## 3 Results and Discussion
Several studies have documented guaiacol's tendency to undergo condensation with formaldehyde [47], a property often exploited for the production of bio-based thermosets [48]. Despite successfully applying a H\({}_{2}\)SO\({}_{4}\)-free protocol with eugenol, chloromethylation of guaiacol proved to be more challenging. The significant activation of the aromatic ring towards Ar-S\({}_{\text{E}}\) reactions, partially enhanced by its small steric hindrance and compounded with the peculiar water solubility, led to very unselective conversion. Mixtures of polyalkylated products, along with minor amounts of condensation byproducts, were consistently obtained, regardless of PF equivalents or the use of low temperatures (0 \({}^{\circ}\)C). To partially deactivate the aromatic ring and adjust the substrate solubility away from the aqueous phase (similar to the behavior of eugenol), guaiacol was first converted to its \(O\)-acyl derivative using Ac\({}_{2}\)O (as detailed in the Materials and Methods section). The chloromethylation of this derivative was then investigated in the presence of DCM. Guaiacol acetate (**1e**) exhibited a strong tendency to form polyalkylated products, even when substoichiometric amounts of PF were used. However, to achieve better conversions of **1e**, more than 2.5 equivalents of PF were required, resulting in the exclusive formation of the trialkylated product **2e**. We soon realized that simultaneous deprotection of the acetate group occurred, which can be attributed to the aqueous acidic environment of the chloromethylation process. It is likely that the first alkylation step proceeded faster than the deprotection, generating a more apolar intermediate capable of undergoing further alkylations in the organic phase. As a result, complete conversion of **1e** into **2e** was achieved using 4.0 equivalents of PF (Figure 6). In addition to the expected activation of the _para_- positions relative to both the acetoxy and methoxy groups, the observed selectivity is explained by the significantly higher propensity for alkylation _ortho_- to the hydroxy group, rather than _ortho_- to the methoxy group. Indeed, no isomers of **2e** were detected in any of the experiments. The first introduced _para_-CH\({}_{2}\)Cl substituent, exhibiting 'chameleon-like' behavior [49], likely contributed to slowing the substitution at the position adjacent to the methoxy group. Transformation of **2e** into the triamide **3e** proceeded smoothly, following the same method applied to other benzyl chlorides. Figure 5: Chloromethylation of eugenol (**1d**) towards dialkyl derivative **2d** and conversion of this to the di-formamide **3d**; (a) **1d**, PF (3.2 eq), CH\({}_{2}\)Cl\({}_{2}\), 37% HCl (16 eq), 25 \({}^{\circ}\)C, 4 h; (b) **2d**, FA (4.0 eq), THF, reflux, 3 h.  
Figure 6: Chloromethylation of guaiacol acetate (**1e**) towards trialkyl derivative **2e** and conversion of this to the tri-formamide **3e**; (a) guaiacol, Ac\({}_{2}\)O (1.3 eq), TEA (1.1 eq), 60 \({}^{\circ}\)C, 3 h; (b) **1e**, PF (4.0 eq), CH\({}_{2}\)Cl\({}_{2}\), 37% HCl (20 eq), 25 \({}^{\circ}\)C, 4 h; (c) **2e**, FA (6.0 eq), THF, reflux, 3 h.  
\(p\)-Cresol (**1f**) is commonly extracted from coal tar but can also be obtained through biomass hydrothermal decomposition [50] and is present in tobacco smoke [51]. It is used in the production of antioxidants, such as di-_tert_-butylhydroxy toluene [52], and in the production of novolac resins where _ortho_-methylol groups are first introduced by reaction with formaldehyde under alkaline conditions [53]. As a'moderately activated' bio-based phenolic, and given that chloromethylation of this substrate has been scarcely investigated [38], we decided to include it within our studies. Despite its significantly lower activation compared to guaiacol, \(p\)-cresol showed a strong tendency for dichloromethylation, with high selectivity for product **2f** (Figure 7).