(question-whilst haloalkylated substituents are (E.g TFM), do haloalkoxy groups still withdraw electron density from aromatic rings?) (such as the difluoromethoxy group in the 3-bromo-4-(1,1-difluoromethoxy)-5-methoxyphenethylamine and amphetamine counterpart?)
You will enjoy this
survey of Hammett parameters from
Chemical Reviews. The
Hammett equation is based on the equilibrium between benzoic acid and hydronium benzoate in water. Adding an electron-withdrawing substituent to benzoic acid will push the equilibrium towards benzoate by stabilizing the anion, while adding an electron-donating substituent will push the equilibrium towards the undissociated acid. The effect of a given substituent on the equilibrium is assigned to the parameter "sigma," where log(rate constant of substituted benzoic acid/rate constant of benzoic acid) = sigma*rho, rho being a constant. If sigma is positive, the substituent is electron-withdrawing and the equilibrium lies towards the carboxylate relative to benzoic acid. If sigma is negative, the substituent is electron-donating and the equilibrium lies towards the undissociated acid relative to benzoic acid. A great advantage of this equation is that by varying rho, the sigma values can be applied to a wide variety of reactions and equilibria. For example, a substituent with a positive sigma value will be a weaker Friedel-Crafts nucleophile than benzene, while a substituent with a negative sigma value will be a stronger Friedel-Crafts nucleophile. A great number of sigma values have been tabulated, for both the position
para to a substituent ("sigma(p)") and
meta to a substituent ("sigma(m)"). Values for
ortho positions are generally not examined as there are confounding steric effects.
For mono-, di-, and trifluoromethoxybenzene, the sigma values are as follows, according to the
Chem. Rev. article:
mono: sigma(p) = 0.02, sigma(m) = 0.20
di: sigma(p) = 0.18, sigma(m) = 0.31
tri: sigma(p) = 0.35, sigma(m) = 0.38
The conclusion, therefore, is that even a monofluoromethoxy group will withdraw electron density from an aromatic ring at the
ortho,
meta, and
para positions, with the withdrawing effect increasing as the number of fluorines increases.
For reference, the values for methoxybenzene are: sigma(p) = -0.27, sigma(m) = 0.12
Alkoxy groups are sigma (inductively) withdrawing while pi (conjugatively) donating. This means that while methoxybenzene, for example, is significantly stronger of a nucleophile than benzene is overall, electrophilic substitution at the
meta positions will actually be slower in methoxybenzene than in benzene, as the conjugation from the oxygen lone pair into the aromatic ring can only push electron density to the
ortho and
para positions. As you add more fluorines to the methyl, the inductive withdrawal gets stronger and the pi donation weaker, making the arene a weaker nucleophile than benzene even at the ortho and para positions. An interesting quirk of this situation, though, is that while pi donation towards the
ortho position and that towards the
para position are roughly equivalent, the inductive effect of the fluorines
weakens with distance. This leads trifluoromethoxybenzene to be a much more
para-selective nucleophile than methoxybenzene, as the inductive deactivation is much stronger at the
ortho position than the
para.
See "Table I" in the
Chem. Rev. article for the full list of sigma parameters.