Approach toward the Understanding of Coupling Mechanism for EDC

Letter pubs.acs.org/OrgLett

Approach toward the Understanding of Coupling Mechanism for EDC Reagent in Solvent-Free Mechanosynthesis Aneta Wróblewska,† Piotr Paluch,† Ewelina Wielgus,† Grzegorz Bujacz,‡ Marta K. Dudek,† and Marek J. Potrzebowski*,† †

Centre of Molecular and Macromolecular Studies, Polish Academy of Sciences, Sienkiewicza 112, 90-363 Lodz, Poland Institute of Technical Biochemistry, Lodz University of Technology, Stefanowskiego 4/10, 90-924 Lodz, Poland

‡

S Supporting Information *

ABSTRACT: A unique approach in mechanosynthesis, joining solid-state NMR spectroscopy, X-ray crystallography, and theoretical calculations, is employed for the first time to study the mechanism of the formation of the C− N amide bond using EDC·HCl as a coupling reagent. It has been proved that EDC·HCl, which in the crystal lattice exists exclusively in the cyclic form (X-ray data), easily undergoes transformation to a pseudocyclic stable intermediate in reaction with carboxylic acid forming a low-melt phase (differential scanning calorimetry, solid-state NMR). The obtained intermediate is reactive and can be further used for synthesis of amides in reaction with appropriate amines.

I

knowledge, there are no systematic studies in the literature that explore this issue. Margetić and Štrukil very recently described, in a comprehensive textbook, a number of chemical reactions which can be carried out employing the mechanochemical approach.9 The formation of a carbon−nitrogen bond is of particular importance among the variety of processes in which new chemical bonds are established.10,4d Great contributions to this field come from laboratories led by Lamaty as well Juaristi and co-workers, who published a number of spectacular mechanosynthetic applications for the class of compounds under discussion.11 In the mechanochemical procedure allowing the formation of a C−N bond, the choice of appropriate coupling reagents, milling (grinding) conditions, and other additives (LAG, bases) is critical and usually experimentally tested. 12 Š trukil et al. have investigated the applicability of different coupling reagents and their usefulness in C−N mechanosynthesis.13 On the basis of extensive experimental studies, the authors concluded that N-(3(dimethylamino)propyl)-N′-ethylcarbodiimide hydrochloride (EDC·HCl) is the best choice. The aim of this work is to answer the question: why? There is no doubt that the crucial information for discussing in detail the mechanism of the formation of a covalent bond in the solid state is knowledge about crystal and molecular structure of a coupling reagent. Searching the literature, we were surprised that despite EDC·HCl being one of the most popular coupling reagents commonly used in organic synthesis, to date there is no

nterest in applications of solid-state mechanochemistry as a versatile platform for producing diverse compounds has grown in recent years.1 There are at least two reasons for the interest in mechanochemistry. First, solid-state processes are usually clear, effective, and high yielding.2 Second, syntheses carried out in the condensed matter are economically and ecologically justified.3 The term mechanochemistry covers a number of procedures including synthesis of inorganic materials, drugs, organic compounds, discrete metal complexes, extended metal−organic materials (MOFs), formation of cocrystals, and supramolecular complexes.4 These processes, leading to new products, can be roughly divided into two groups; those where a new covalent bond is formed5 and those where new material is formed by noncovalent interactions (e.g., hydrogen bonding, van der Waals, aromatic−aromatic, and/or electrostatic interactions, etc.).6 From the point of view of mechanochemistry, the processes in which a covalent bond is formed are especially demanding, and few prerequisites have to be fulfilled.7 First, in the mechanosynthesis of organic compounds the problem of the state of matter is crucial. It has been suggested that such reactions occur principally, or even exclusively, through bulk liquid eutectic states. Thus, the knowledge about the formation of low-melting eutectic intermediate phases and transport mechanisms in solid matter is vital for development of the method.8 On the opposite end of questions related to further progress in mechanochemistry is the problem associated with the mechanism of reactions in the solid state, in particular, when supporting reagents are used in synthesis of new compounds. The question whether the mechanisms in the liquid and solid states are exactly the same is not trivial, and the answer is not obvious. To the best of our © 2017 American Chemical Society

Received: August 24, 2017 Published: September 22, 2017 5360

DOI: 10.1021/acs.orglett.7b02637 Org. Lett. 2017, 19, 5360−5363

Letter

Organic Letters

Figure 2. Change of the state of the matter: (a) mixture of equimolar amount of EDC·HCl and benzoic acid before grinding; (b) reaction mixture after 1 h of grinding.

the question arises whether in the condensed matter a cyclic form is also capable of carboxylic function activation or if there is a rearrangement of this form to a linear one during mechanosynthesis. To answer this question, we employed benzoic acid (BA) as a reference sample. Mechanosynthetic reaction of BA with EDC· HCl was carried out under solvent-free conditions with one 5 mm stainless steel ball. The reaction was performed with and without the presence of NaHCO3, which is generally regarded as necessary for the activation of the carboxylic function. In both cases, after 1 h of ball-milling of an equimolar amount of both substrates, a change of the state of the matter was clearly visible (Figure 2). This observation is in agreement with literature reports, which suggest that in all mechanochemical reactions the liquid orlow-melt phase has to occur at some stage of the process,17 but it also clearly indicates that in this case the presence of NaHCO3 is not required. It is also worth stressing that grinding EDC·HCl alone does not lead to any changes in its appearance or structure. The 13C MAS NMR spectrum registered for a crude reaction mixture after 1 h of grinding shows almost complete consumption of starting materials (Figure 3), with the small

Figure 1. 13C (a) and 15N (b) CPMAS NMR spectra of the solid form of EDC·HCl recorded with a spinning rate 8 kHz at ambient temperature. (c, d) ORTEP plots of the crystalline sample and crystal packing, respectively, together with solid-state structure and numbering of EDC· HCl.

information about its structure in condensed matter. On the other hand, the literature describing its behavior in the liquid phase is extensive.14 It is postulated that EDC exists in three isomeric forms (see the Supporting Information). Our studies therefore began with the solid-state NMR analysis of pure EDC·HCl. Parts a and b of Figure 1 show 13C and 15N CPMAS NMR spectra of the commercially available reagent. In both a single set of signals is clearly observable, which may suggest that there is only one (out of possible three) form of EDC. In the 13C CPMAS spectrum seven aliphatic signals in the region of 10−70 ppm are observable, in addition to one quaternary carbon at 143.2 ppm, which originates from the  CN carbon atom. Such a spectral picture may arise from both linear and cyclic forms of EDC·HCl. On the contrary, the 15N CPMAS spectrum, which displays three signals resonating at 66.0, 84.2, and 197.3 ppm, indicates that one of the cyclic forms is present, rather than a linear one, as only one signal has a chemical shift characteristic for double-bonded nitrogen. To confirm the solid-state structure of EDC·HCl, singlecrystal X-ray measurements were carried out after recrystallization from an equivolume mixture of methylene chloride and hexane. The structure for the obtained monocrystal (Figure 1c) is consistent with the NMR-driven results (see the SI for structural details). The lack of a chairlike conformation of the cyclic ring in the crystal indicates that the proton is localized at the side chain. To confirm this result, geometries of both crystal structures with proton localized either at the side chain or in the cyclic hexahydropirymidine ring were optimized under periodic boundary conditions, and the NMR parameters were calculated for both structures with the GIPAW approach.15 On the basis of the performed calculation, a full signal assignment was made. The agreement between calculated shielding constants and experimental chemical shifts for 13C and 15N was noticeably better for structure with a proton located at the side-chain nitrogen (see the SI for details on the performed calculations and chemical shift assignment). These surprising results clearly indicate that EDC·HCl in solid matter has only one form, a cyclic one. Keeping in mind that the linear form is considered to be the only activating carboxylic function in solution during the C−N bond formation16 and that EDC·HCl is an efficient coupling agent also in the solid phase,

Figure 3. (a−c) 13C NMR MAS spectra registered for (a) benzoic acid, (b) EDC·HCl, (c) reaction mixture of benzoic acid and EDC·HCl after 1h grinding under neat condition; (d) the 1H−1H MAS NOESY spectrum registered for reaction mixture of benzoic acid and EDC·HCl after 1 h of grinding under neat conditions showing correlation between aliphatic and aromatic protons present in the obtained intermediate. Asterisks (a) represent the spinning sidebands, and red arrows (c) show residual signals coming from unreacted EDC·HCl. Residual signals of BA are not seen due to the very long relaxation time.

intensity signals originating from pure EDC·HCl. Apart from that, a new set of signals is visible, with two characteristic peaks originating from quaternary carbons at 160.1 and 162.5 ppm. The latter signal reveals the presence of esterified carbonyl, as it is noticeably upfield shifted, as compared to the carboxyl signal of BA at 175 ppm. On the contrary, the signal at 160.1 ppm, assignable to C-2 carbon from EDC·HCl moiety, is downfield shifted as compared to the C-2 signal of pure EDC·HCl, which 5361

DOI: 10.1021/acs.orglett.7b02637 Org. Lett. 2017, 19, 5360−5363

Letter

Organic Letters resonates at 143.2 ppm. Such a shift indicates that an electronwithdrawing substituent was linked to C-2. The remaining 13C signals originate either from aromatic carbons from the benzoic moiety (signals at 134.7−128.8 ppm) or from aliphatic carbons from the EDC·HCl moiety (signals at 16−56 ppm). All this data suggests that the formation of a new product occurred, which is further confirmed by 1H−1H correlation peaks in the 1H−1H MAS NOESY spectrum between aromatic signals from benzoic acid and aliphatic signals from EDC·HCl moiety (Figure 3d). As a consequence, it may be stated that the activation of a carboxylic function was indeed achieved, but it is not yet clear whether it was done by the cyclic or linear form of EDC·HCl. To determine that, a detailed structural analysis of the obtained intermediate was performed, employing quantum chemical calculations and high-power decoupled (HPDEC) MAS experiments, as the cross-polarization for the obtained soft matter was ineffective. As in the case of pure EDC·HCl, the 13C MAS spectrum does not unambiguously specify which form is present in the studied sample, but the 15N MAS spectrum seems to be much more indicative (Figure 4).

Figure 6. Computational model of a 3D structure of the obtained intermediate.

= 0.521). On the contrary, the cyclic form showed better (but still not satisfactory) agreement for 15N (R2 = 0.766), but much poorer for 13C (R2 = 0.938), with the C-2 predicted shielding (ca. 118 ppm) being considerably different than the experimentally observed value (160.2 ppm). Therefore, we decided to reexamine the proposed intermediate structures. Usually, it is assumed that the N(CH3)2 nitrogen atom in the linear form of EDC·HCl intermediate bears a proton, but it seems also plausible that the proton is localized at N-3 nitrogen, while the double bond is delocalized as shown in Figure 5c. It is also known that an unwanted isomerization of an intermediate may occur, thus leading to a urea derivative (Figure 5d). These two possible outcomes of the performed mechanosynthesis were therefore also accounted for in our calculations. Both structures yielded very decent agreement in terms of both 13C and 15N shieldings, with structure c being still better than structure d (13C and 15N correlation coefficients, R2, for structure c are 0.993 and 0.999, respectively, while for structure d 0.980 and 0.985, respectively). A detailed analysis of differences between calculated and experimental chemical shifts for particular carbon and nitrogen atoms in both structures finally proves that structure c is the correct one for the obtained intermediate. All computational details, together with the calculated shieldings and experimental chemical shifts, and the discussion on the differences between them are included in the SI. The presented results clearly indicate that solid EDC·HCl undergoes ring opening during mechanosynthesis. The geometry of the calculated species is shown in Figure 6. The inspection of the computed structure proves that the coordinates of atoms forming the six-membered ring of EDC· HCl after reaction with BA are only slightly changed and the pseudocyclic form of intermediate is preserved. Thus, the formation of a new compound is a low energy process which does not require translation and/or rotation of atoms or groups. Having in hand a stable intermediate product formed by BA and EDC, in the next step we have tested its reactivity with selected solid aromatic amines. Syntheses were performed via ball-milling for 1h with equimolar amount of substrates in a jar with one stainless steel ball. After that time, crude products were washed several times with water, what allowed for the separation of the water-soluble side product (1-[3-(dimethylamino)propyl]-3-ethylurea) from the poorly water-soluble aromatic amides. The mass spectrometry results indicate that in all cases the desired products were obtained. The methane chemical ionization mass spectra of the obtained amides are summarized in Table 1 (for MS spectra seeSI). All amides are characterized by a protonated molecular ion [M + H]+ and a few prominent fragment ions. The main fragmentation peaks correspond to the benzoyl ions [C6H5C(O)]+ formed by a simple cleavage of an amide bond of a protonated amide. Such fragmentation pathway is one of the most important fragmentations of protonated amides, as well as of peptides and proteins, and is well

Figure 4. 15N MAS NMR spectra registered for (a) EDC·HCl and (b) reaction mixture of benzoic acid and EDC·HCl after 1 h of grinding under neat conditions; the 15N signals from pure EDC·HCl are at the noise level in the reaction mixture spectrum.

In the spectrum, three 15N signals at 41.8, 83.1, and 89.2 ppm are discernible, indicating that the CN bond is not present in the intermediate structure. This would suggest a cyclic form being a correct one, as in this structure all nitrogen atoms are single-bonded (Figure 5b). To confirm this first crude

Figure 5. Possible molecular structures of intermediate obtained in mechanosynthetic reaction of EDC·HCl and benzoic acid with numbering for crucial atoms.

assumption quantum chemical calculations (geometry optimization and NMR parameters calculations) were performed for both linear (Figure 5a) and cyclic (Figure 5b) structures. The obtained results definitely excluded a and b structures: the linear form agreed quite decently with the experimental results in terms of 13C shieldings (R2 value of 0.984, where R2 is a correlation coefficient obtained from linear regression after plotting experimental chemical shifts against theoretical shieldings), but totally disagreed in terms of 15N shieldings (R2 5362

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Organic Letters Table 1. Yield of the Mechanochemical Organic Synthesisa and CI-MS Data of the Obtained Aromatic Amides*

(2) (a) Czaja, A.; Leung, E.; Trukhan, N.; Müller, U. Industrial MOF synthesis. In Metal-Organic Frameworks: Application from Catalysis to Gas Storage; Farrusseng, D., Ed.; Wiley-VCH: Weinheim, 2011. (b) Jiménez-González, C.; Constable, D. J. C.; Ponder, C. S. Chem. Soc. Rev. 2012, 41, 1485. (3) Baig, R. B. N.; Varma, R. S. Chem. Soc. Rev. 2012, 41, 1559. (4) (a) James, S. L.; Adams, C. J.; Bolm, C.; Braga, D.; Collier, P.; Frišcǐ ć, T.; Grepioni, F.; Harris, K. D. M.; Hyett, G.; Jones, W.; Krebs, A.; Mack, J.; Maini, L.; Orpen, A. G.; Parkin, I. P.; Shearouse, W. C.; Steedk, J. W.; Waddelli, D. C. Chem. Soc. Rev. 2012, 41, 413. (b) Beillard, A.; Bantreil, X.; Métro, T.-X.; Martinez, J.; Lamaty, F. New J. Chem. 2017, 41, 1057. (c) Mascitti, A.; Lupacchini, M.; Guerra, R.; Taydakov, I.; Tonucci, L.; d’Alessandro, N.; Lamaty, F.; Martinez, J.; Colacino, E. Beilstein J. Org. Chem. 2017, 13, 19. (d) Wang, G.-W. Chem. Soc. Rev. 2013, 42, 7668. (5) (a) Beyer, M. K.; Clausen-Schaumann, H. Chem. Rev. 2005, 105, 2921. (b) Kaupp, G. CrystEngComm 2009, 11, 388. (6) (a) Caruso, M. M.; Davis, D. A.; Shen, Q.; Odom, S. A.; Sottos, N. R.; White, S. R.; Moore, J. S. Chem. Rev. 2009, 109, 5755. (b) Métro, T.X.; Colacino, E.; Martinez, J.; Lamaty, F. Green Chem. 2015, 31, 114. (c) Frišcǐ ć, T. Green Chem. 2015, 31, 151. (d) Mottillo, C.; Frišcǐ ć, T. Molecules 2017, 22, 144. (e) Tan, D.; Štrukil, V.; Mottillo, C.; Frišcǐ ć, T. Chem. Commun. 2014, 50, 5248. (7) Baláz,̌ P.; Achimovičová, M.; Baláz,̌ M.; Billik, P.; CherkezovaZheleva, Z.; Criado, J. M.; Delogu, F.; Dutková, E.; Gaffet, E.; Gotor, F. J.; Kumar, R.; Mitov, I.; Rojac, T.; Senna, M.; Streletskii, A.; WieczorekCiurowa, K. Chem. Soc. Rev. 2013, 42, 7571. (8) Bowmaker, G. A. Chem. Commun. 2013, 49, 334. (9) Margetić, D.; Štrukil, V. Mechanochemical Organic Synthesis, 1st ed.; Elsevier, Inc., 2016. (10) (a) Duangkamol, C.; Jaita, S.; Wangngae, S.; Phakhodee, W.; Pattarawarapan, M. RSC Adv. 2015, 5, 52624. (b) Tan, D.; Mottillo, C.; Katsenis, A. D.; Štrukil, V.; Frišcǐ ć, T. Angew. Chem., Int. Ed. 2014, 53, 9321. (c) Konnert, L.; Gauliard, A.; Lamaty, F.; Martinez, J.; Colacino, E. ACS Sustainable Chem. Eng. 2013, 1, 1186. (d) Métro, T.-X.; Bonnamour, J.; Reidon, T.; Sarpoulet, J.; Martinez, J.; Lamaty, F. Chem. Commun. 2012, 48, 11781. (e) Konnert, L.; Reneaud, B.; de Figueiredo, R. M.; Campagne, J.-M.; Lamaty, F.; Martinez, J.; Colacino, E. J. Org. Chem. 2014, 79, 10132. (f) Hernández, J. G.; Juaristi, E. J. Org. Chem. 2010, 75, 7107. (g) Hernández, J. G.; Ardila-Fierro, K. J.; Crawford, D.; James, S. L.; Bolm, C. Green Chem. 2017, 19, 2620. (11) (a) Porte, V.; Thioloy, M.; Pigoux, T.; Métro, T.-X.; Martinez, J.; Lamaty, F. Eur. J. Org. Chem. 2016, 2016, 3505. (b) Konnert, L.; Gonnet, L.; Halasz, I.; Suppo, J.-S.; de Figueiredo, R. M.; Campagne, J.-M.; Lamaty, F.; Martinez, J.; Colacino, E. J. Org. Chem. 2016, 81, 9802. (c) Bonnamour, J.; Métro, T.-X.; Martinez, J.; Lamaty, F. Green Chem. 2013, 15, 1116. (d) Declerck, V.; Nun, P.; Martinez, J.; Lamaty, F. Angew. Chem., Int. Ed. 2009, 48, 9318. (12) (a) Konnert, L.; Lamaty, F.; Martinez, J.; Colacino, E. J. Org. Chem. 2014, 79, 4008. (b) Lanzillotto, M.; Konnert, L.; Lamaty, F.; Martinez, J.; Colacino, E. ACS Sustainable Chem. Eng. 2015, 3, 2882. (c) Landeros, J. M.; Juaristi, E. Eur. J. Org. Chem. 2017, 2017, 687. (d) Hernández, J. G.; Juaristi, E. Chem. Commun. 2012, 48, 5396. (e) Gonnet, L.; Tintillier, T.; Venturini, N.; Konnert, L.; Hernandez, J.F.; Lamaty, F.; Laconde, G.; Martinez, J.; Colacino, E. ACS Sustainable Chem. Eng. 2017, 5, 2936. (f) Machuca, E.; Rojas, Y.; Juaristi, E. Asian J. Org. Chem. 2015, 4, 46. (13) Štrukil, V.; Bartolec, B.; Portada, T.; Dilović, I.; Halasz, I.; Margetić, D. Chem. Commun. 2012, 48, 12100. (14) Williams, A.; Ibrahim, I. T. J. Am. Chem. Soc. 1981, 103, 7090. (15) Pickard, C. J.; Mauri, F. Phys. Rev. B: Condens. Matter Mater. Phys. 2001, 63, 245101. (16) (a) Sehgal, D.; Vijay, I. K. Anal. Biochem. 1994, 218, 87. (b) Sureshbabu, V. V.; Lalithamba, H. S.; Narendra, N.; Hemantha, H. P. Org. Biomol. Chem. 2010, 8, 835. (17) Rothenberg, G.; Downie, A. P.; Raston, C. L.; Scott, J. L. J. Am. Chem. Soc. 2001, 123, 8701. (18) Wysocki, V. H.; Resing, K. A.; Zhang, Q.; Cheng, G. Methods 2005, 35, 211.

*

Relative abundances (%) of the selected ions in CI mass spectra are given in parentheses. aSynthesis conditions: a single 5 mm diameter stainless steel ball, 60 min, 25 Hz frequency, neat conditions, equimolar amount of the intermediate (EDC·HCl + BA) and an aromatic amine. bIsolated yield after aqueous workup.

understood and documented.18 The reaction yields, determined after aqueous workup, were in the range of 70−83% (Table 1). In this work, we employed an unique approach in mechanosynthesis joining solid-state NMR spectroscopy, X-ray crystallography and theoretical calculations to study the mechanism of formation of the C−N amide bond. Our results prove that one of the most efficient coupling agent, EDC·HCl, has a cyclic form in the solid phase. Upon grinding, this form undergoes ring opening, as was evidenced from solid-state structure of an intermediate. The ring opening permits the mechanochemical reaction to proceed, as it is related with the low-melt phase formation (see DSC profile attached in SI). Finally, it is worth noting that the applied mechanochemical pathway requires neither an addition of LAG nor that of a base (NaHCO3), which were previously regarded in the literature as necessary to successfully perform that kind of reaction.

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.7b02637. Experimental details and crystallographic data (PDF)

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Marta K. Dudek: 0000-0003-3412-0177 Marek J. Potrzebowski: 0000-0001-5672-0638 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS PL-GRID and ICM Infrastructures (computational grant G6711) are gratefully acknowledged for providing computational resources.

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REFERENCES

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DOI: 10.1021/acs.orglett.7b02637 Org. Lett. 2017, 19, 5360−5363