Syntheses and crystal structures of 2,2,5-trimethyl-1,3-dioxane-5-carboxylic acid and 2,2,5-trimethyl-1,3-dioxane-5-carboxylic anhydride

The title compounds, C8H14O4 and C16H26O7, are precursors to dendrimers. The strong and weak hydrogen bonds in their extended structures are described.


Chemical context
Dendrimers are perfectly branched, monodisperse, multivalent polymeric structures that exhibit enhanced solubility, increased reactivity and reduced dispersity compared to linear polymer analogs (Ihre et al., 1996a). While there are several varieties of dendrimers, a protected monomer has been used to make most dendrimers (Buhleier et al., 1978;Tomalia et al. 1985;Hawker & Fré chet, 1992). 2,2-Bis(hydroxymethyl)propionic acid (bis-MPA) is one of the most popular (Ihre et al., 1996b), useful and well-studied because of its low cost and relative ease of synthesis yielding extremely precise structures (Grayson et al., 2014), while also being biocompatible, biodegradable and extremely modular. The synthesis of these polyester-based dendrimers relies on first protecting the hydroxyl groups of the monomer and then, after an exhaustive protection of the core, complete removal of the protecting group exposing the hydroxyl groups of the next generation. To that end, the isopropyl acetal (isopropylidene/acetonide) has become one of the most commonly compounds used in the production of the monomeric unit (Stenströ m et al., 2016;García-Gallego et al., 2015). Anhydride-catalyzed esterification has become the preferred route of synthesis to produce these highly precise, bis-functional structures by decreasing the steps of purification and improving the efficiency of deprotection to the final poly-ol. The scope and diversity of these types of structures can be seen in the increase in publications on dendrimers and the numerous reviews published in recent years. We report here the syntheses and crystal structures of two important intermediates in our work on dendrimer syntheses, viz. 2,2,5-trimethyl-1,3-dioxane-5carboxylic acid (C 8 H 14 O 4 ) and 2,2,5-trimethyl-1,3-dioxane-5carboxylic anhydride (C 16 H 26 O 7 ). The asymmetric unit of II with 50% probability displacement ellipsoids. The C-HÁ Á ÁO hydrogen bonds are indicated by dashed lines.

Figure 1
Perspective view of I with 50% probability displacement ellipsoids.

Database survey
A search of the Cambridge Crystallographic Database (Version 5.40, updated to September 2019;Groom et al., 2016) with fragment A yielded only the one structure which is closely related to I and II (B, WARLIN; Garmendia et al., 2017). The geometry of the substituted dioxane portion here is similar to those in I and II. In the 22 additional structures found, one, C, (AKEKOR; Simmons et al., 2011) contained a single 1,3dioxane ring. The remaining hits were spirocyclic molecules, e.g. D (MINPEH; Gao et al., 2018).

Figure 4
Packing of I viewed along the c-axis direction with C-HÁ Á ÁO hydrogen bonds depicted by black dashed lines. Fré chet, 2002;André n et al., 2017). 2,2-Bis(hydroxymethyl)propionic acid (bis-MPA, 30.68 g, 0.229 mol) was added to a 500 ml round-bottom flask equipped with a magnetic stir bar and suspended in acetone (200 ml) under stirring. 2,2-Dimethoxypropane (50.0 ml, 42.5 g, 0.408 mol) and p-toluenesulfonic acid monohydrate (1.17 g, 6.13 mmol) were added to the reaction flask and the residue rinsed down with acetone (50 ml). The reaction was allowed to proceed under stirring at room temperature for 8 h. Subsequently a 1:1 triethylamine:ethanol solution (1 ml) was used to quench the reaction for 3 h. The solvent was evaporated to yield a white solid residue that was then dissolved in dichloromethane (DCM, 300 ml), transferred to a 500 ml separatory funnel and washed with deionized H 2 O (5 Â 50 ml). The organic layer was collected in an Erlenmeyer flask equipped with a stir bar and dried over anhydrous sodium sulfate (Na 2 SO 4 ) under stirring for 30 min. The Na 2 SO 4 was removed via vacuum filtration, the solvent was removed by rotary evaporation, the crude product was dissolved in fresh acetone (60 ml) and recrystallized at 249 K overnight. Synthesis of 2,2,5-trimethoxy-1,3-dioxane-5-carboxylic anhydride (II): 2,2,5-Trimethoxy-1,3-dioxane-5-carboxylic anhydride was prepared according to the literature but with an optimized purification (Malkoch et al., 2002;Giesen et al., 2018). Isopropylidene-protected acid (I, 2.334 g, 13.40 mmol) was added to a 100 ml round-bottom flask equipped with a stir bar and the solid was dissolved in dichloromethane (25 ml). N,N-Dicyclohexylcarbodiimide was warmed to a liquid, transferred to a tared vial (1.349 g, 6.58 mmol) and dissolved in dichloromethane (10 ml). This solution was slowly added to the acid while stirring and the reaction was allowed to proceed overnight. The solid dicyclohexylurea (DCU) that formed was removed via gravity filtration through fluted Q2 filter paper. The filtrate was collected and evaporated to dryness in vacuo affording a viscous oil that was subsequently dissolved in a minimal amount of diethyl ether under stirring and the remaining solid again removed via gravity filtration using Q2 filter paper. This filtrate was collected, the solvent removed, and the resulting residue dissolved in a minimal amount of warm hexanes. This solution was stirred overnight, affording a white solid that was removed via filtration and the filtrate was evaporated to yield the anhydride as a transparent viscous oil (1.956 g, 5.92 mmol, 88.4%). This was previously reported (Giesen et al., 2018) and crystals of the anhydride were grown from hexanes. Additional purification can be achieved with removal of additional DCU by dissolving the crude viscous product in warm hexanes and cooling the solution at 276 K

Refinement
Crystal data, data collection and structure refinement details are summarized in Table 3. H atoms in II were included as riding contributions in idealized positions with C-H = 0.98-0.99 Å and U iso (H) = 1.2U eq (C) or 1.5U eq (C-methyl).

Special details
Experimental. The diffraction data were obtained from 3 sets of 400 frames, each of width 0.5° in ω, colllected at φ = 0.00, 90.00 and 180.00° and 2 sets of 800 frames, each of width 0.45° in φ, collected at ω = -30.00 and 210.00°. The scan time was 10 sec/frame. Geometry. All esds (except the esd in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell esds are taken into account individually in the estimation of esds in distances, angles and torsion angles; correlations between esds in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell esds is used for estimating esds involving l.s. planes. Refinement. Refinement of F 2 against ALL reflections. The weighted R-factor wR and goodness of fit S are based on F 2 , conventional R-factors R are based on F, with F set to zero for negative F 2 . The threshold expression of F 2 > 2sigma(F 2 ) is used only for calculating R-factors(gt) etc. and is not relevant to the choice of reflections for refinement. R-factors based on F 2 are statistically about twice as large as those based on F, and R-factors based on ALL data will be even larger.

Special details
Experimental. The diffraction data were obtained from 3 sets of 400 frames, each of width 0.5° in ω, colllected at φ = 0.00, 90.00 and 180.00° and 2 sets of 800 frames, each of width 0.45° in φ, collected at ω = -30.00 and 210.00°. The scan time was 20 sec/frame. Geometry. All esds (except the esd in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell esds are taken into account individually in the estimation of esds in distances, angles and torsion angles; correlations between esds in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell esds is used for estimating esds involving l.s. planes. Refinement. Refinement of F 2 against ALL reflections. The weighted R-factor wR and goodness of fit S are based on F 2 , conventional R-factors R are based on F, with F set to zero for negative F 2 . The threshold expression of F 2 > 2sigma(F 2 ) is used only for calculating R-factors(gt) etc. and is not relevant to the choice of reflections for refinement. R-factors based on F 2 are statistically about twice as large as those based on F, and R-factors based on ALL data will be even larger. Hatoms attached to carbon were placed in calculated positions (C-H = 0.95 -0.98 Å). All were included as riding contributions with isotropic displacement parameters 1.2 -1.5 times those of the attached atoms.