Chapter 5. Progress Towards Excited State Proton Transfer
5.2 Introduction to Photoacidity
The initial reports of excited state proton transfer (ESPT) were made by Fӧrster (1949) and Weller (1955), based on large bathochromic shifts in fluorescence spectra of amino- and hydroxyaromatics. Since then, the field has been intensely researched, and ESPT has been the
photoexcitation (typically S1), and these molecules are therefore referred to as photoacids.
Hydroxyarenes are the predominantly studied photoacids and can display substantially enhanced acidities of 5-12 pKa units in the electronically excited states. ESPT from a photoacid is a reversible adiabatic process, and is therefore distinct from the photoacid generators (PAG) common to lithography, which produce a ground-state acid irreversibly on photolysis.1-5
. Figure 5.1 Fӧrster cyclephotoacidity
𝑝𝐾𝑎∗ = 𝑝𝐾𝑎−(ℎ𝜈1−ℎ𝜈2)
2.3𝑅𝑇 = 𝑝𝐾𝑎− ∆𝐸0,0
2.3𝑅𝑇 (1)
The F rster cycle is a model of photoacidity first proposed by F rster, who used it to approximate excited state acidity constants.1,2 Photoacidity is thermodynamically treated as a change in the relative free energies of the acid and conjugate base in the excited state.1-3
Following the Kasha rule that internal conversion outcompetes direct relaxation from Sn, the Fӧrster cycle only considers the S0 – S1 electronic transition energies (E0,0) of the acid and conjugate base. E0,0 values are typically estimated by averaging the S0-S1 and S1-S0 transition band energies taken at their maxima in the absorbance and fluorescence spectra of both the acid and conjugate base.2 A Fӧrster cycle diagram is depicted in Figure 5.1, where h is E0,0 for the acid, h is E0,0 for the conjugate base, h is Planck’s constant, pKa (pKa*(S1)) is the acidity constant in the ground (excited S1) state, ΔGa (ΔGa*) is the difference in free energies between the acid and conjugate base in the ground (excited) state. Fluorescence and non-radiative decay are in competition with photoacidity, and are represented as their respective rates, kf and knr. Depending on the photoacid, other quenching processes exist, such as proton-quenching.3 The excited state pKa, pKa*, is then calculated using the Fӧrster equation (eq 1), where the pKa
is obtained from ground state data, (hν1 - hν2) = ΔE0,0 = ΔGa - ΔGa* for the photoacid and conjugate base, R is the gas constant, and T is temperature.3 Estimated pKa*s derived this way are typically within one pKa unit of those obtained by the more accurate, but experimentally challenging, methods that measure the protonation and deprotonation rates directly.2
Origins of Photoacidity
Pines argues that an electronic rearrangement on excitation results in preferential stabilization of the conjugate base in S1. The stabilization of the excited conjugate base accounts for its diminished proton affinity, and a more thermodynamically favorable reaction.2 Agmon et al. support this notion with the observation of solvatochromatic shifts for 2-naphthol derivatives. The authors found that in the S1 state, 2-naphthol becomes a stronger hydrogen- bond donor while the 2-naphtholate anion becomes a weaker hydrogen-bond acceptor. These observations are consistent with both destabilization of the photoacid and stabilization of its conjugate base in the excited state, and through comparison to the methyl ether, the authors conclude that both the excited acid and base contribute to the pKa*.6,7
best explained by Hückel molecular orbital theory. The authors describe the photoacid conjugate base as an odd-alternate hydrocarbon anion, with a non-bonding molecular orbital (NBMO) that has a large coefficient on the oxygen. Excitation of an electron from this NBMO to the lowest unoccupied molecular orbital (LUMO) delocalizes the charge on oxygen as the LUMO is more diffuse. The resulting intramolecular charge transfer (ICT) state leads to enhanced acidity in S1.3
The same argument for ICT can be made by comparison of the La and Lb spectroscopic states of 1-naphthol and 2-naphthol.4,8 Hydroxyl group substitution to give either of the naphthol isomers breaks the degeneracy of napthalene’s two spectroscopic states, La and Lb. For 1-naphthol, the La is lower in energy than Lb, and the converse is true for 2-naphthol. Since the La state is more polarized than the Lb state, a greater transfer of charge from oxygen to the distal ring is possible for 1-naphthol. The relative populations of the La and Lb states of 1-naphthol (1N) and 2-naphthol (2N) manifests itself in a lower pKa* by nearly 3 pK units for 1-naphthol.
Proton quenching also occurs at carbons 5 and 8 of 1-naphthol, where the negative charge localizes in the excited state, but not for 2-naphthol. The proton quenching of 1-naphthol suggests that negative charge localizes on C5 and C8 in the excited state.8
Tolbert et al. prepared a series of “super” photoacids with pKa* < 0 by stabilization of the conjugate base with electron withdrawing cyano substituents. The cyano-naphthols investigated by the authors and the measured pKa and pKa* values are shown in table 1.
Remarkably, the 5,8-dicyano-2-naphthol (DC2N) derivative has a pKa* of - 4.5, while the ground state pKa is less affected (DC2N pKa = 7.8 compared to 9.6 for 2N).8,9
1N 5CN1N 2N 5C2N 6C2N 7C2N 8C2N 5,8DC2N
apKa 9.4 8.5 9.45 8.75 8.40 8.75 8.35 7.8
bpKa* - 0.2 - 2.8 2.8 - 1.2 0.2 - 1.3 - 0.4 - 4.5 Table 5.1.Acidity constants of cyano napthols in the ground and excited statesa
(5C2N), 6-cyano-2-naphthol (6C2N), 7-cyano-2-naphthol (7C2N), 8-cyano-2-naphthol (8C2N), 5,8-dicyano-2- naphthol (5,8C2N). aGround state pKa values measured via absorption titration. bCalculated Fӧrster pKa*values.
In a related work, Agmon et al. calculated the ground and excited state charge distributions for the cyano-2-naphthol derivatives with good correlations to experimental data.
The Mulliken charges calculated decrease on carbons 1 and 6, and increase on carbons 3, 5, and 8 on excitation of 2-naphtholate. The effective shift in Mulliken charges is qualitatively shown in Figure 5.2, and the effect is larger for the naphtholate anions. These calculations complement the findings of Tolbert et al. that cyano substituents at C5 and C8 of 2-naphthol give stronger photoacids and that C5 substitution has a smaller effect on ground state pKa than at C8.8,10
Figure 5.2 Localization of negative charge in the naphtholate ring in the ground and excited states.
The origin of photoacidity in the case of 2-naphthol and its cyano derivatives therefore appears to be migration of charge from the oxygen to the aromatic ring.1-3,6-10 The resulting intramolecular charge transfer (ICT) character in the S1 state is larger for the excited 2- naphtholate anion than the parent photoacid.10 Stabilization of the excited conjugate base, therefore, predominately induces the large pKa shift in the S1 state for 2-naphthol derivatives.10
Agmon et al. argue that the underlying cause for increased ICT character of the excited anion arises from the reversal of Hückel’s rules for aromaticity in S1.10 In the ground state, (4n+
2) π electrons is aromatic and 4n π electrons is antiaromatic by Hückel’s rules. In the T1 and S1
excited states, the reverse is true by Baird’s rules.11,12 2-Naphthol has 10 π-electrons and is aromatic by the criteria of a large singlet-triplet gap and its similar geometry to the aromatic parent, naphthalene. In the ground state, the stabilizing delocalization of oxygen’s charge into the aromatic ring comes at the cost of some aromatic character (12 π electron system). The excited anion enjoys a reduction in the antiaromatic character, if any, gained by delocalization of charge into the ring to create a 12 π electron system. ICT is therefore more favorable in the
the anion.10
While Tobert et al. had only investigated electron withdrawing groups in the distal ring of 2-naphthol (5,6,7, or 8- substitution)8,9, Agmon et al. calculated that the most electronegative naphtholate carbon is actually C3, followed by C5, and then C8.10 Since 8- and 5-cyano-2- naphthol are strong photoacids8,9, Agmon et al. suggest that 3-cyano-2-naphthol would also be a strong photoacid (perhaps the strongest mono-substituted cyanonaphthol), and that 3,5,8- dicyano-2-naphthol would be a very strong photoacid with a reasonable ground-state pKa.10 The pKa* of 3-cyano-2-naphthol has still not been reported.
The 2-naphthol derivatives discussed above are informative examples of the processes driving photoacidity in hydroxyarenes. These and other common photoacids are shown (Figure 5.3) with acidity constants for the ground and excited states. For consistency, the pKa and pKa* values are taken from the same source,2 however, discrepancies between sources are common.
Figure 5.3 Ground state (pKa) and excited state pKa*(S1) of Common Photoacids
Photochemical excited state acid-base chemistry has been reviewed.12 pH and pOH jump experiments resulting from intermolecular ESPT have applications in photolithography and proton hydration dynamics as mechanistic tools and in probing the micro-environments of micelles, proteins, cyclodextrins, and films. Intramolecular ESPT reactions have been used for chemical lasers, data and energy storage systems, polymer stabilizers, and radiation detectors.1
One relatively unexplored application for photoacids is their utility in conjunction with photolabile protecting groups, which comprise a growing field with many important biological applications. The photolabile starting compound is referred to as a caged molecule, and decaging is therefore photochemical release of the protected compound. Established photochemical decaging reactions involving the heterolytic or homolytic cleavage of C-R (R = H, C, O, N, halogen) bonds potentially require energies corresponding to UV-light, thus limiting the wavelength at which one-photon reactions of this type can occur.13,14
One attractive aspect of photoacidity is the potential for acid-base reactions caused by irradiation at long wavelengths. The Fӧrster cycle predicts a pKa shift in the excited state as only the difference in relative free energies of the excited acid and conjugate base. As an example, a generous pKa shift of 10 units is calculated to only require a ΔE0,0 of 13.6 kcal/mol by equation 1. Thermodynamically, a significant enhancement of acidity is therefore associated with a relatively small energetic perturbation. The relatively large excess excitation energy in UV- absorbing photoacids is released as fluorescence from the excited conjugate base. One can imagine a system where the S0-S1 gap is small relative to ΔE0,0 for photoacid and conjugate base.
Such a system would theoretically maintain photoacidity at long wavelengths. To our knowledge, excited state proton transfer as the photochemical process resulting in release of a caged molecule at any wavelength, has not been reported. We have therefore chosen 2-naphthol as a starting point to develop photoacid-mediated release of labile caged molecules at short wavelengths, with the goal of long wavelength application in the delivery of pharmaceuticals.
Rationale for Initial Design
The appropriate substrate design for an excited state proton transfer reaction is expected to be essential for an efficient reaction. Excited state lifetimes of 2-naphthol and its derivatives
conjugate base occurs quickly.1,3 In most cases, the photoacid proton is not expected to diffuse far into solution, if at all.15 The large effective concentrations displayed in intramolecular acid catalysis were therefore desired.16 A ground-state intramolecular hydrogen bond to the photoacid would also mitigate these challenges by directing the proton transfer to the appropriate position to immediately affect the acid-catalyzed reaction. We therefore envisioned the photochemical reaction as intramolecular ESPT from 2-naphthol to a closely tethered acid- labile group. ESPT along the hydrogen bond coordinate to give departure of the protonated leaving group yields the generalized products shown in Figure 5.4.
Figure 5.4 General design of a photoacid mediated photocage
The first photocage designs investigated (1a, 1b, 2, and 3; figure 5) consisted of a tert- butyl ester moiety capable of making an intramolecular hydrogen bond to the hydroxyl group of 2-naphthol. The rationale behind this design was the low ring-strain of a 10-membered ring favoring ground state hydrogen bond (HB) formation16 coupled with the knownacid lability of tert-butyl esters.17 The tert-butyl ester-like moiety was constructed by acylation of a tertiary alcohol on the side chain. This design also incorporates geminal methyl groups that enforce a favorable conformation for hydrogen bonding through angle compression in the side chain (Thorpe-Ingold effect).18 The aryl ether of 1a,b was incorporated for both synthetic utility and the heteroatom effect16 expected to promote the 10-membered HB ring.
Figure 5.5 First generation photocage designs involving tert-butyl esters