Photo-Fries Rearrangement

Dayita Saha (MP23001), Shivam Kumar (MS21084), Apurva Sharma (MS21200)

ABSTRACT: The Photo-Fries rearrangement is a photochemical transformation of aryl esters into hydroxyaryl ketones via homo-
lytic cleavage and radical recombination. Experimental techniques, including ESR spectroscopy, kinetic studies, and isotopic label-
ing, support a radical mechanism initiated by n→π* excitation. Theoretical analyses confirm orbital interactions and regioselectivity
patterns. This rearrangement enables mild, selective functionalization of aromatic compounds, with broad synthetic utility in phar-
maceuticals and materials chemistry. Its mechanistic clarity enhances its value in photochemical synthesis.

Introduction This method requires high-energy light and may lead to lower
The Photo-Fries rearrangement is a photochemical reaction in selectivity due to possible side reactions. In contrast, sensitized
which aryl esters undergo homolytic cleavage upon ultraviolet conditions involve the use of a sensitizer that absorbs light and
(UV) irradiation, leading to the formation of hydroxy aryl ke- transfers the energy to the ester. This allows the reaction to oc-
tones. This reaction is analogous to the thermal Fries rearrange- cur at longer wavelengths and under milder conditions. Sensi-
ment but is initiated by light rather than heat. As compared to tized reactions often provide better selectivity and can influence
the classic thermal, Lewis acid-catalyzed Fries rearrangement, the distribution of ortho and para products by favoring the for-
(often carried out at temperatures in excess of 100°C), the mation of a specific isomer through efficient triplet energy
photo-Fries rearrangement occurs under mild conditions (room transfer. Both methods are well-supported by spectroscopic and
temperature, hν<260 nm). For this reason, the photo-Fries rear- kinetic studies that offer strong experimental evidence for their
rangement has utility as a synthetic tool. underlying mechanisms.1,2

Mechanism
Evidence Supporting the Mechanism
Upon UV irradiation, the aryl ester absorbs energy, leading to
the homolytic cleavage of the carbon–oxygen bond and forming Over the years, several experimental approaches have sup-
two radicals—an acyl radical and an aryloxy radical. These rad- ported the radical mechanism proposed for the photo-Fries re-
icals can then recombine at different positions on the aromatic arrangement. These include time-resolved spectroscopy, kinetic
ring, most commonly at the ortho and para positions relative to analysis, isotope labeling, and studies on surface effects and
the original ester linkage, resulting in the formation of new car- substituent variation. Together, these investigations have clari-
bon–carbon bonds. This process yields ortho- and para-hydroxy fied the reaction pathway, confirmed short-lived intermediates,
aryl ketones as the main products. The ratio of these products is and explained how various conditions and molecular features
influenced by factors such as the polarity of the solvent and the influence product distribution and efficiency.
nature and position of substituents on the aromatic ring. 1. Study of Transient Species: Jiménez et al. used two-
photon-two-color spectroscopic techniques to demon-
strate the existence of short-lived cyclohexadienone
intermediates before they undergo tautomerization.3
Lochbrunner et al. used similar techniques to demon-
strate the excited state occurs through a π→π* excita-
tion with acyloxy bond cleavage occurring within 2 ps
and radical recombination occurring within 13 ps.1

Figure 1. General scheme of the photo-Fries rearrangement.

Reaction Conditions
The photo-Fries rearrangement can proceed either through di-
rect irradiation or under sensitized conditions. In direct irradia-
tion, the aryl ester absorbs UV light directly, generating radical Figure 2. Model for the first steps of the photo-Fries
intermediates that recombine to form the rearranged product. rearrangement.
 2. Mechanistic and Substituent Effects: Sláma et al. substituted products through intramolecular 1,3-hydrogen tun-
has explored the mechanism and energy states in- neling.
volved in the photo-Fries rearrangement, particularly The active space for phenyl acetate is shown in Figure 3 and is
focusing on the effects of substituents on quantum composed of seven occupied and five virtual orbitals: 4 π and 4
yields.2 The investigation of the effect of substituents π*, 1 orbital pair σ/σ* of the OC—O bond, and two non-bonded
upon quantum yields, ΦE, in the photorearrangement electrons pairs, one in the oxygen of the carbonyl group and
of meta and para substituted phenyl benzoates re- another one in the oxygen bonded to the phenyl ring.
vealed that electron-donating substituents increased
the value of ΦE whereas a decrease was observed for
substituents acting as electron acceptors. In the case
of identical substituents, the ΦE value was higher for
meta derivatives.
3. Surface Photochemistry: Investigations into the
Photo-Fries rearrangement on surfaces have provided
insights into the reaction mechanism and the influence
of the environment on the rearrangement process.4
4. Kinetic Studies: A study by Kalmus and Hercules
presented evidence for a radical mechanism in the
photo-Fries rearrangement of phenyl acetate.5 Phe-
noxyl radicals were observed in the flash spectra of
phenyl acetate in various solvents, supporting the in-
volvement of radical intermediates. In another study,
the photo-Fries reaction of 1- and 2-naphthyl acetates Figure 3. Active space chosen at the ground state of phenyl ac-
was explored using stationary and laser flash photoly- etate.
sis techniques, providing kinetic data that supports the
radical mechanism of the rearrangement.6
For phenyl acetate, the transfers between these three states oc-
5. Isotopic Experiments: Schutte and Havinga investi- cur with a small barrier between 1 ππ* and 1 nπ*, and without
gated the photo-Fries rearrangement of p-methoxy- any significant barrier between 1 nπ* and 1 πσ*. Direct transfer
phenyl acetate in order to evaluate a possible 14C iso- from 1 ππ* to 1 πσ* is precluded by large energy barriers. Tri-
tope effect at the carboxyl carbon.7 A KIE of 1.007 ± plet dissociation is also not possible due to El-Sayed rules. After
0.018 was obtained, from which it was concluded that, transferring to 1 πσ* and reaching a conical intersection, the
within an experimental error of 2%, this reaction molecule may return to the parent species, dissociate, or form
showed no isotope effect at the carboxyl carbon. cyclohexadienone intermediates, which are precursors for PFR.
Later, Shine and Subotkowski measured the KIE for In the gas phase and in nonpolar aprotic solvents, the orthosub-
the photorearrangement of 4-methoxyphenyl acetate stituted product is obtained after slow hydrogen tunneling,
(1) into 2-acetyl-4-methoxyphenol (2) in ethanol so- while in protic solvents, intermolecular H shift should domi-
lution.8 The KIE for labeling the phenolic oxygen nate. The three-state model for PFR provides a general picture
atom with 18O was 1.0000 ± 0.0023. The KIE for la- beyond the PA prototype, as the photodissociation process in
beling with 14C at the ⍺-carbon atom of the acetyl phenyl acetate should be analogous to that in other aromatic es-
group was measured in two ways: with recovered 1 ters, amides, carbamates, and carbonates.
(0.9988 ± 0.0051) and with isolated 2 (1.007 ± 0.008).
Labeling with 13C at the ⍺-carbon atom led to a mag-
netic, inverse isotope effect (0.9511 ± 0.0042). The re-
sults show that there is not a detectable activation bar-
rier for breaking the ester bond and that 2 is formed
by recombination of a caged radical pair which origi-
nates from an excited singlet state.

Molecular Orbital Description of the Reaction Mechanism

Gonçalves and Toldo revealed a three-state model for the
Photo-Fries rearrangement (PFR) based on multiconfigura-
tional calculations. 9 According to this model, three key excited
states are involved. The process begins with absorption of light
by an aromatic singlet ππ* state. This is followed by a transition
to a predissociative nπ* state, which facilitates energy transfer Figure 4. Schematic overview of the three-state model for PFR
towards bond cleavage. Finally, the system evolves to a disso- applied to PA. The insets show the main orbital transitions of
ciative πσ* state along which the ester bond breaks. The transi- the states involved in the PFR. Along the solid lines, the OC-O
tion from ππ* to nπ* involves pyramidalization of the carbonyl bond distance is the main reaction coordinate. Along the dashed
carbon, while the shift from nπ* to πσ* is driven by elongation curve, the hydrogen shifts between the oxygen and ortho carbon
of the C–O bond. After passing through a conical intersection is the main reaction coordinates.
with the ground state, various products may form. Among them
is a recombined radical intermediate that can give rise to ortho-
 In recent years, organic semiconductors have gained significant
attention in both industrial and academic research due to their
potential in electronic devices. The fabrication and integration
of these devices require precise patterning of multiple layers.
Various methods have been explored for structuring organic
materials, including embossing, printing, and photolithography.
Among these, photolithographic techniques stand out as highly
versatile and effective. However, conventional lithographic
processes often rely on wet chemical etching and solvent-based
steps.
To address this, researchers have recently developed new poly-
mers capable of undergoing photo-Fries rearrangement upon
exposure to UV light. These materials have shown promising
potential in optoelectronic applications.
Figure 5. MS-CASPT2 energies long the Photo-Fries rearrange- Ramil et al. developed photosensitive polymeric interlayers
ment of PA. CI: Conical intersection; TS: Transition state. based on the photo-Fries rearrangement, which enable direct
photopatterning in organic electronic devices without the need
for additional chemical processing.11 The study realized on the
Synthetic Utility of PFR use of the polymer PPNB, which undergoes a photo-Fries rear-
Beyond its mechanistic interest, the Photo-Fries rearrangement rangement upon irradiation with UV light, and its blend with
(PFR) has found valuable applications in both synthetic organic poly-vinylcarbazole (PVK) as photosensitive layers in OFETs
chemistry and materials science. These reactions have found di- and OLEDs, respectively, built with evaporable small organic
verse applications, including the total synthesis of natural prod- molecules as semiconducting active films. The UV treatment
ucts, polymer modification, surface patterning and etching. Ad- allows for direct photolithographic patterning of organic semi-
ditionally, they have been employed in photoinitiation, photo- conductors, improving device performance and offering a novel
stabilization, and refractive index modulation technologies. approach to device fabrication without additional chemical pro-
An efficient one-pot method was developed by Ponticelli for cessing.
synthesizing functionalized quinolines and tetrahydronaphthy-
ridines, two important classes of organic scaffolds via photo-
Fries rearrangement of p-substituted anilides.10 The resulting o-
amino ketones react in situ with acetylenic Michael acceptors
like dimethyl acetylenedicarboxylate (DMAD) to yield 6,4-di-
substituted quinoline 2,3-dicarboxylates. They reported that ar-
omatic o-amino ketones (II) can be used for a one-pot two-step
procedure that starts from the anilide (I) and gives directly quin-
olines 2,3-dicarboxylate (III), easily transformed, through an
additional high-yielding step, into benzo[c][2,7]-naphthy-
ridines (IV).

Figure 7. (a) Structure of the PPNB. (b) Scheme of the photo-

Fries rearrangement which takes place in PPNB upon UV illu-
mination.

Conclusions
In conclusion, the Photo-Fries rearrangement stands as a well-
characterized photochemical reaction, proceeding through rad-
ical intermediates supported by robust experimental and theo-
Figure 6. Possible reaction paths of anilides (I). retical evidence. Its ability to selectively functionalize aryl es-
ters under mild conditions, combined with its mechanistic clar-
ity, makes it a valuable tool in synthetic organic chemistry. The
reaction’s broad scope and utility underscore its relevance in the 5. Kalmus, C. E.; Hercules, D. M. A Mechanistic Study of
development of pharmaceuticals and advanced materials. the Photo-Fries Rearrangement of Phenyl Acetate. J. Am.
Chem. Soc. 1974, 96, 449-456.

6. Molokov, I. F.; Tsentalovich, Yu. P.; Yurkovskaya, A.

ACKNOWLEDGMENT V.; Sagdeev, R. Z. Investigation of the photo-Fries rear-
We would like to express our sincere gratitude to Dr. Sugumar Ven- rangement reactions of 1- and 2-naphthyl acetates. J.
kataramani for assigning this group project, which provided us with Photochem. Photobiol. A. Chem. 1997, 110, 159-165.
an enriching learning experience.
7. Schutte, L.; Havinga, E. Investigations into a possible 14C
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