[3+2] click chemistry approach to tetrazine containing polymers

We report a [3+2] cycloaddition using 3,6-bis-propargyloxy-1,2,4,5-tetrazine and azides to synthesize energetic polymers containing 1,2,4,5-tetrazine within the scaffold. This work also includes [3+2] cycloaddition to crosslink azide containing glycidyl azide polymer (GAP). These reactions provide pathways for incorporation of 1,2,4,5-tetrazine into novel energetic materials using click-chemistry and provide an alternative polymer curing approach.

Due to their versatility and unique chemical and physical properties, tetrazines have found utility in organic solar cells, 1,2 sensors, 3,4 on/off uorescence [5][6][7][8] and energetic materials applications. 9,10 A signicant increase in 1,2,4,5-tetrazine chemistry synthesis has also occurred over the past several years. [11][12][13][14] A number of investigations have focused in large part on bioorthogonal, inverse electron demand hetero-Diels-Alder reactions with 1,2,4,5-tetrazines for numerous applications, such as in situ synthesis of uorogenic probes for live cell imaging, and near infrared uorogenic probes. 8 Unfortunately, the inverse electron demand hetero-Diels-Alder reaction of 1,2,4,5-tetrazines is not a promising pathway in energetic materials chemistry as a concomitant reduction in the inherent energy of the molecule results during these types of transformations due to the loss of N 2 . Thus alternative pathways for the incorporation of 1,2,4,5-tetrazine into novel energetic materials are warranted.
One very interesting possibility for the preparation of new energetics is to employ a [3+2] cycloaddition (click-chemistry) strategy. In this case, a Huisgen 1,3-dipolar cycloaddition between 1,3-dipoles such as azides, and 1,2-dipolarophiles such as acetylenes could be incorporated onto the tetrazine ring system at the 3 and 6 positions either directly or through linkers of varying length. The challenge presented with this approach is the possibility for the 1,2,4,5-tetrazine system to undergo competitive inverse electron demand [4+2] hetero-Diels-Alder chemistry with acetylene functional groups. Indeed, Rusinov and co-workers found that the reaction of but-3-yn-1-ol with 3,6bis(3,5-dimethylpyrazol-1-yl)-1,2,4,5-tetrazine (1) in the presence of triethylamine in acetonitrile led to the two products 2 and 3 (5 : 1) as shown in Scheme 1. 15 These two products both are a result of inverse electron demand hetero-Diels-Alder processes. Changing the leaving group from 3,5-dimethylpyrazole to imidazole led to the exclusive isolation of the bicyclic product 2.
While these literature results were not encouraging, we decided to pursue the synthesis of 3,6-bispropargyloxy-1,2,4,5tetrazine (4). We found that shortening the distance between the alcohol group and the acetylene moiety allowed for nucleophilic addition to proceed exclusively with no evidence of inter-or intramolecular hetero-Diels-Alder cyclization occurring. Thus propargyl alcohol reacted with 1 in the presence of potassium carbonate to provide 4 in excellent yield (Scheme 2). Ultimately, we were able to perform the reaction neat, using propargyl alcohol as the solvent, although only in minimal amounts.
To conrm the structure of 4, X-ray quality crystals were obtained from slow diffusion of diethyl ether into a solution of 4 in acetone. The compound was found to have the monoclinic crystal system with a P2 1 /c space group. 7 It displayed a density of 1.46 g cm −3 at 293 K (see ESI †). The Ortep representation of the crystal structure is displayed in Fig. 1. Overall, the transformation resulting in 4 is unprecedented and allowed for a "click" chemical approach to make energetic, tetrazine containing polymers.
Scheme 1 But-3-yn-1-ol reaction with 1 in the presence of TEA . With 4 in hand, we attempted to perform the Huisgen cycloaddition reaction with azide containing materials employing the Cu(I)-catalyzed azide/alkyne cycloaddition approach (CuAAC) to accomplish prepolymer curing, polymerization and self-polymerization. 8 We rst investigated a [3+2] cross-linking strategy using 4 as a curing agent for azide containing prepolymers, such as the glycidyl azide (GAP) prepolymer. A similar approach has been described with other polyacetylene compounds. 9 Typically GAP is cured using a urethane crosslinking approach, but this method presents challenges, such as sensitivity to moisture and the use of reactive isocyanates. A [3+2] curing approach with a high energy cross linker could provide higher energy GAP polymers. Initial results found that 5 wt% 4 was successful at curing the GAP prepolymer (5) in the presence of a catalytic amount of CuCl, to produce polymer 6 (Scheme 3).
These results were expanded on to include a curing study of GAP (5) and GAP plasticizer (GAPp, 5p) with varying weight percentages of 4 in the presence of a copper halide species to produce polymer 6 and 6p, respectively. The GAP (also called GAP 5527-Polyol) is a high molecular weight prepolymer with a hydroxyl equivalent between 2.5-3 used in urethane cures, while the GAPp is a lower viscosity prepolymer with an average MW of 700, and a hydroxyl equivalent close to 1. As the clickchemistry cure for these GAP pre-polymers is independent of hydroxyl terminal group content, the two materials were utilized to evaluate rheological properties over the course of reaction. Rheometry measurements were conducted on samples containing 3% of 4 for both polymers (see ESI †). The transition from liquid to solid, or gel point, for 6 occurred at roughly 83 minutes compared to 6p at about 4 hours.
Aer demonstrating that 4 could be used to cure GAP, we turned our attention to polymerization studies of 4 with diazide compounds. One such material was 2,2-bisazidomethyl-1,3propanediol (7). 16 Since 7 is a liquid, we performed the cycloaddition neat by thoroughly mixing 4, 7 with a catalytic amount of a copper halide (CuCl or CuI). Heating for several hours at 60 C led to the polymerized product (8)  Further studies for single compound self-polymerization were explored by incorporation of the azide group and an acetylene group on the same tetrazine ring. We began with the reaction of propargyl alcohol with 3,6-dichloro-1,2,4,5-tetrazine (11) in the presence of 2,4,6-collidine, using tert-butyl methyl ether as a solvent. This provided 12 in good yield (Scheme 5). Subsequent treatment of 12 with sodium azide in acetone provided the 3-azido-6-propargyloxy-1,2,4,5-tetrazine (13). 10 This material melts at 50 C and begins to polymerize if le in the melt for several hours to provide polymer 14. Unfortunately, the extreme sensitivity of 13 precluded further studies on the properties of the resultant polymer.
In conclusion, propargyl alcohol and 1 reacted to give the unprecedented product 4 which maintained the 1,2,4,5-tetrazine ring system intact. With this result in hand, we implemented a [3+2] cycloaddition strategy using alkyne and azide moieties to accomplish prepolymer curing, polymerization and self-polymerization reactions. The resultant energetic polymers contain the 1,2,4,5-tetrazine within the polymer scaffolds. All polymers presented here display explosive sensitivity properties either less than or equal to PETN. Further work on studying these energetic polymers and developing new energetic materials are currently being pursued.

General methods
Unless otherwise noted, all 1 H-and 13 C-NMR spectra were recorded in DMSO-d 6 at ambient temperature using a Bruker Avance 400 spectrometer operating at 400 MHz for H and 100 MHz for 13 C. Chemical shi values (d) are reported in ppm, referenced to the residual DMSO solvent signal ( 1 H: 2.50 ppm & 13 C: 39.52 ppm). FT-IR spectra were measured with a Thermo-Nicolet iS5 FTIR spectrophotometer using the OMNIC soware, and data collection are reported in reciprocal centimeters (cm −1 ). IR spectra measurements were made using an ATR cell. Elemental Analyses (EA) were performed with a PerkinElmer series II 2400 CHNS/O analyzer. All reagents and solvents were used as received (Sigma-Aldrich, Fluka, Acros Organics and Mach 1 Specialty Chemicals). 2,2-Diazidomethyl-1,3 propanediol (7) 16 and 2-hydroxy-1,3-diazido-propane (9) 17,18 were synthesized according to literature procedure.
Caution! The compounds and polymers presented here are highly energetic with sensitivity to various stimuli. While we encountered no issues while working with this material, proper protective measures (Kevlar® gloves, face shield, and grounded equipment) should still be used at all times. The [3+2] cycloaddition between alkyne and azide moieties is highly exothermic and should only be undertaken in small amounts with sufficient heat-dissipation to avoid ignition during reaction.