Crystals 2013, 3(1), 248-256; doi:10.3390/cryst3010248

Article
Iminium Salts by Meerwein Alkylation of Ehrlich’s Aldehyde
Carmen Froschauer 1,2, Hedda K. Weber 2, Volker Kahlenberg 3, Gerhard Laus 1,* and Herwig Schottenberger 1,*
1
Faculty of Chemistry and Pharmacy, University of Innsbruck, 6020 Innsbruck, Austria; E-Mail: carmen.froschauer@uibk.ac.at
2
Competence Centre of Wood Composites and Wood Chemistry K-Plus, Altenbergerstraße 69, 4021 Linz, Austria; E-Mail: h.weber@kplus-wood.at
3
Institute of Mineralogy and Petrography, University of Innsbruck, 6020 Innsbruck, Austria; E-Mail: volker.kahlenberg@uibk.ac.at
*
Authors to whom correspondence should be addressed; E-Mails: gerhard.laus@uibk.ac.at (G.L.); herwig.schottenberger@uibk.ac.at (H.S.); Tel.: +43-512-507-57004 (H.S.); Fax: +43-512-507-57099 (G.L.;H.S.).
Received: 25 January 2013; in revised form: 6 March 2013 / Accepted: 11 March 2013 /
Published: 18 March 2013

Abstract

: 4-(Dimethylamino)benzaldehyde is alkylated at the N atom by dialkyl sulfates, MeI, or Me3O BF4. In contrast, ethylation by Et3O BF4 occurs selectively at the O atom yielding a quinoid iminium ion. 4-(Diethylamino)benzaldehyde is alkylated only at O by either Et or Me oxonium reagent. The iminium salts are prone to hydrolysis giving the corresponding hydrotetrafluoroborates. Five crystal structures were determined.
Keywords:
alkylation; Ehrlich’s aldehyde; iminium salt; quinoid; quinone

1. Introduction

During unrelated work, the need arose for low-melting quaternary ammonium salts (“ionic liquids”) bearing an aldehyde functional group. Our obvious choice was 4-(dimethylamino)benzaldehyde (Ehrlich’s aldehyde) as inexpensive starting material which was to be N-alkylated. Common alkylating reagents such as dialkyl sulfates or methyl iodide readily gave the desired products [1,2]. However, a surprising selectivity was observed when trialkyloxonium tetrafluoroborates (Meerwein reagents) were employed. Thus, methylation occurred at the N atom as expected, whereas ethylation took place at the O atom. The crystal structures of the new compounds and byproducts were determined by single crystal X-ray diffraction (Table 1).

2. Results and Discussion

As noted above, for most of the different methods of alkylating 4-(dialkylamino)benzaldehydes (Figure 1a), including the use of trimethyloxonium tetrafluoroborate, the electrophilic attack occurs at the aniline N atom as expected, whereas Meerwein ethylation takes place at the carbonyl O atom, creating the quinoid iminium ion 1 in high yield and purity. Only traces of N-alkyl derivative of 4-(diethylamino)benzaldehyde were observed with either Et or Me oxonium reagent. Iminium ions are very reactive electrophilic intermediates, allowing a large range of nucleophiles to be trapped. For example, cyclizations involving iminium ions belong to the most powerful methods of forming nitrogen-containing heterocycles [3]. They are easily available by various well-established methods, but unprecedented pathways towards new iminium vehicles are emerging by serendipity, thus inviting multifaceted follow-up chemistry [4]. Iminium species are sensitive compounds and are typically prepared immediately prior to use. In the present case, the new iminium salts can be stored under an inert atmosphere for prolonged periods at room temperature. They are however prone to hydrolysis in solution, yielding the corresponding protic salts 2 and 5, which gave suitable single crystals. Exhibiting the interesting motif of a quinoid spacer between an imine moiety and an enol ether, the new bright green iminium salts 1 and 4 (Figure 1b) belong to the subfamily of quinone imine dyes, featuring specific reactivity patterns on their own [5]. Analogous products of O-alkylation and silylation were obtained from the related 4,4’-bis(dimethylamino)benzophenone [6,7]. Another example was found in 3,6-bis(dimethylamino)-9-ethoxyacridine [8]. The N-alkylated product, 4-(trimethylammonio)­benzaldehyde, is known as a useful precursor for 4-fluorobenzaldehyde [9,10]. The product of N-alkylation was converted to the low-melting triflimide 3 by ion metathesis, thus achieving the goal of the initial unrelated project. Protonation of Ehrlich’s aldehyde has also been reported to result in low-melting salts [11], and two crystal structures of such salts are known [12,13].

Crystals 03 00248 g001 200
Figure 1. (a) Alkylation of 4-(dialkylamino)benzaldehydes with Meerwein reagents; (b) Colorful reaction of Ehrlich’s aldehyde resulting in green crystals of iminium salt 1.

Click here to enlarge figure

Figure 1. (a) Alkylation of 4-(dialkylamino)benzaldehydes with Meerwein reagents; (b) Colorful reaction of Ehrlich’s aldehyde resulting in green crystals of iminium salt 1.
Crystals 03 00248 g001 1024
Table 1. Crystal data and structure refinement details.

Click here to display table

Table 1. Crystal data and structure refinement details.
Compound12345
Chemical formulaC11H16NO·BF4C9H12NO·BF4C10H14NO·C2F6NO4S2C13H20NO·BF4C11H16NO·BF4
Mr265.06237.01444.37293.11265.06
Crystal systemMonoclinicMonoclinicTriclinicTriclinicTriclinic
Space groupC2/cP21/nP Crystals 03 00248 i001P Crystals 03 00248 i001P Crystals 03 00248 i001
a18.9425 (5)8.4727 (4)7.7374 (4)8.1170 (12)7.2055 (5)
b7.4564 (3)13.5659 (6)10.3506 (7)9.2368 (16)9.0529 (6)
c21.134 (1)10.4411 (5)12.6004 (8)10.6937 (17)10.2060 (7)
α909072.577 (6)67.069 (15)94.378 (6)
β118.979 (7)109.730 (6)73.231 (5)77.760 (13)90.403 (6)
γ909072.301 (9)89.080 (13)97.839 (5)
V32611.3 (2)1129.64 (9)895.34 (10)719.6 (2)657.50 (8)
Z84222
Dx/g·cm−31.351.391.651.351.34
μ/mm−11.080.130.391.030.12
Crystal size/mm30.32 × 0.24 × 0.240.32 × 0.32 × 0.020.28 × 0.16 × 0.120.20 × 0.20 × 0.120.32 × 0.2 × 0.08
F(000)/e1104488452308276
Θ range/°4.8–67.62.6–25.22.8–25.44.6–67.53.2–25.3
h, k, l range–22 ≤ h ≤ 16–10 ≤ h ≤ 10–7 ≤ h ≤ 9–9 ≤ h ≤ 9–8 ≤ h ≤ 7
–8 ≤ k ≤ 8–16 ≤ k ≤ 16–11 ≤ k ≤ 12–11 ≤ k ≤ 10–10 ≤ k ≤ 10
–19 ≤ l ≤ 25–11 ≤ l ≤ 12–14 ≤ l ≤ 15–10 ≤ l ≤ 12–12 ≤ l ≤ 9
Measured reflections710310599549342834097
Independent reflections (Rint)2337 (0.022)2020 (0.033)3248 (0.019)2421 (0.027)2369 (0.025)
Observed reflections [I ≥ 2σ(I)]19021641252919281893
Restraints/parameters21/1850/1530/2510/188132/261
R1/wR2 [I ≥ 2σ(I)]0.059/0.1720.039/0.110.029/0.0670.043/0.1080.039/0.084
R1/wR2 (all data)0.069/0.1810.048/0.1160.039/0.0710.055/0.1190.053/0.093
ρmax/min/e Å−30.50/–0.330.32/–0.280.35/–0.340.18/–0.200.17/–0.17

2.1. N-(4-(Ethoxymethylene)cyclohexa-2,5-dienylidene)-N,N-dimethylammonium Tetrafluoroborate (1)

The quinoid nature of the ring can be readily recognized by the presence of two short double bonds, 1.343(4) Å and 1.350(4) Å, and four long single bonds, from 1.418(4) Å to 1.436(5) Å. The two exocyclic bonds, C=N with 1.330(3) Å and C=C with 1.375(4) Å, are clearly double bonds. The molecular structure of the ion pair and the packing in the unit cell (Z = 8) are shown in Figure 2.

Crystals 03 00248 g002 200
Figure 2. (a) Ion pair (ellipsoids at 50 percent probability level); (b) Packing of compound 1 in the unit cell.

Click here to enlarge figure

Figure 2. (a) Ion pair (ellipsoids at 50 percent probability level); (b) Packing of compound 1 in the unit cell.
Crystals 03 00248 g002 1024

2.2. 4-(Dimethylamino)benzaldehyde hydrotetrafluoroborate (2)

This protic salt was obtained by hydrolysis of the quinone 1. An interionic hydrogen bond is observed between N1-H and F1. The H...F distance is 1.99(3) Å and the N...F distance, 2.818(2) Å. The N...H...F angle was found to be 152(2)°. The bond lengths in the ring, ranging from 1.378(2) Å to 1.391(3) Å, reveal its aromatic character. The two exocyclic bonds, C-N with 1.478(2) Å and C-C with 1.473(3) Å, are typical single bonds. The molecular structure of the ion pair and the packing in the unit cell (Z = 4) are shown in Figure 3.

Crystals 03 00248 g003 200
Figure 3. (a) Ion pair (ellipsoids at 50 percent probability level); (b) Packing of compound 2 in the unit cell.

Click here to enlarge figure

Figure 3. (a) Ion pair (ellipsoids at 50 percent probability level); (b) Packing of compound 2 in the unit cell.
Crystals 03 00248 g003 1024

2.3. 4-(Trimethylammonio)benzaldehyde bis(trifluoromethylsulfonyl)imide (3)

The 4-(trimethylammonio)benzaldehyde cation obtained by methylation of Ehrlich’s aldehyde using Me3O BF4 was converted by ion metathesis and isolated as triflimide, a low-melting salt. Again, the bond lengths in the ring, ranging from 1.379(3) Å to 1.386(2) Å, indicate an aromatic system. The exocyclic single bonds, C-N with 1.500(2) Å and C-C with 1.482(3) Å, are longer than in the protic salt 2. The triflimide anion adopts a typical anti conformation [14] with a C-S1...S2-C torsion angle of 167.1(1)° and exhibits only weak C-H...O interactions with the cation. The molecular structure of the ion pair and the packing in the unit cell (Z = 2) are shown in Figure 4.

Crystals 03 00248 g004 200
Figure 4. (a) Ion pair (ellipsoids at 50 percent level); (b) Packing of compound 3.

Click here to enlarge figure

Figure 4. (a) Ion pair (ellipsoids at 50 percent level); (b) Packing of compound 3.
Crystals 03 00248 g004 1024

2.4. N-(4-(Ethoxymethylene)cyclohexa-2,5-dienylidene)-N,N-diethylammonium Tetrafluoroborate (4)

Again, the quinoid character of the ring can be seen by the presence of two short double bonds, 1.356(2) Å and 1.359(2) Å, and four long single bonds, from 1.420(3) Å to 1.439(2) Å. The two exocyclic bonds, C=N with 1.336(2) Å and C=C with 1.379(2) Å, are clearly double bonds. The molecular structure of the ion pair and the packing in the unit cell (Z = 2) are shown in Figure 5.

Crystals 03 00248 g005 200
Figure 5. (a) Ion pair (ellipsoids at 50 percent level); (b) Packing of compound 4.

Click here to enlarge figure

Figure 5. (a) Ion pair (ellipsoids at 50 percent level); (b) Packing of compound 4.
Crystals 03 00248 g005 1024

2.5. 4-(Diethylamino)benzaldehyde Hydrotetrafluoroborate (5)

The hydrolysis of quinone 4 gave this protic salt, in analogy to the conversion of 1 to 2. The anion exhibits positional disorder (ratio of components 0.33:0.26:0.41). A short hydrogen bond, as in compound 2, is observed between N1-H and F3. The bond lengths in the ring, from 1.376(2) Å to 1.388(2) Å, indicate aromatic character. The two exocyclic bonds, C-N with 1.476(2) Å and C-C with 1.474(2) Å, are of almost equal length as in salt 2. The molecular structure of the ion pair and the packing in the unit cell (Z = 2) are shown in Figure 6.

Crystals 03 00248 g006 200
Figure 6. (a) Ion pair (ellipsoids at 50 percent probability level); (b) Packing of compound 5 in the unit cell.

Click here to enlarge figure

Figure 6. (a) Ion pair (ellipsoids at 50 percent probability level); (b) Packing of compound 5 in the unit cell.
Crystals 03 00248 g006 1024

3. Experimental Section

Intensity data were collected on an Oxford Diffraction Gemini-R Ultra diffractometer with graphite-monochromatized Cu Kα (1 and 4) or Mo Kα (2, 3, and 5) radiation. Data were measured via ω scans, and an empirical absorption correction (multi-scan) was applied. CCDC reference numbers: 921104–921108. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre.

3.1. N-(4-(Ethoxymethylene)cyclohexa-2,5-dienylidene)-N,N-dimethylammonium Tetrafluoroborate (1) and 4-(Dimethylamino)benzaldehyde Hydrotetrafluoroborate (2)

4-(Dimethylamino)benzaldehyde (5.94 g, 39.8 mmol) was added to a solution of Et3O BF4 (7.57 g, 39.8 mmol) in anhydrous CH2Cl2 (10 mL) in an argon atmosphere. The colour of the solution changed from yellow to red to brown and finally to green after 3 hours of stirring at room temperature. After 3.5 h anhydrous Et2O (50 mL) was added, and a green solid precipitated. The solid was washed with anhydrous Et2O and dried. Single crystals of 1 and 2 were grown concomitantly by diffusion of hexane into a CH2Cl2 solution under inert gas.

1: 1H NMR (300 MHz, DMSO-d6): 1.46 (t, 3H), 3.38 (s, 6H), 4.73 (q, 2H), 7.11 (d, J = 9.5 Hz, 2H), 7.87 (d, J = 9.5 Hz, 2H), 8.68 (s, 1H) ppm; 13C NMR (75 MHz, DMSO-d6): 14.9, 41.3 (2C), 76.5, 115.2 (2C), 128.0, 138.0, 159.7, 180.5 ppm.

2: 1H NMR (300 MHz, DMSO-d6): 3.04 (s, 6H), 6.79 (d, J = 8.9 Hz, 2H), 7.68 (d, J = 8.9 Hz, 2H), 9.66 (s, 1H) ppm; 13C NMR (75 MHz, DMSO-d6): 39.7 (2C), 111.1 (2C), 124.6, 131.6 (2C), 154.2, 189.9 ppm.

3.2. 4-(Trimethylammonio)benzaldehyde Bis(trifluoromethylsulfonyl)imide (3)

4-(Dimethylamino)benzaldehyde (1.53 g, 10.3 mmol) was added to a solution of Me3O BF4 (1.52 g, 10.3 mmol) in anhydrous CH2Cl2 (50 mL) under inert gas. The colour of the solution changed from yellow to orange to yellow-light green. After stirring at room temperature for 20 h anhydrous Et2O (50 mL) was added, and a light orange solid formed, which was vacuum-dried. Then K2CO3 (1.42 g, 10.3 mmol), lithium bis(trifluoromethylsulfonyl)imide (1.71 g, 5.96 mmol), and H2O (50 mL) were added and stirred at room temperature for 1 h. The formation of a heavy organic phase was observed. The aqueous phase was discarded, and the lower phase was washed twice with Et2O. After addition of CH2Cl2 (50 mL) the organic phase was washed twice with water. The solvent was removed, and the resulting light-green product was vacuum-dried. Single crystals were obtained by diffusion of hexane into a solution in anhydrous CH2Cl2. m.p. 67–69 °C.

1H NMR (300 MHz, DMSO-d6): 3.65 (s, 9H), 8.14–8.23 (m, 4H), 10.11 (s, 1H) ppm; 13C NMR (75 MHz, DMSO-d6): 56.4 (3C), 119.5 (q, J = 322 Hz), 121.8 (2C), 130.9 (2C), 136.8, 151.1, 192.2 ppm.

3.3. N-(4-(Ethoxymethylene)cyclohexa-2,5-dienylidene)-N,N-diethylammonium Tetrafluoroborate (4)

4-(Diethylamino)benzaldehyde (5.25 g, 29.6 mmol) was added to a solution of Et3O BF4 (5.62 g, 29.6 mmol) in anhydrous CH2Cl2 (15 mL) under argon. The color of the solution changed from yellow to orange to yellow-green after 24 h of stirring at room temperature. Anhydrous Et2O (10 mL) was added to precipitate a light green solid, which was filtered and dried. Single crystals were grown by diffusion of hexane into a solution in anhydrous CH2Cl2.

1H NMR (300 MHz, DMSO-d6): 1.23 (t, 6H), 1.46 (t, 3H), 3.74 (q, 4H), 4.73 (q, 2H), 7.13 (d, J = 9.2 Hz, 2H), 7.87 (d, J = 9.2 Hz, 2H), 8.69 (s, 1H) ppm; 13C NMR (75 MHz, DMSO-d6): 12.6 (2C), 15.0, 46.2 (2C), 76.5, 115.0 (2C), 128.4, 138.4, 158.3, 180.3 ppm.

3.4. 4-(Diethylamino)benzaldehyde Hydrotetrafluoroborate (5)

4-(Diethylamino)benzaldehyde (1.80 g, 10.2 mmol) was added to a solution of Me3O BF4 (1.50 g, 10.2 mmol) in anhydrous CH2Cl2 (30 mL) under inert gas. The orange suspension turned into a green solution after stirring at room temperature for 24 h. Addition of anhydrous Et2O (10 mL) precipitated a light green solid. Unfortunately, only the hydrolyzed product crystallized by diffusion of hexane into a solution in CH2Cl2.

1H NMR (300 MHz, DMSO-d6): 1.11 (t, J = 7.0 Hz, 6H), 3.43 (q, J = 7.0 Hz, 4H), 6.79 (d, J = 8.9 Hz, 2H), 7.67 (d, J = 8.9 Hz, 2H), 9.64 (s, 1H) ppm; 13C NMR (75 MHz, DMSO-d6): 12.3 (2C), 44.5 (2C), 111.3 (2C), 124.7, 132.0 (2C), 151.6, 189.7 ppm.

4. Conclusions

Of course, it would be far beyond the scope of this study, and even a chemist’s lifespan could be consumed, to supplement this preliminary report by a representative selection of subsequent conversions. Consequently, this communication is focused mainly on crystallography. However, due to the affordability and ease with which these carbon-substituted representatives are accessible, it is also intended to stimulate further exploration of such iminium derivatives.

Acknowledgments

Financial support was provided by the Austrian government as well as by the Lenzing AG.

References

  1. Fahim, H.A.; Galaby, M. Quaternary ammonium salts. The formation and decomposition of ethyldimethylanilinium salts. The synthesis of N-ethyl-N-methylanilines. J. Chem. Soc. 1950, 1950, 3529–3532, doi:10.1039/jr9500003529.
  2. Yuan, H.; Zhou, Z.; Xiao, J.; Liang, L.; Dai, L. Preparation of quarternary ammonium salt-tagged ferrocenylphosphine-imine ligands and their application to palladium-catalyzed asymmetric allylic substitution. Tetrahedron Asymmetry 2010, 21, 1874–1884, doi:10.1016/j.tetasy.2010.05.047.
  3. Royer, J.; Bonin, M.; Micouin, L. Chiral heterocycles by iminium ion cyclization. Chem. Rev. 2004, 104, 2311–2352, doi:10.1021/cr020083x.
  4. El Kaim, L.; Grimaud, L. Beyond the Ugi reaction: Less conventional interactions between isocyanides and iminium species. Tetrahedron 2009, 65, 2153–2171, doi:10.1016/j.tet.2008.12.002.
  5. Brown, E.R. Quinonediimines, monoimines, and related compounds. In Chemistry of Quinonoid Compounds; Patai, S., Rappoport, Z., Eds.; Wiley: Chichester, UK, 1988; pp. 1231–1292.
  6. Meerwein, H.; Florian, W.; Schön, N.; Stopp, G. Acid amide acetals, urea acetals, and lactam acetals (in German). Ann. Chem. 1961, 641, 1–39, doi:10.1002/jlac.19616410102.
  7. Emde, H.; Götz, A.; Hofmann, K.; Simchen, G. Reaktionen der Trialkylsilyl-trifluormethansulfonate, I. Synthese von Trialkylsilyl-Enolethern (in German). Ann. Chem. 1981, 1981, 1643–1657.
  8. Elslager, E.F.; Haley, N.F.; McLean, J.R.; Perricone, S.C.; Potoczak, D.; Veloso, H.; Worth, D.F.; Wheelock, R.H. Inhibitors of platelet aggregation. 2. 9-{[(Dialkylamino)alkyl]thio]-3-(dimethylamino)acridines and related acridine derivatives. J. Med. Chem. 1971, 14, 782–788, doi:10.1021/jm00291a002.
  9. Bruus-Jensen, K.; Poethko, T.; Schottelius, M.; Hauser, A.; Schwaiger, M.; Wester, H.-J. Chemoselective hydrazone formation between HYNIC-functionalized peptides and 18F-fluorinated aldehydes. Nucl. Med. Biol. 2006, 33, 173–183, doi:10.1016/j.nucmedbio.2005.10.010.
  10. Poethko, T.; Schottelius, M.; Thumshirn, G.; Hersel, U.; Herz, M.; Henriksen, G.; Kessler, H.; Schwaiger, M.; Wester, H.-J. Two-step methodology for high-yield routine radiohalogenation of peptides: 18F-labeled RGD and octreotide analogs. J. Nucl. Med. 2004, 45, 892–902.
  11. Shamsuri, A.A.; Abdullah, D.K. Protonation and complexation approaches for production of protic eutectic ionic liquids. J. Phys. Sci. 2010, 21, 15–28.
  12. Dattagupta, J.K.; Saha, N.N. The crystal structure of p-dimethylaminobenzaldehyde hydrobromide. Acta Crystallogr. 1973, B29, 1228–1233.
  13. Thakuria, H.; Borah, B.M.; Pramanik, A.; Das, G. Solid state synthesis and hierarchical supramolecular self-assembly of organic salt cocrystals. J. Chem. Cryst. 2007, 37, 807–816, doi:10.1007/s10870-007-9252-3.
  14. Laus, G.; Hummel, M.; Többens, D.M.; Gelbrich, T.; Kahlenberg, V.; Wurst, K.; Griesser, U.J.; Schottenberger, H. The 1:1 and 1:2 salts of 1,4-diazabicyclo[2.2.2]octane and bis(trifluoromethyl-sulfonyl)amine: Thermal behaviour and polymorphism. CrystEngComm 2011, 13, 5439–5446, doi:10.1039/c1ce05310h.
Crystals EISSN 2073-4352 Published by MDPI AG, Basel, Switzerland RSS E-Mail Table of Contents Alert