substituents, were used (Table 1). The reagents were ground for 15 min. This time was selected as suitable for all types of substrates used in our studies. For activated amines, 10 min was sufficient. However, this was not enough in the case of deactivated amines. Prolonged grinding (20 min) did not result in a better yield. Therefore, in order to standardize the reaction time and to develop the most general method possible, we chose 15 min, bearing in mind that fine tuning of the reaction conditions is very likely for each individual combination of substrates.
The products were obtained in good-to-excellent yields (68-99%, Table 1) with three outliers, 2b, 3b and 3i, whose yields were, respectively, 58%, 56% and 45% only. To improve the yield, the synthesis with an auxiliary additive (K2CO3) was attempted in the case of 2b. However, any yield benefits were observed; therefore, no more reactions were performed this way. Most of the 36 crude products did not contain substrates, indicating their full conversion. These imines were directly subjected to structural studies. In the 1 H, The synthetic method was based on the manual grinding of equimolar amounts of the reagents and was used for the substrates being in a solid state (aldehydes: 3, 4 and amines: a, c, d, e, i, Table 1) as well as in a liquid state (compounds: 1, 2, b, f, g, h, Table 1). In order to study the scope of the reaction, activated amines, having electron-donating groups, as well as deactivated amines, containing electron-withdrawing substituents, were used (Table 1). The reagents were ground for 15 min. This time was selected as suitable for all types of substrates used in our studies. For activated amines, 10 min was sufficient. However, this was not enough in the case of deactivated amines. Prolonged grinding (20 min) did not result in a better yield. Therefore, in order to standardize the reaction time and to develop the most general method possible, we chose 15 min, bearing in mind that fine tuning of the reaction conditions is very likely for each individual combination of substrates.
The products were obtained in good-to-excellent yields (68-99%, Table 1) with three outliers, 2b, 3b and 3i, whose yields were, respectively, 58%, 56% and 45% only. To improve the yield, the synthesis with an auxiliary additive (K2CO3) was attempted in the case of 2b. However, any yield benefits were observed; therefore, no more reactions were performed this way. Most of the 36 crude products did not contain substrates, indicating their full conversion. These imines were directly subjected to structural studies. In the 1 H,  [42], 95 [34]] [34]] "*" Calculated from the 1 H NMR spectrum by an internal standard method with DCM used as internal standard. [ ] Yields reported in the literature.
The synthetic method was based on the manual grinding of equimolar amounts the reagents and was used for the substrates being in a solid state (aldehydes: 3, 4 a amines: a, c, d, e, i, Table 1) as well as in a liquid state (compounds: 1, 2, b, f, g, h, Table  In order to study the scope of the reaction, activated amines, having electron-donati groups, as well as deactivated amines, containing electron-withdrawing substituen were used (Table 1). The reagents were ground for 15 min. This time was selected suitable for all types of substrates used in our studies. For activated amines, 10 min w sufficient. However, this was not enough in the case of deactivated amines. Prolong grinding (20 min) did not result in a better yield. Therefore, in order to standardize t reaction time and to develop the most general method possible, we chose 15 min, beari in mind that fine tuning of the reaction conditions is very likely for each individu combination of substrates.
The products were obtained in good-to-excellent yields (68-99%, Table 1) with thr outliers, 2b, 3b and 3i, whose yields were, respectively, 58%, 56% and 45% only. To i prove the yield, the synthesis with an auxiliary additive (K2CO3) was attempted in t case of 2b. However, any yield benefits were observed; therefore, no more reactions we performed this way. Most of the 36 crude products did not contain substrates, indicati their full conversion. These imines were directly subjected to structural studies. In the 1 1g 98%  [42], 95 [34]] [34]] "*" Calculated from the 1 H NMR spectrum by an internal standard method with DCM used as an internal standard. [ ] Yields reported in the literature.
The synthetic method was based on the manual grinding of equimolar amounts of the reagents and was used for the substrates being in a solid state (aldehydes: 3, 4 and amines: a, c, d, e, i, Table 1) as well as in a liquid state (compounds: 1, 2, b, f, g, h, Table 1). In order to study the scope of the reaction, activated amines, having electron-donating groups, as well as deactivated amines, containing electron-withdrawing substituents, were used (Table 1). The reagents were ground for 15 min. This time was selected as suitable for all types of substrates used in our studies. For activated amines, 10 min was sufficient. However, this was not enough in the case of deactivated amines. Prolonged grinding (20 min) did not result in a better yield. Therefore, in order to standardize the reaction time and to develop the most general method possible, we chose 15 min, bearing in mind that fine tuning of the reaction conditions is very likely for each individual combination of substrates.
The products were obtained in good-to-excellent yields (68-99%, Table 1) with three outliers, 2b, 3b and 3i, whose yields were, respectively, 58%, 56% and 45% only. To improve the yield, the synthesis with an auxiliary additive (K2CO3) was attempted in the case of 2b. However, any yield benefits were observed; therefore, no more reactions were performed this way. Most of the 36 crude products did not contain substrates, indicating their full conversion. These imines were directly subjected to structural studies. In the 1 H,  [42], 95 [34]] [34]] "*" Calculated from the 1 H NMR spectrum by an internal standard method with DCM used as an internal standard. [ ] Yields reported in the literature.
The synthetic method was based on the manual grinding of equimolar amounts of the reagents and was used for the substrates being in a solid state (aldehydes: 3, 4 and amines: a, c, d, e, i, Table 1) as well as in a liquid state (compounds: 1, 2, b, f, g, h, Table 1). In order to study the scope of the reaction, activated amines, having electron-donating groups, as well as deactivated amines, containing electron-withdrawing substituents, were used (Table 1). The reagents were ground for 15 min. This time was selected as suitable for all types of substrates used in our studies. For activated amines, 10 min was sufficient. However, this was not enough in the case of deactivated amines. Prolonged grinding (20 min) did not result in a better yield. Therefore, in order to standardize the reaction time and to develop the most general method possible, we chose 15 min, bearing in mind that fine tuning of the reaction conditions is very likely for each individual combination of substrates.
The products were obtained in good-to-excellent yields (68-99%, Table 1) with three outliers, 2b, 3b and 3i, whose yields were, respectively, 58%, 56% and 45% only. To improve the yield, the synthesis with an auxiliary additive (K2CO3) was attempted in the case of 2b. However, any yield benefits were observed; therefore, no more reactions were performed this way. Most of the 36 crude products did not contain substrates, indicating their full conversion. These imines were directly subjected to structural studies. In the 1 H,  [42], 95 [34]] [34]] "*" Calculated from the 1 H NMR spectrum by an internal standard method with DCM used as an internal standard. [ ] Yields reported in the literature.
The synthetic method was based on the manual grinding of equimolar amounts of the reagents and was used for the substrates being in a solid state (aldehydes: 3, 4 and amines: a, c, d, e, i, Table 1) as well as in a liquid state (compounds: 1, 2, b, f, g, h, Table 1). In order to study the scope of the reaction, activated amines, having electron-donating groups, as well as deactivated amines, containing electron-withdrawing substituents, were used (Table 1). The reagents were ground for 15 min. This time was selected as suitable for all types of substrates used in our studies. For activated amines, 10 min was sufficient. However, this was not enough in the case of deactivated amines. Prolonged grinding (20 min) did not result in a better yield. Therefore, in order to standardize the reaction time and to develop the most general method possible, we chose 15 min, bearing in mind that fine tuning of the reaction conditions is very likely for each individual combination of substrates.
The products were obtained in good-to-excellent yields (68-99%, Table 1) with three outliers, 2b, 3b and 3i, whose yields were, respectively, 58%, 56% and 45% only. To improve the yield, the synthesis with an auxiliary additive (K2CO3) was attempted in the case of 2b. However, any yield benefits were observed; therefore, no more reactions were performed this way. Most of the 36 crude products did not contain substrates, indicating their full conversion. These imines were directly subjected to structural studies. In the 1 H,  [42], 95 [34]] [34]] "*" Calculated from the 1 H NMR spectrum by an internal standard method with DCM used as an internal standard. [ ] Yields reported in the literature.
The synthetic method was based on the manual grinding of equimolar amounts of the reagents and was used for the substrates being in a solid state (aldehydes: 3, 4 and amines: a, c, d, e, i, Table 1) as well as in a liquid state (compounds: 1, 2, b, f, g, h, Table 1). In order to study the scope of the reaction, activated amines, having electron-donating groups, as well as deactivated amines, containing electron-withdrawing substituents, were used (Table 1). The reagents were ground for 15 min. This time was selected as suitable for all types of substrates used in our studies. For activated amines, 10 min was sufficient. However, this was not enough in the case of deactivated amines. Prolonged grinding (20 min) did not result in a better yield. Therefore, in order to standardize the reaction time and to develop the most general method possible, we chose 15 min, bearing in mind that fine tuning of the reaction conditions is very likely for each individual combination of substrates.
The products were obtained in good-to-excellent yields (68-99%, Table 1) with three outliers, 2b, 3b and 3i, whose yields were, respectively, 58%, 56% and 45% only. To improve the yield, the synthesis with an auxiliary additive (K2CO3) was attempted in the case of 2b. However, any yield benefits were observed; therefore, no more reactions were performed this way. Most of the 36 crude products did not contain substrates, indicating their full conversion. These imines were directly subjected to structural studies. In the 1 H, The synthetic method was based on the manual grinding of equimolar amounts the reagents and was used for the substrates being in a solid state (aldehydes: 3, 4 a amines: a, c, d, e, i, Table 1) as well as in a liquid state (compounds: 1, 2, b, f, g, h, Table  In order to study the scope of the reaction, activated amines, having electron-donati groups, as well as deactivated amines, containing electron-withdrawing substituen were used (Table 1). The reagents were ground for 15 min. This time was selected suitable for all types of substrates used in our studies. For activated amines, 10 min w sufficient. However, this was not enough in the case of deactivated amines. Prolong grinding (20 min) did not result in a better yield. Therefore, in order to standardize reaction time and to develop the most general method possible, we chose 15 min, beari in mind that fine tuning of the reaction conditions is very likely for each individu combination of substrates.
The products were obtained in good-to-excellent yields (68-99%, Table 1) with th outliers, 2b, 3b and 3i, whose yields were, respectively, 58%, 56% and 45% only. To i prove the yield, the synthesis with an auxiliary additive (K2CO3) was attempted in case of 2b. However, any yield benefits were observed; therefore, no more reactions w performed this way. Most of the 36 crude products did not contain substrates, indicati their full conversion. These imines were directly subjected to structural studies. In the 1h 86% The synthetic method was based on the manual grinding of equimolar amounts of the reagents and was used for the substrates being in a solid state (aldehydes: 3, 4 and amines: a, c, d, e, i, Table 1) as well as in a liquid state (compounds: 1, 2, b, f, g, h, Table 1). In order to study the scope of the reaction, activated amines, having electron-donating groups, as well as deactivated amines, containing electron-withdrawing substituents, were used (Table 1). The reagents were ground for 15 min. This time was selected as suitable for all types of substrates used in our studies. For activated amines, 10 min was sufficient. However, this was not enough in the case of deactivated amines. Prolonged grinding (20 min) did not result in a better yield. Therefore, in order to standardize the reaction time and to develop the most general method possible, we chose 15 min, bearing in mind that fine tuning of the reaction conditions is very likely for each individual combination of substrates.
The products were obtained in good-to-excellent yields (68-99%, Table 1) with three outliers, 2b, 3b and 3i, whose yields were, respectively, 58%, 56% and 45% only. To improve the yield, the synthesis with an auxiliary additive (K2CO3) was attempted in the case of 2b. However, any yield benefits were observed; therefore, no more reactions were performed this way. Most of the 36 crude products did not contain substrates, indicating their full conversion. These imines were directly subjected to structural studies. In the 1 H, The synthetic method was based on the manual grinding of equimolar amounts of the reagents and was used for the substrates being in a solid state (aldehydes: 3, 4 and amines: a, c, d, e, i, Table 1) as well as in a liquid state (compounds: 1, 2, b, f, g, h, Table 1). In order to study the scope of the reaction, activated amines, having electron-donating groups, as well as deactivated amines, containing electron-withdrawing substituents, were used (Table 1). The reagents were ground for 15 min. This time was selected as suitable for all types of substrates used in our studies. For activated amines, 10 min was sufficient. However, this was not enough in the case of deactivated amines. Prolonged grinding (20 min) did not result in a better yield. Therefore, in order to standardize the reaction time and to develop the most general method possible, we chose 15 min, bearing in mind that fine tuning of the reaction conditions is very likely for each individual combination of substrates.
The products were obtained in good-to-excellent yields (68-99%, Table 1) with three outliers, 2b, 3b and 3i, whose yields were, respectively, 58%, 56% and 45% only. To improve the yield, the synthesis with an auxiliary additive (K2CO3) was attempted in the case of 2b. However, any yield benefits were observed; therefore, no more reactions were performed this way. Most of the 36 crude products did not contain substrates, indicating their full conversion. These imines were directly subjected to structural studies. In the 1 H, The synthetic method was based on the manual grinding of equimolar amounts of the reagents and was used for the substrates being in a solid state (aldehydes: 3, 4 and amines: a, c, d, e, i, Table 1) as well as in a liquid state (compounds: 1, 2, b, f, g, h, Table 1). In order to study the scope of the reaction, activated amines, having electron-donating groups, as well as deactivated amines, containing electron-withdrawing substituents, were used (Table 1). The reagents were ground for 15 min. This time was selected as suitable for all types of substrates used in our studies. For activated amines, 10 min was sufficient. However, this was not enough in the case of deactivated amines. Prolonged grinding (20 min) did not result in a better yield. Therefore, in order to standardize the reaction time and to develop the most general method possible, we chose 15 min, bearing in mind that fine tuning of the reaction conditions is very likely for each individual combination of substrates.
The products were obtained in good-to-excellent yields (68-99%, Table 1) with three outliers, 2b, 3b and 3i, whose yields were, respectively, 58%, 56% and 45% only. To improve the yield, the synthesis with an auxiliary additive (K2CO3) was attempted in the case of 2b. However, any yield benefits were observed; therefore, no more reactions were performed this way. Most of the 36 crude products did not contain substrates, indicating their full conversion. These imines were directly subjected to structural studies. In the 1 H, The synthetic method was based on the manual grinding of equimolar amounts of the reagents and was used for the substrates being in a solid state (aldehydes: 3, 4 and amines: a, c, d, e, i, Table 1) as well as in a liquid state (compounds: 1, 2, b, f, g, h, Table 1). In order to study the scope of the reaction, activated amines, having electron-donating groups, as well as deactivated amines, containing electron-withdrawing substituents, were used (Table 1). The reagents were ground for 15 min. This time was selected as suitable for all types of substrates used in our studies. For activated amines, 10 min was sufficient. However, this was not enough in the case of deactivated amines. Prolonged grinding (20 min) did not result in a better yield. Therefore, in order to standardize the reaction time and to develop the most general method possible, we chose 15 min, bearing in mind that fine tuning of the reaction conditions is very likely for each individual combination of substrates.
The products were obtained in good-to-excellent yields (68-99%, Table 1) with three outliers, 2b, 3b and 3i, whose yields were, respectively, 58%, 56% and 45% only. To improve the yield, the synthesis with an auxiliary additive (K2CO3) was attempted in the case of 2b. However, any yield benefits were observed; therefore, no more reactions were performed this way. Most of the 36 crude products did not contain substrates, indicating their full conversion. These imines were directly subjected to structural studies. The synthetic method was based on the manual grinding of equimolar amounts the reagents and was used for the substrates being in a solid state (aldehydes: 3, 4 a amines: a, c, d, e, i, Table 1) as well as in a liquid state (compounds: 1, 2, b, f, g, h, Table  In order to study the scope of the reaction, activated amines, having electron-donati groups, as well as deactivated amines, containing electron-withdrawing substituen were used (Table 1). The reagents were ground for 15 min. This time was selected suitable for all types of substrates used in our studies. For activated amines, 10 min w sufficient. However, this was not enough in the case of deactivated amines. Prolong grinding (20 min) did not result in a better yield. Therefore, in order to standardize t reaction time and to develop the most general method possible, we chose 15 min, beari in mind that fine tuning of the reaction conditions is very likely for each individu combination of substrates.
The products were obtained in good-to-excellent yields (68-99%, Table 1) with thr outliers, 2b, 3b and 3i, whose yields were, respectively, 58%, 56% and 45% only. To i prove the yield, the synthesis with an auxiliary additive (K2CO3) was attempted in t case of 2b. However, any yield benefits were observed; therefore, no more reactions we performed this way. Most of the 36 crude products did not contain substrates, indicati their full conversion. These imines were directly subjected to structural studies. The synthetic method was based on the manual grinding of equimolar amounts of the reagents and was used for the substrates being in a solid state (aldehydes: 3, 4 and amines: a, c, d, e, i, Table 1) as well as in a liquid state (compounds: 1, 2, b, f, g, h, Table 1). In order to study the scope of the reaction, activated amines, having electron-donating groups, as well as deactivated amines, containing electron-withdrawing substituents, were used (Table 1). The reagents were ground for 15 min. This time was selected as suitable for all types of substrates used in our studies. For activated amines, 10 min was sufficient. However, this was not enough in the case of deactivated amines. Prolonged grinding (20 min) did not result in a better yield. Therefore, in order to standardize the reaction time and to develop the most general method possible, we chose 15 min, bearing in mind that fine tuning of the reaction conditions is very likely for each individual combination of substrates.
The products were obtained in good-to-excellent yields (68-99%, Table 1) with three outliers, 2b, 3b and 3i, whose yields were, respectively, 58%, 56% and 45% only. To improve the yield, the synthesis with an auxiliary additive (K2CO3) was attempted in the case of 2b. However, any yield benefits were observed; therefore, no more reactions were performed this way. Most of the 36 crude products did not contain substrates, indicating their full conversion. These imines were directly subjected to structural studies. In the 1 H, The synthetic method was based on the manual grinding of equimolar amounts of the reagents and was used for the substrates being in a solid state (aldehydes: 3, 4 and amines: a, c, d, e, i, Table 1) as well as in a liquid state (compounds: 1, 2, b, f, g, h, Table 1). In order to study the scope of the reaction, activated amines, having electron-donating groups, as well as deactivated amines, containing electron-withdrawing substituents, were used (Table 1). The reagents were ground for 15 min. This time was selected as suitable for all types of substrates used in our studies. For activated amines, 10 min was sufficient. However, this was not enough in the case of deactivated amines. Prolonged grinding (20 min) did not result in a better yield. Therefore, in order to standardize the reaction time and to develop the most general method possible, we chose 15 min, bearing in mind that fine tuning of the reaction conditions is very likely for each individual combination of substrates.
The products were obtained in good-to-excellent yields (68-99%, Table 1) with three outliers, 2b, 3b and 3i, whose yields were, respectively, 58%, 56% and 45% only. To improve the yield, the synthesis with an auxiliary additive (K2CO3) was attempted in the case of 2b. However, any yield benefits were observed; therefore, no more reactions were performed this way. Most of the 36 crude products did not contain substrates, indicating their full conversion. These imines were directly subjected to structural studies. In the 1 H,  The synthetic method was based on the manual grinding of equimolar amounts of the reagents and was used for the substrates being in a solid state (aldehydes: 3, 4 and amines: a, c, d, e, i, Table 1) as well as in a liquid state (compounds: 1, 2, b, f, g, h, Table 1). In order to study the scope of the reaction, activated amines, having electron-donating groups, as well as deactivated amines, containing electron-withdrawing substituents, were used (Table 1). The reagents were ground for 15 min. This time was selected as suitable for all types of substrates used in our studies. For activated amines, 10 min was sufficient. However, this was not enough in the case of deactivated amines. Prolonged grinding (20 min) did not result in a better yield. Therefore, in order to standardize the reaction time and to develop the most general method possible, we chose 15 min, bearing in mind that fine tuning of the reaction conditions is very likely for each individual combination of substrates.
The products were obtained in good-to-excellent yields (68-99%, Table 1) with three outliers, 2b, 3b and 3i, whose yields were, respectively, 58%, 56% and 45% only. To improve the yield, the synthesis with an auxiliary additive (K2CO3) was attempted in the case of 2b. However, any yield benefits were observed; therefore, no more reactions were performed this way. Most of the 36 crude products did not contain substrates, indicating their full conversion. These imines were directly subjected to structural studies. In the 1 H, 4i 68% * [54 [34]] "*" Calculated from the 1 H NMR spectrum by an internal standard method with DCM used as an internal standard.
[ ] Yields reported in the literature.
The synthetic method was based on the manual grinding of equimolar amounts of the reagents and was used for the substrates being in a solid state (aldehydes: 3, 4 and amines: a, c, d, e, i, Table 1) as well as in a liquid state (compounds: 1, 2, b, f, g, h, Table 1). In order to study the scope of the reaction, activated amines, having electron-donating groups, as well as deactivated amines, containing electron-withdrawing substituents, were used (Table 1). The reagents were ground for 15 min. This time was selected as suitable for all types of substrates used in our studies. For activated amines, 10 min was sufficient. However, this was not enough in the case of deactivated amines. Prolonged grinding (20 min) did not result in a better yield. Therefore, in order to standardize the reaction time and to develop the most general method possible, we chose 15 min, bearing in mind that fine tuning of the reaction conditions is very likely for each individual combination of substrates.
The products were obtained in good-to-excellent yields (68-99%, Table 1) with three outliers, 2b, 3b and 3i, whose yields were, respectively, 58%, 56% and 45% only. To improve the yield, the synthesis with an auxiliary additive (K 2 CO 3 ) was attempted in the case of 2b. However, any yield benefits were observed; therefore, no more reactions were performed this way. Most of the 36 crude products did not contain substrates, indicating their full conversion. These imines were directly subjected to structural studies. In the 1 H, 13 C and 19 F NMR spectra obtained for these compounds, no side products or unreacted substrates could be detected (for the NMR spectra of all synthesized imines, see ESI, Figures S1-S108). The yields of these imines were calculated on the basis of the crude products masses. When the monitoring of the reaction progress showed the presence of unreacted starting material (amine) among the product formed, the reaction yield was calculated from the 1 H NMR spectrum by an internal standard method and was marked with "*" ( Table 1). The synthetic method should provide analytically pure products; therefore, we developed a very rapid, easy and simple procedure for purification of imines in case of incomplete reactions. The procedure was based on the filtration of the mixture solution through a 3 cm thick layer of silica gel placed on the foam funnel. This resulted in the separation of the product from traces of unreacted amine with no loss of the yield ( Table 2, entries: 2 and 4), with a slightly lower yield ( Table 2, entries: 1, 3, 5, 6 and 7) or with a lower yield of about 10% (Table 2, entries: 8-10). The 1 H NMR spectra of 4c recorded before (A) and after purification (B) can be a visualization of the method's effectiveness (Figure 1). The 1 H NMR spectra of 4c recorded before (A) and after purification visualization of the method's effectiveness (Figure 1). The yields of imines obtained were influenced by the substituents in t rings of amines. The nucleophilic addition occurring with the amines h tron-donating groups produced the corresponding imines in better yields, in to the reactions performed with deactivated amines (Table 1). It is worth n among the obtained imines, 12 (shown in blue, Table 1), to the best of our kno new compounds, previously not reported in the literature. Six of them (2g, 3 represent derivatives of chiral benzylamines. It should be stressed that all taining a stereogenic center were obtained with the high yields (72-98%, Tab  1-4 g and 1-4 h). With regard to the other obtained imines, we were surpris the literature yields reported for only nine compounds: 3a, 4c, 1-4d, 2e, 4e a 1). A few of these imines were synthesized by classical methods based on boiling toluene and the Dean-Stark apparatus (3a [32] and 3d [33]) or chlorob dowex (2d [42]). For the synthesis of 1d, 2e, 4d and 4e, milder conditions, suc and magnesium sulfate under an inert atmosphere [18], or ethanol [41] methane [36,42] at ambient temperatures were used. The mechanochemical scribed in this work produced imines with yields comparable to or highe reported in the literature (Table 1), and under more environmentally friendly The yields of imines obtained were influenced by the substituents in the aromatic rings of amines. The nucleophilic addition occurring with the amines having electron-donating groups produced the corresponding imines in better yields, in comparison to the reactions performed with deactivated amines (Table 1). It is worth noticing that, among the obtained imines, 12 (shown in blue, Table 1), to the best of our knowledge, are new compounds, previously not reported in the literature. Six of them (2g, 3g and 1-4 h) represent derivatives of chiral benzylamines. It should be stressed that all imines containing a stereogenic center were obtained with the high yields (72-98%, Table 1, imines 1-4 g and 1-4 h). With regard to the other obtained imines, we were surprised to find in the literature yields reported for only nine compounds: 3a, 4c, 1-4d, 2e, 4e and 4i (Table 1). A few of these imines were synthesized by classical methods based on the use of boiling toluene and the Dean-Stark apparatus (3a [32] and 3d [33]) or chlorobenzene and dowex (2d [42]). For the synthesis of 1d, 2e, 4d and 4e, milder conditions, such as hexane and magnesium sulfate under an inert atmosphere [18], or ethanol [41] or dichloromethane [36,42] at ambient temperatures were used. The mechanochemical method described in this work produced imines with yields comparable to or higher than those reported in the literature (Table 1), and under more environmentally friendly conditions: in a short reaction time of only 15 min and without the use of a solvent (Table 1). The majority of the reports described the remaining imines as generated in situ intermediates involved in various syntheses. Therefore, the imines were not analyzed by spectroscopic methods and their yields were not determined. In this work, for the first time, we presented their NMR spectra and determined the yields of syntheses performed by the mechanochemical method. Moreover, the imines being in the solid state were subjected to crystallization and crystals suitable for X-ray diffraction studies were obtained for 1c (this structure was reported previously [43]), 2a, 3d and 4d. X-ray analyses unambiguously confirmed the molecular structures of these imines. To the best of our knowledge, the crystal structures of 2a, 3d and 4d have not been reported to date. Single crystals of the compounds were obtained by slow evaporation from hexane (1c), chloroform (2a and 3d) and dichloromethane (4d) solutions. Perspective views of the molecules 2a, 3d and 4d, as observed in their crystal structures, are presented in Figure 2. An analogous view of the molecule 1c is shown in ESI ( Figure S109). The scalability of the developed mechanochemical method was examined further. For this purpose, larger-scale reactions were performed for the exemplified substrates. The reaction of 2,4-difluorobenzaldehyde with p-anisidine performed at a 10-times-larger scale (2.6 mmol) than the original one (0.26 mmol) proceeded without any problems with a 95% yield ( Table 2, entry 5). The reactions performed at 2-, 4-, 6and 8-times-larger scales also led to the formation of products in very high yields ( Table  3). The yields were only slightly lower than those of the original scale reactions (Table 3, entries: 1-6 and 8) or even slightly higher (entry 7). These results show the great potential of the scalability of our method.  The scalability of the developed mechanochemical method was examined further. For this purpose, larger-scale reactions were performed for the exemplified substrates. The reaction of 2,4-difluorobenzaldehyde with p-anisidine performed at a 10-times-larger scale (2.6 mmol) than the original one (0.26 mmol) proceeded without any problems with a 95% yield ( Table 2, entry 5). The reactions performed at 2-, 4-, 6-and 8-times-larger scales also led to the formation of products in very high yields ( Table 3). The yields were only slightly lower than those of the original scale reactions (Table 3, entries: 1-6 and 8) or even slightly higher (entry 7). These results show the great potential of the scalability of our method. The reaction of 2,4-difluorobenzaldehyde with p-anisidine performed at a 10-times-larger scale (2.6 mmol) than the original one (0.26 mmol) proceeded without any problems with a 95% yield ( Table 2, entry 5). The reactions performed at 2-, 4-, 6and 8-times-larger scales also led to the formation of products in very high yields ( Table  3). The yields were only slightly lower than those of the original scale reactions (Table 3, entries: 1-6 and 8) or even slightly higher (entry 7). These results show the great potential of the scalability of our method.

Conclusions
A number of imines derived from differently fluorinated benzaldehydes were synthesized in good-to-excellent yields by the mechanochemical method based on manual grinding with various aniline derivatives as well as chiral benzylamines. Most reactions occurred without any problems, the resulting imines were not contaminated by the remaining substrates and did not require any post-synthetic purification or isolation.
It seems that the amine structures affected the yields stronger than the structures of the aldehydes used. The highest yields were obtained for products formed from amines containing electron-donating groups, as could be rationalized by the stronger nucleophilic character of these substrates resulting from the greater reactivity of the electron pair of the amine nitrogen atom. However, it must be stressed that yields of imines derived from amines having electron-withdrawing substituents were also good.
12 out of 36 synthesized imines represent new compounds that had not been previously reported in the literature. In this study, we provided the NMR data not only for the newly synthesized compounds, but also for all other imines, which in earlier works, were reported only as spectroscopically uncharacterized intermediates. Moreover, we provided crystal structures for 2a, 3d and 4d as representatives of imines having 2, 3 and 5 fluorine atoms, respectively.
Consuming only mechanical energy, not requiring a solvent and producing products in a very short time, this method prevents environment pollution and meets some of the criteria of "green chemistry". The mechanochemical strategy presented in this work is very convenient and useful, particularly for the preparation of fluorinated imines, and can be easily extended to larger-scale syntheses.

General Methods
Reagent-grade chemicals were used. TLC was performed on Merck Kieselgel 60-F254 with EtOAc/hexane as an eluent, and products were detected by UV light (254 nm). NMR spectra were recorded with the instrument operating at 600 MHz ( 1 H), 150 MHz ( 13 C) and 300 MHz ( 19 F). Chemical shifts (δ) are presented in ppm and calibrated from the residual signals of CDCl 3 (7.26 ppm) and CD 3 OD (3.30 ppm) for 1 H NMR, and CDCl 3 (77.16 ppm) and CD 3 OD (49.05 ppm) for 13 C NMR. High-resolution mass spectra were measured using electrospray ionization (ESI, positive-ion mode) and spectrometer mass QTOF (Impact HD, Bruker Daltonics, Billerica, MA, USA).

General Procedure for the Imines Synthesis
The syntheses were conducted in a fume hood. Equimolar amounts of aldehyde (0.26 mmol) and amine (0.26 mmol) were placed in a glass round-bottom flask and ground manually with a glass rod without solvent at room temperature for 15 min. The obtained solid or oil was subjected to TLC analysis without any purification. When the analysis showed the presence of unreacted starting material, in addition to the expected product, the mixture was subjected to NMR studies performed with DCM (dichloromethane) as an internal standard, the use of which enabled the calculation of the reaction yield. The yields calculated from the imines' 1 H NMR spectra by an internal standard method are marked with "*". In most cases, TLC analysis showed the presence of pure product. The reaction yield was then calculated from the mass of the crude product, the purity of which was confirmed by the NMR spectra recorded without the internal standard. The spectra ( 1 H, 13 C and 19 F NMR) obtained for all imines synthesizes are presented in ESI. For the 12 new imines, HRMS spectra were also measured and included into ESI.

X-ray Crystallography
Diffraction data were collected by the ω-scan technique for 1c, 2a and 4d at 100(1) K on a Rigaku XCalibur four-circle diffractometer with am Eos CCD detector equipped with a graphite-monochromatized MoK α radiation source (λ = 0.71073 Å), and for 3d at 130(1) K on a Rigaku SuperNova four-circle diffractometer with an Atlas CCD detector equipped with a Nova microfocus CuK α radiation source (λ = 1.54178 Å). The data were corrected for Lorentz polarization as well as for absorption effects [44]. The structures were solved with SHELXT [45] and refined with the full-matrix least-squares procedure on F 2 by SHELXL-2013 [46]. All non-hydrogen atoms were refined anisotropically; hydrogen atoms were placed in idealized positions and refined as 'riding model' with isotropic displacement parameters set at 1.2 (1.5 for methyl groups) times U eq of appropriate carrier atoms. The relevant crystallographic data for 2a, 4d and 3d together with the details of structure refinement are listed in Table 4. The appropriate data obtained for 1c are presented in ESI, Table S1.