To gain a better understanding of the mechanism of this new reaction we decided to investigate the feasibility of this transformation using calculations performed at DFT level.
Scheme 32 – The single-electron oxidation/reduction reactions of starting materials used with Ir-3 (Gibbs energies for single-electron transfer reactions).
Our starting hypothesis is that the photocatalyst Ir-3 reacts as an excited state oxidant. This is, in fact, often postulated[62,118] as Ir-3 is a strong single-electron oxidant
(E1/2*/red (Ir-3) = +1.21 V) at the excited state and a poorer single-electron reductant
(E1/2ox/* (Ir-3) = -0.89 V). In this system, we are not using a single-electron donor capable
to oxidise Ir-3* (e.g. 4-cyanopyridine, Ered (154) = -1.78 V). We therefore initially
postulated that Ir-3 follows a reductive quenching cycle, being quenched by good single- electron donors present in solution, as we postulated with the benzyl trifluoroborate salts previously (Eox (153) = +1.10 V).
Using this rationale, we initially calculated the standard reaction Gibbs energy for SET events of the starting materials (51, 153, 154, 179, 206, 209 and 210) with iridium species
Photoredox arylations: from trifluoroborates to boronic esters 58
from the reductive quenching cycle of Ir-3 (Scheme 32). Single-electron oxidation of boronic species (in blue) was initially investigated. Equation (I) shows that our model predicts the thermodynamic feasibility (negative ΔrG) of the reductive quenching of Ir-3*
with trifluoroborate salt (153) to spontaneously generate the dissociated benzyl radical 34
and BF3 (207). However, under the same conditions, the single-electron oxidation of
benzyl pinacol boronic ester 179 (equation (II)) was not calculated to lead to a dissociation and was attributed with a positive reaction Gibbs energy, meaning that the process is not thermodynamically favourable.
On the single-electron reduction side (in red), all cyanoarenes computed (51, 154, 206, 209
and 210) are unable to accept an electron from the highly reducing Ir-3red (equation (III)). It
can be noted that in his arylation methods employing cyanoarenes, MacMillan employed the more potent single-electron donors such as Ir-1[74,96] to reduce similar cyanoarenes (E1/2ox/* (Ir-1) = -1.73 V for Ered (51)= -1.61 V).
These initial calculations informed us that the starting materials used cannot react favourably in SET reactions with the photoredox catalyst as such. These calculations are also in line with the redox potential comparison method that would predict the same outcome. Also, we started to think of more favourable reaction pathways.
When investigating the scope of this transformation (Table 7), we observed that only nitrogen-containing cyanoarenes were reactive in couplings with 179. We consequently proposed that interactions between the heterocyclic compounds and the boronic ester (179) could be responsible for this significant reactivity difference. The reactive characteristic of the boronic ester functional group is its Lewis acidity (cf. 1.3.1). Since nitrogen-containing heteroaromatics are Lewis basic, we postulated that a Lewis acid- base adduct could be formed between the two starting materials and result in their activation towards single-electron transfers.
Complexations of model boronic ester (179) with various Lewis bases, either cyanoarenes used in the reaction (LB = 154, 206, 209, 210) or other pyridine derived Lewis bases
Photoredox arylations: from trifluoroborates to boronic esters 59
Scheme 33 – A favourable single-electron oxidation/reduction cascade pathway (reaction Gibbs energies for single-electron transfer reactions; mixture 179 + LB is set as a ground state for all the transformation).
Ease of complex formation (217–223) greatly depended on the Lewis basicity of pyridine- derived ring. With respect to 179, the most favourable calculated complexation partner is the electron-rich DMAP (cf. 223 in Figure 9) and the least favourable is the sterically hindered 2,6-lutidine (221) whose 2- and 6-methyl groups clash with the methyl groups of the pinacol ligand of 179.
Complexation events, although being endergonic, are equilibria and could be driven forward if consecutive reactions are favourable. We therefore calculated the Gibbs energies for single-electron oxidations of the complexes instead of 179 alone (blue arrow). Despite the instability of the intermediate radical cation produced (224–230), these oxidations allow a subsequent thermodynamically favourable C-B cleavage to the radical
7 and the cationic intermediates (232–238). C–B bond cleavage is characterised by a low barrier (1.7 kcal mol-1 for LB = 4-cyanopyridine, 224-TS ) thus occurring spontaneously
after the single-electron oxidation step. These possible dissociations significantly transform the reaction energy profile of the oxidation (blue sequence) compared to the non-activated case ((II) in Scheme 32 vs. 231 + 232–238 in Scheme 33).
Complex formation equilibria will then be driven forward as a result of the thermodynamically favourable C–B cleavage to the radical 231. As the formation of
Photoredox arylations: from trifluoroborates to boronic esters 60
most efficient Lewis base among those tested to activate 179 towards single-electron oxidation.
Figure 9 – Calculated structure of the complex 223 between 179 and DMAP.
This pathway also produces heterocyclic cationic adducts 232–235 (after C–B cleavage),
which are more electron-deficient and consequently easier to reduce than the neutral cyanoarenes. Therefore, we tested a subsequent single-electron reduction from the Ir-3red
species (red arrow). Formation of the radicals 239–242 from the cationic intermediates
232–235 was calculated to be extremely favourable (Scheme 32).
As a result, complex formation not only activated the boronic ester towards single- electron oxidation but also significantly activated Lewis basic cyanoarenes towards single-electron reduction.
To better illustrate the transformation, potential energy surface for the reaction of 179
with 154 was plotted representing the energies of all the intermediates and transition states involved in the calculated mechanism (Scheme 35). No transition states for pure single-electron transfer events (217 to 224 and 231 + 232 to 231 + 239) were located as these steps only consist of a pure vertical excitation with minimal nuclear rearrangements.
From this diagram, it can be seen that the oxidative fragmentation of the complex (217 to
231 + 232) is the rate-determining step of the reaction (224-TS having the highest energy on the potential energy surface). Both the initial complex formation and electronics of the boronic species will play a role in this critical step. Subsequent single-electron reduction from the pyridinium intermediate (232) is favourable (red dotted line), leading to two radicals (231 + 239) that can engage in radical-radical coupling to finally lead to the coupling product. These final steps will be exergonic from the radical intermediates.
Photoredox arylations: from trifluoroborates to boronic esters 61
With this model in mind, we can try to explain the effects observed earlier. Increase in the concentration of starting materials would increase the concentration of the complex 217
involved in the rate determining step (cf. Table 6). Temperature increase leads to increasing reaction rate to allow completion within the residence time of the reactor (cf.
Table 6). Less Lewis basic heterocycles lead to less efficient couplings because of poorer
complex formation, whilst and non-Lewis basic ones are not coupled at all due to the absence of the redox-activating adduct formation (cf. Table 7).
Scheme 34 – Potential energy surface of reaction between 179 and 154.
To see if the rationalisation using redox potentials is also applicable, we estimated the standard reduction potentials of the species involved in the mechanism. This was achieved by calibrating the computed Gibbs reaction energies for electron transfer reactions against measured redox potentials of potassium benzyl trifluoroborate (Eox (153) = +1.10 V)[62] and 1,4-dicyanobenzene (Ered (51) = -1.61 V)[74]
as two structurally similar experimental reference points. Using these estimated potentials, we could describe the thermodynamic feasibility of the coupling between 4-cyanopyridine (154) and the boronic ester (179) using the calculated redox potentials
Photoredox arylations: from trifluoroborates to boronic esters 62
Scheme 35 – Proposed mechanistic description for the photoredox net-neutral coupling of cyanoarenes with boronic esters.
As described earlier, 154 and 179 can form a complex 217 (Scheme 35). This complex formation facilitates the single-electron oxidation of 179 (Eox (217) = +0.73 V vs.
Eox (179) = +1.57 V). This value makes this SET event possible within the reductive
quenching cycle of Ir-3. Based on our assumption, the excited Ir-3* species (E1/2*/red = +1.21 V)[228] is first quenched by 217 (Eox = +0.73 V) leading, after rapid C–B
bond cleavage (1.7 kcal mol-1 barrier), to a carbon-centred radical 231 and the pyridinium
232. The Ir-3red (E1/2gd/red = -1.37 V)[228] species thus generated can reduce the activated
pyridinium 232 (Ered = -0.32 V) in a cascade fashion, generating the radical 239 that
quickly couples with 231 to form an intermediate (243) that eliminates a boron-cyano species (244) to give the coupled product (162). The aqueous washing layer of the reaction workup was tested negative to cyanide with a commercial Quantofix® cyanide test (1 mg/L lower sensitivity).
Photoredox arylations: from trifluoroborates to boronic esters 63
Scheme 36 – Calculated reduction potentials of the species involved in the boronic ester arylation against
the reductive quenching cycle redox window of Ir-3.
Again, the redox window of the reductive quenching cycle of Ir-3 is depicted in
Scheme 36 to better visualise the feasibility of the transformations described. The
discovery that pyridinium species (232) are more easily reduced suggests that the 0.41 V difference observed in the trifluoroborate arylation (i.e. Scheme 30) could be easily overcome by complexation of the 4-cyanopyridine with BF3 (liberated by oxidation of
Photoredox arylations: from trifluoroborates to boronic esters 64