(E)-3-Mesityl-1-(2,3,5,6-tetramethylphenyl)prop-2-en-1-one

Abstract

We report the synthesis and characterisation of the previously unknown (E)-3-Mesityl-1-(2,3,5,6-tetramethylphenyl)prop-2-en-1-one by NMR spectroscopy, IR spectroscopy, melting point, mass spectrometry, and X-ray crystallography.

1. Introduction

(E)-3-Mesityl-1-(2,3,5,6-tetramethylphenyl)prop-2-en-1-one (1) is hitherto unknown in the literature; however, closely-related ketones, such as compound 2, have been reported previously [1,2]. A Claisen–Schmidt reaction of the durene-derivative 3 with benzaldehyde in the presence of sodium hydroxide delivers 2 in good yield [1]. Alternatively, the Friedel–Crafts acylation of durene (4) with cinnamoyl chloride has also been shown to be an efficient method for preparing compound 2 (Scheme 1) [2].

Organometallic reagents have also been employed to prepare sterically demanding chalcone derivatives such as compound 5. The carbonyl group of trimethyl, tetramethyl and pentamethyl ketones is known to be unreactive to the addition of nucleophiles; this lack of reactivity is attributed to the shielding effect of the 2,6-methyl groups [3,4,5]. Due to this steric effect, Grignard reagents have been reported to preferentially form magnesium enolates instead of 1,2-nucleophilic addition products. The reaction of ketone 6 with ethylmagnesium bromide to form enolate 7 serves as a useful example (Scheme 2) [4]. Enolate 7 can undergo an addition/elimination reaction with 2,4,6-trimethylbenzaldehyde to afford ketone 5; however, the yields are reportedly low (39–50%).

Sterically hindered aryl ketones can also be used to prepare dimethylaluminium enolates; spectroscopic and X-ray crystallography evidence for these species has been reported [6]. Dimethylaluminium enolate 8 is prepared under a nitrogen atmosphere using Schlenk techniques, and reacting ketone 6 with an excess of trimethylaluminium allows the enolate to be isolated. In a subsequent step, the enolate can then react with 2,4,6-trimethylbenzaldehyde to afford ketone 5 with 64% yield after purification by column chromatography (Scheme 3).

2. Results and Discussion

2.1. Synthesis and Spectroscopy

Ketone 3 reacts with 2,4,6-trimethylbenzaldehyde under adapted Claisen–Schmidt conditions. The title compound (1) was prepared via the addition of an aqueous solution of KOH to a mixture of ketone 3 and 2,4,6-trimethylbenzaldehyde 95% aqueous ethanol (Scheme 4). The reaction mixture was stirred for 5 h until the product was observed as a colourless precipitate. This was isolated by filtration and purified by recrystallisation from ethanol, affording crystals of suitable quality for X-ray diffraction. The melting point of 1 was determined to be in the 117.4–118.5 °C range. The IR spectrum of 1 shows a slightly lowered C=O stretching frequency, at 1652 cm⁻¹ compared to 1691 cm⁻¹ for acetyldurene (3) and 1686 cm⁻¹ for acetophenone.

The ¹H NMR spectrum (see Supporting Information Figure S1) of chalcone 1 shows that the E configuration of the alkene is formed exclusively in this rection. The ³J_HH between the alkene hydrogens is 16.5 Hz, which is typical for E-alkenes, as predicted by Karplus [7]. The ¹H and ¹³C DEPTQ NMR spectra (see Supporting Information Figures S1 and S2) confirm that the methyl groups in the ortho positions of the durene ring are significantly shielded at δ_H 2.13 and δ_C 16.3 ppm (cf. others are δ_H 2.24–2.27 and δ_C 19.6–21.2 ppm). This is due to their proximity to the carbonyl group. These values are consistent, with limited conjugation between the durene ring and the carbonyl, suggesting that the structure is not planar. The structure of 1 was confirmed by single-crystal X-ray diffraction (Figure 1).

2.2. Structural Study

The structure of 1 confirms the lack of conjugation between both aromatic rings and the α,β-unsaturated ketone. The durene ring shows an interplanar angle to the mean plane of the α,β-unsaturated ketone (C1-C2-C3-C14) of 84.34(4)° (

Table 1. Selected bond lengths (Å) and angles (°) for BZYACO, ZOYWAP and 1.

	BZYACO	ZOYWAP	1
Bond Lengths
Alkene C=C	1.319(6)	1.326(3)	1.3344(16)
C=O	1.204(6)	1.222(3)	1.2243(14)
Torsion Angles
ring1−ring2 (a)	11.4	56.2	75.28(4)
ring1−alkene	21.0	50.4	84.34(4)
ring2−alkene	9.8	6.3	54.91(14)
O1=C1−C2−H2	170.6	167.4	13.88(14)

^a ring 1 = phenyl in BZYACO; xylyl in ZOYWAP; duryl in 1. Ring 2 = phenyl in BZYACO and ZOYWAP; mesityl in 1.

), while the mesityl group shows an angle of 54.91(14)°. The bond lengths are all comparable to chalcone (CSD code BZYACO) and our recently reported (E)-1-(2,5-dimethylphenyl)-3-phenylprop-2-en-1-one (CSD code ZOYWAP) [8,9]. The C2−C3 bond length is 1.3344(16) Å, which is slightly elongated compared to BZYACO and ZOYWAP (cf. 1.319(6) and 1.326(3) Å, respectively).

The major differences between these three structures are the angles between the rings and the α,β-unsaturated ketone. Chalcone has a very small angle between the two rings and the alkene, suggesting full conjugation due to the near planar nature of the molecule (Figure 2). With the steric bulk increased on the ring directly bound to the carbonyl (phenyl to xylyl), the change is rather dramatic, as discussed previously [9]. However, when the steric bulk of the second ring is also increased (phenyl to mesityl), both rings show twisting relative to the alkene mean plane and each other.

The other major structural difference is the direction in which the C=O group is pointing compared to BZYACO and ZOYWAP. In 1, the carbonyl is trans to the β-carbon of the alkene, with a torsion (O1-C1-C2-C3) of 166.12(11)°. This contrasts with both BZYACO and ZOYWAP, where the C=O group is cis to the β-carbon of the alkene, with torsion angles of 16.8 and 12.6°, respectively (Figure 3).

There are weak non-classical intermolecular C-H···O hydrogen bonds between the carbonyl oxygen (O1) and hydrogens of both the ortho methyl groups of the mesityl ring (H21a, H22b), with H···O distances of 2.3552(8) and 2.5891(8) Å (Figure 4). This results in the formation of one-dimensional tapes running along the [1 0 1] axis.

3. Materials and Methods

All synthetic manipulations were performed in air. Glassware was dried in an oven (ca. 110 °C) prior to use. Solvents and chemicals were used as provided without further purification. IR spectra were recorded on a Perkin Elmer Spectrum Two instrument with a DTGS detector and diamond ATR attachment (Bruker, Billerica, MA, USA). The HRMS data were acquired from the University of St Andrews Mass Spectrometry Service. All NMR spectra were recorded using a Bruker Avance II 400 (MHz) spectrometer at 20 °C (Bruker, Billerica, MA, USA). The ¹³C NMR spectrum was recorded using the DEPTQ-135 pulse sequence with broadband proton decoupling. Tetramethylsilane was used as an internal standard (δ_H, δ_C 0.00 ppm). Chemical shifts (δ) are given in parts per million (ppm) relative to the TMS peak. Spectra were analysed using the MestReNova software package (Santiago de Compostela, Spain) (version 14). The NMR numbering scheme for 1 is provided in Figure 5.

3.1. Synthesis of (E)-3-Mesityl-1-(2,3,5,6-tetramethylphenyl)prop-2-en-1-one (1)

A solution of 1-(2,3,5,6-tetramethylphenyl)ethan-1-one (2.00 g, 11.3 mmol) in 95% aqueous ethanol (30 mL) was prepared. Gentle heating was required to achieve full dissolution. To this, mesitaldehyde (1.68 g, 1.7 mL, 11.3 mmol) was added in one portion. An aqueous solution of potassium hydroxide (4 mL, 7.1 M) was added dropwise over 1 min with stirring, turning the mixture yellow. After stirring in ambient conditions for 5 h, a white precipitate was collected via vacuum filtration, washed with ice-cold ethanol (3 × 5 mL), and dried in vacuo to afford 1 as a white powder (2.53 g, 72%) (Mp 117.4−118.5 °C).

¹H NMR (400.3 MHz, CDCl₃) δ_H 7.36 (1H, d, ³J_HH 16.6 Hz, H-6), 6.99 (1H, s, H-1), 6.88 (2H, s, H-10), 6.56 (1H, d, ³J_HH 16.5 Hz, H-7), 2.27 (3H, s, H-11’), 2.25 (6H, s, H-9), 2.24 (6H, s, H-2), 2.13 (6H, s, H-3’). ¹³C DEPTQ (100.6 MHz, CDCl₃) δ_C 203.0 (s, qC-5), 146.7 (s, C-6), 140.2 (s, qC-4), 138.9 (s, qC-9), 136.8 (s, qC-8), 134.3 (s, qC-3), 134.2 (s, C-7), 131.8 (s, C-1), 131.0 (s, qC-11), 129.6 (s, qC-2), 129.3 (s, C-10), 21.2 (s, C-11’), 21.1 (s, C-9’), 19.6 (s, C-2’), 16.4 (s, C-3’). Infrared (IR) ν_max (ATR/cm⁻¹) 3000w (ν_C−H), 2910w (ν_C−H) 1652vs (ν_C=O), 1468m, 1307s, 1173s, 981s, 864s, 762m, 544m. HRMS (ESI+) m/z (%) Calcd. for C₄₄H₅₂O₂Na 635.3865, found 635.3857 [2M + Na] (100); Calcd. for C₂₂H₂₆ONa 329.1881, found 329.1873 [M + Na] (90).

3.2. X-Ray Crystallography

X-ray diffraction data for compound 1 were collected at 100 K using a Rigaku FR-X Ultrahigh Brilliance Microfocus RA generator/confocal optics with a XtaLAB P200 diffractometer [Mo Kα radiation (λ = 0.71073 Å)] (Rigaku Corporation, Tokyo, Japan). The data were collected (using a calculated strategy) and processed (including correction for Lorentz, polarization and absorption) using CrysAlisPro [10]. The structure was solved by dual-space methods (SHELXT) [11] and refined by full-matrix least-squares against F² (SHELXL-2019/3) [12]. Non-hydrogen atoms were refined anisotropically, and hydrogen atoms were refined using a riding model. All calculations were performed using the Olex2 interface [13].

Selected crystal data, including C₂₂H₂₆O, M = 306.43, monoclinic, a = 8.8689(3), b = 26.7082(7), c = 8.4255(3) Å, β = 117.195(4)°, U = 1775.14(12) ų, T = 100 K, space group P2₁/c (no. 14), Z = 4, 38,562 reflections measured and 4320 unique (R_int = 0.0327), were used in all calculations. The final R₁ [I > 2σ (I)] was 0.0428 and the wR₂ (all data) was 0.1165.