On the mechanism of phenolic formylation mediated by TiCl4 complexes: Existence of diradical intermediates induced by valence tautomerism

Article abstract of DOI:10.1002/ejoc.201403548

The conventional electrophilic intramolecular aromatic substitution pathway proposed by Cresp et al. [J. Chem. Soc., Perkin Trans. 1 1973, 340-345] is confirmed by the observed products of phenolic formylation mediated by TiCl₄. However, when the nucleophilic path is quenched by appropriate ligand modification, the initial equilibria between the possible neutral complexes of TiCl₄ with 3,5-dimethoxyphenol and/or diethyl ether lead to different stable diradical intermediates induced by valence tautomerism that provide valuable activated reagents. Some of these species have been detected by EPR, characterized theoretically and captured by TEMPO, thus providing a consistent mechanism for the reaction with one or more equivalents of TEMPO per phenol.

Full text of DOI:10.1002/ejoc.201403548

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201403548
On the Mechanism of Phenolic Formylation Mediated by TiCl4 Complexes:
Existence of Diradical Intermediates Induced by Valence Tautomerism
Carlos Heras,[a] Iván Ramos-Tomillero,[a,b] Marc Caballero,[c] Marta Paradís-Bas,[a,b]
Ernesto Nicolás,*[a,d] Fernando Albericio,*[a,b,e] Ibério de P. R. Moreira,*[c,f] and
Josep Maria Bofill*[a,f]
Keywords: Valence tautomerism / Titanium tetrachloride / Radicals / Reaction mechanisms / Ab initio calculations
The conventional electrophilic intramolecular aromatic sub-
stitution pathway proposed by Cresp et al. [J. Chem. Soc.,
Perkin Trans. 1 1973, 340–345] is confirmed by the observed
products of phenolic formylation mediated by TiCl4. How-
ever, when the nucleophilic path is quenched by appropriate
ligand modification, the initial equilibria between the
possible neutral complexes of TiCl4 with 3,5-dimethoxy-
phenol and/or diethyl ether lead to different stable diradical
intermediates induced by valence tautomerism that provide
valuable activated reagents. Some of these species have
been detected by EPR, characterized theoretically and cap-
tured by TEMPO, thus providing a consistent mechanism for
the reaction with one or more equivalents of TEMPO per
phenol.
Cl2CHOCH3 system,[1,2] which has proved to be of con-
siderable synthetic potential.[3] In our hands, this methodol-
Introduction
Phenolic aldehydes are valuable intermediates in many ogy afforded key electron-rich phenolic aldehydes for the
synthetic protocols. These derivatives can be readily syntesis of de novo designed handles and protecting groups
accessed by formylation of phenols by using the TiCl4/ to be used in solid-phase chemistry.[4,5] The most interesting
Scheme 1. Formylation of phenols by using TiCl4 and Cl2CHOCH3.
[a] Departament de Química Orgànica, Universitat de Barcelona,
Martí i Franquès 1, 08028 Barcelona, Catalunya, Spain
E-mail: jmbofill@ub.edu
feature of this synthetic methodology deals with the
regioselectivity of formylation towards the ortho-position to
the hydroxy phenolic group, that is more specific than in
other formylation protocols.[6,7] The process seems to go
through the formation of a 1-chloro-1-methoxymethyl aro-
matic intermediate resulting from titanium mediated C–C
bond formation and further hydrolysis of this intermediate
to afford the phenolic aldehyde (Scheme 1). In principle, an
electrophilic aromatic substitution pathway could account
for this result, as shown by Cresp et al.[2] However, it is well
known that titanium can promote free radical reactions.[8]
Thus, the diradical character of titanium enolates has been
proven by some of us[9] and confirmed by Zakarian et al.,[10]
suggesting that this diradical, which belongs to a large
manifold, termed [RЈ–O(Ti·Cl4)O–R·]–, enables a range of
transformations, including those such as polyene cycliza-
tion. In this sense, from a structural point of view, phenol
albericio@ub.edu
enicolas@ub.edu
http://www.ub.edu
[b] Institute for Research in Biomedicine, Barcelona Science Park,
Baldiri Reixac 10, 08028 Barcelona, Catalunya, Spain
http://www.irbbarcelona.org
[c] Departament de Química Física, Universidad de Barcelona,
Martí i Franquès 1, 08028 Barcelona, Catalunya, Spain
E-mail: i.moreira@ub.edu
http://www.ub.edu
[d] Institut de Biomedicina, University of Barcelona,
Martí i Franquès 1, 08028 Barcelona, Catalunya, Spain
http://www.ub.edu
[e] CIBER-BBN, Networking Centre on Bioengineering,
Biomaterials and Nanomedicine
[f] Institut de Química Teòrica i Computacional (IQTCUB),
University of Barcelona,
Martí i Franquès 1, 08028 Barcelona, Catalunya, Spain
http://www.iqtc.ub.edu
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201403548.
Eur. J. Org. Chem. 2015, 2111–2118
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2111

E. Nicolás, F. Albericio, I. de P. R. Moreira, J. M. Bofill et al.
SHORT COMMUNICATION
can be considered as the enolic form of cyclohexan-2,4-di- tautomer 1. To prove this assertion we initiated an investi-
enone, thus becoming a candidate for the generation of rad- gation into the role of 2,2,6,6-tetramethylpiperidine-1-oxyl
ical species promoted by TiCl4. These precedents prompted (TEMPO).
us to get a deeper insight into the mechanism of phenolic
formylation.
The unconventional diradical character of the Ti com-
plex (Scheme 2) suggests that this intermediate should be
an efficient radical acceptor. Indeed, when the initial
Cl2CHOCH3 reactant was replaced with dimethyl ether to
avoid the nucleophilic substitution pathway, the resulting Ti
complex was treated with TEMPO (1.1 equiv.) in anhydrous
CH2Cl2 under an argon atmosphere, a product was ob-
tained in an essentially quantitative yield. Hydrolysis of
such species would liberate the observed 2-(3,5-dimeth-
oxyphenoxy)-3,5-dimethoxyphenol, 7. A plausible mecha-
nism that justifies the generation of product 7 is reported
in Scheme 3. In the first step of this mechanism, namely the
proton subtraction in anhydrous CH2Cl2, one molecule of
3,5-dimethoxyphenol acts as a base (B) to accept the acidic
proton of complex 3 in the present experimental set up.
The mechanistic hypothesis in Scheme 3 is based on the
well-established radical activity of TEMPO widely used in
radical reactions and its action is similar to that proposed
by Greci et al.[11] In the present case, however, the resulting
triradical anion 6 after hydrogen abstraction by TEMPO
should be strongly stabilized by electron delocalization onto
both titanium and the phenyl ring. This effect has been
found in a series of electronic structure calculations in a
model system described below and in the Supporting Infor-
mation. After the intramolecular rearrangement of the tri-
radical anion 6, the resulting radical anion recovers the aro-
matic character of the tetrasubstituted ring by hydrogen ab-
straction by the action of TEMPO. Thus, in the last step of
the process, there is a new tautomeric equilibrium and, after
water addition, 7 is formed.
Results and Discussion
In an effort to understand the mechanism of this
formylation process, we initiated an investigation into the
role of 3,5-dimethoxyphenolate–TiCl4 as a purported dirad-
ical-phile in the reaction shown in Scheme 1. With this in
mind, we undertook mechanistic studies to determine
whether the reaction proceeds through a diradical acti-
vation pathway via 2, involved in the tautomeric equilib-
rium, or through 1 by a direct intramolecular nucleophilic
attack that takes place when the TiCl4 complex is formed
(see Scheme 2). To this end we substituted 1,1-dichloro-
methylmethyl ether with diethyl ether to preclude the intra-
molecular nucleophilic substitution of Cl– ions in the
formylation process and to detect the possible intermediate
TiCl4 complex in anhydrous CH2Cl2. The use of diethyl
ether provides an equivalent quenched complex and largely
facilitates the experimental procedure (dimethyl ether is a
gas at ambient conditions). The comparison of the experi-
mental results by using 1,1-dichloromethylmethyl ether con-
firmed that the formylation reaction in Scheme 1 proceeds
through the traditional (intramolecular) nucleophilic substi-
tution pathway proposed by Cresp et al.[2] involving inter-
mediate 1 shown in Scheme 2.
To provide a theoretical justification of the proposed
mechanism several wave function calculations were per-
formed to show the stability of the intermediate diradical
and triradical structures essential for this mechanism (i.e.,
those corresponding to structures 3, 4, 5, and 6 in the
mechanism and the competing equilibria involving one or
two ether molecules). The electronic structure of these com-
plexes and their molecular structures were investigated by
using a simplified molecular model in vacuo that is repre-
Scheme 2. The valence tautomerism in TiCl4–phenolate complexes.
However, the use of the equivalent quenched complex sentative of the description of the formation process of the
with diethyl ether provides an excellent opportunity to TiCl4–enolate complexes described in Scheme 3 by means
analyze fine details of the nature of the essential inter- of ab initio wave function electronic structure calculations.
mediate and possible derivatives. To this end, we performed Hence, benzene-1,3,5-triol was adopted as a model system
a series of NMR and EPR spectroscopy experiments of the to represent 3,5-dimethoxyphenol and 3,5-dihydroxyphen-
quenched intermediate complex shown in Scheme 2 includ- olate to represent 3,5-dimethoxyphenolate, TEMPO was
ing TiCl4 and 3,5-dimethoxyphenol in CH2Cl2 alone or in substituted by H2NO (see the Supporting Information).
the presence of diethyl ether. In both experiments, a series The proton extraction by 3,5-dimetoxyphenol (see descrip-
of pre-equilibria between the neutral TiCl4–diphenol, tion of Scheme 3) was modelled by means of a tertiary
TiCl4–diether and phenol–TiCl4–ether takes place and the amine to simplify the calculations. Using this simplified
presence of the diradical complex 2 was detected and as- model, we investigated the stability of the intermediate spe-
signed to the TiCl4–diphenol diradical after proton subtrac- cies (neutral, anionic, diradical, and triradical) involved in
tion (see Figure S4 in the Supporting Information).
the initial equilibria and the following reactions with a base
The next series of experiments was designed to probe the and TEMPO. A sketch of the resulting minimum energy
reaction mechanism. As a first hypothesis we suggested that stable structures is reported in Figure 1 in the Experimental
the mechanism of the reaction takes place through the Section.
2112
www.eurjoc.org
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2015, 2111–2118

On the Mechanism of TiCl4-Mediated Phenolic Formylation
Scheme 3. Proposed mechanism for 1 equiv. of TEMPO per phenol.
In a first step, the initial equilibria between the possible cal per phenol to the [Ph·–TiIII·–Ph]– complex leads to a
complexes that can be formed between TiCl4 with benzene- stable anion triradical [Ph·–TiIII·–Ph·]– complex that pro-
1,3,5-triol and/or diethyl ether was analyzed to elucidate the vides a consistent pathway to reach the final product 7 by
stable precursors of the possible radical structures observed an internal bond formation between both aromatic rings
in EPR experiments. As shown in Figure 1 (panel a) in the (Scheme 3). The [Ph·–TiIII·–Ph·]– anion triradical complex
Experimental Section, the three possible complexes have a is the key structure for the proposed mechanism and the
very similar stability and the calculations suggest a slightly subsequent rearrangement is clear from the observed prod-
larger dominance of the Ph–TiIV–Eth complex. The ucts using an increasing number of TEMPO equivalents per
addition of a tertiary amine to these species to model the phenol as described in the Experimental Section. Clearly, a
proton extraction by benzene-1,3,5-triol (see description of competition between both mechanisms takes place if the
Scheme 3), has different effects as shown in Figure 1 (pan- number of TEMPO equivalents per phenol present in the
els b and c). The Eth–TiIV–Eth complex is not reactive in reaction medium is between 1 and 6. When more than one
front of the base or the H2NO species and will not be rel- equivalent of TEMPO was added the 3-(3Ј,5Ј-dimethoxy-
evant for the rest of the mechanism. However, the base ex- phenoxy)-4,6-dimethoxy-5-[(2Ј,2Ј,6Ј,6Ј-tetramethylpiperid-
tracts a proton from the phenol group of the phenolic com- in-1-yl)oxy]benzene-1,2-diol (9) begins to form and with 6
plexes to generate the anionic structures that exhibit valence or more TEMPO equivalents formation of compound 7 is
tautomerism, showing an accessible, stable, diradical elec- not observed anymore, as shown in Scheme 4.
tronic state. In both cases, the open shell singlet is 0.3 kcal
This compound can be mechanistically justified through
more stable that the triplet state. The relative stability of the an addition of TEMPO to the last tautomeric equilibrium
two possible diradical species is clearly favorable to the drawn in Scheme 4, and briefly illustrated in Scheme 5. The
[Ph·–TiIII·–Ph]– complex that, overall, displaces the previous justification of this mechanism is supported by the well-
equilibrium as long as the reaction proceeds. In Figure 1 known fact that TEMPO easily reacts with radical spe-
(panel c) the key structures of the present proposed mecha- cies.[12] A TEMPO molecule can abstract hydrogen. Finally,
nism are shown. Addition of one equivalent of H2NO radi- in the formation of product 9, the addition of a hydroxyl
Eur. J. Org. Chem. 2015, 2111–2118
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2113

E. Nicolás, F. Albericio, I. de P. R. Moreira, J. M. Bofill et al.
SHORT COMMUNICATION
Scheme 4. Proposed mechanism for more than 1 equiv. of TEMPO per phenol.
group can be justified by the action of TEMPO on a water
Conclusions
molecule to produce a hydroxyl radical that is added to the
last Ti complex, 8, in Scheme 4. Water is added (as a satu-
In conclusion, we have reported a comprehensive mech-
rated aqueous solution of NH4Cl) to the anhydrous reac- anistic description for the TiCl4-mediated phenolic form-
tion solution when complex 8 has been formed as part of ylation confirming the intramolecular nucleophilic substitu-
the workup procedure. This last step is shown in Scheme 5. tion pathway proposed by Cresp et al.[2] and, simulta-
Scheme 5. Proposed mechanism for hydroxyl addition.
2114
www.eurjoc.org
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2015, 2111–2118

On the Mechanism of TiCl4-Mediated Phenolic Formylation
with Ar and cooled with an ice bath. Then, TiCl4 (800 μL,
7.30 mmol in anhydrous CH2Cl2) was added dropwise. The reac-
tion mixture was left to react for 1 h. Since the reaction occurs even
without adding a base, the proton extraction in anhydrous CH2Cl2
is performed by one molecule of 3,5-dimethoxyphenol acting as a
base to form complex 3 in the present experimental set up. After-
wards, a solution of different equivalents of TEMPO in anhydrous
CH2Cl2 (5 mL) was added by syringe to the solution and the mix-
ture left to react for a further 45 min. The reaction was quenched
by the addition of a saturated aqueous NH4Cl solution (10 mL)
neously, this research has provided theoretical and experi-
mental evidence of diradical and triradical intermediates
that lead to new and interesting active reagents for general
use. It is found that the valence tautomerism is essential
to understand the different nature of the active species for
possible nucleophilic or radical processes in all the pro-
posed mechanisms. In this sense, the implication of these
kinds of diradical complexes in this and related reactions is
expected to be of fundamental significance in organic and
bioorganic chemistry. In particular, the formation of prod- and the mixture was left to stand for 2 h. The organic layer was
ucts such as lignines[17] or reactivity of phenolic deriva-
separated and washed with 0.1 n HCl solution (3ϫ 50 mL) and
brine (3ϫ 50 mL). The organic layer was dried with Na2SO4, fil-
tives[18] may occur through diradical mechanisms similar to
tered, and the solvent was evaporated under reduced pressure. The
the ones reported in the present study.
crude reaction mixtures were analyzed by HPLC with 5% MeCN
for 2 min and from 5 to 95% MeCN in 10 min. Products 7 and 9
were obtained in different proportions according to the equivalents
Experimental Section
of TEMPO used, as shown in Table 1.
EPR Experiments
Table 1. Amounts of TEMPO used in this study and yields of 7
and 9 obtained under these conditions.
Experiment 1: Following the conventional procedure for the
formylation reaction, a solution of 3,5-dimethoxyphenol (231.0 mg,
1.50 mmol) in anhydrous CH2Cl2 (10 mL) was stirred at 0 °C.
Then, TiCl4 (170 μL, 1.55 mmol) was added dropwise, then the
mixture was left for a period of 30 min. Afterwards, anhydrous
Et2O (170 μL, 1.62 mmol) [instead of dichloromethyl methyl ether]
was added and after 30 min, 400 μL of the mixture, which presum-
ably contains the blocked intermediate (compound 3 in Scheme 3),
was introduced into an EPR tube for characterization. The com-
plete procedure was carried out under Ar to avoid contamination
by O2. The mixture was prepared the day before and kept at –80 °C
in the EPR tube under Ar. The reference sample used as a blank in
the EPR experiment contained 3,5-dimethoxyphenol in anhydrous
CH2Cl2 in the same concentration as the experiment mixture
(0.15 m). The EPR spectra in solution at 4 K shows a clear |Δms| =
1 signal at ≈ 3350 G (g ≈ 2.000) without fine structure and the spin
forbidden half field |Δms| = 2 signal at ≈ 3350 G (g ≈ 4.392). The
observation of the half field signal at low temperature and the de-
crease in intensity of the observed signals with temperature suggest
that the diradicals formed in the solution have a triplet ground
state. However, these signals are almost undistinguishable from the
background signal above 100 K in this experiment. This fact
suggests that the pre-equilibria suggested by the theoretical model
described in Figure 1 (panel a) start to play a role since the signal
in experiment 2 is observable even at ambient temperature.
TEMPO ([g]/[mmol])
TEMPO [equiv.] 7 [%][a] 9 [%][a]
[b]
0.608/3.9
1.267/8.1
2.534/16.2
3.042/19.5
1.2
2.5
5.0
6.0
quant.
35
–
65
82
quant.
18
–
[b]
[a] Determined by integration of chromatographic areas. [b]Not de-
tected.
From 6 equiv. of TEMPO the reaction stops progressing and shows
the same chromatographic profile, only with product 9. No varia-
tion of the temperature in the reactions improved the ratio of the
desired products. Conversely, a lower yield was obtained due to
what we believe is the stability of the titanium complex with in-
creasing temperature.
A notable result was obtained when a solution of product 7
(500 mg, 3.25 mmol) in anhydrous CH2Cl2 (10 mL) purged with Ar
and cooled with an ice bath was mixed with one equivalent of
TEMPO in anhydrous CH2Cl2 (5 mL) added by syringe to the solu-
tion. The mixture did not show any change or reaction for 45 min
since in the analysis only the initial reactants and no other product
could be seen. This negative result is a clear indication that only
the radical reaction proceeds in the presence of TiCl4 in front of
other possible chemical equilibria such as H·or H+ extraction by
TEMPO on phenols.
Experiment 2: A solution of 3,5-dimethoxyphenol (500.0 mg,
3.25 mmol) in anhydrous CH2Cl2 (10 mL) and under an argon at-
mosphere was stirred at 0 °C. Then, TiCl4 (800 μL, 7.30 mmol) was
added by syringe and the mixture was left for a period of 30 min.
The mixture was introduced into an EPR tube for characterization
also under an argon atmosphere. The mixture was prepared and
analyzed at the same time. The EPR spectra in solution shows a
clear |Δms| = 1 signal even at 300 K at ≈ 3350 G. To justify the EPR
signal observed in this experiment we propose what we believe is
the most plausible explanation, an intermediate coordination con-
sisting of two phenols bonded with TiCl4 in an open shell singlet
or triplet state. In the case of experiment 1, the competing pre-
equilibria between TiCl4 with phenol and/or ether molecules (neu-
tral, anions and diradical tautomers described in Figure 1) is
responsible for the rapid decay of the intensity of the EPR signal
above 50 K.
Products 7 and 9 were isolated by flash chromatography and char-
acterized as follows:
2-(3,5-Dimethoxyphenoxy)-3,5-dimethoxyphenol (7): White solid.
TLC: Rf = 0.77 (AcOEt). HPLC-MS: (X-Terra MS C18, H2O/
MeCN from 95:5 to 0:100 over 11 min) tR = 7.3 min, m/z = 307.1
[M + H]+. HRMS (ESI): calcd for (C16H19O6) 307.1182; found
1
307.1175 [M + H]+. H NMR (400 MHz, [D6]DMSO): δ = 6.04 (s,
1 H, Ar-H), 6.03 (s, 2 H, Ar-H), 6.01 (s, 1 H, Ar-H), 5.93 (s, 1 H,
Ar-H), 3.66 (s, 3 H), 3.52 (s, 3 H), 3.51 (s, 6 H) ppm. UV/Vis
(methanol): λmax = 243.6 nm.
2-(3,5-Dimethoxyphenoxy)-3,5-dimethoxy-4-[(2,2,6,6-tetramethyl-
pipe-ridin-1-yl)oxy]phenol (9): Brown oil. TLC: Rf = 0.71 (AcOEt).
HPLC-MS: (X-Terra MS C18, H2O/MeCN from 95:5 to 0:100 over
11 min) tR = 9.1 min, m/z = 478.2 [M + H]+. HRMS (ESI): calcd
for (C25H37NO8) 478.2442; found 478.2439 [M + H]+. 1H NMR
(400 MHz, [D6]DMSO): δ = 6.17 (s, 1 H, Ar-H), 6.08 (s, 1 H, Ar-
TEMPO Experiments:
A solution of 3,5-dimethoxyphenol
(500 mg, 3.25 mmol) in anhydrous CH2Cl2 (10 mL) was purged
Eur. J. Org. Chem. 2015, 2111–2118
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2115

E. Nicolás, F. Albericio, I. de P. R. Moreira, J. M. Bofill et al.
SHORT COMMUNICATION
Figure 1. Optimized geometries of the calculations on the simplified model described in the text. In panel a) the preliminary equilibria
present in the TiCl4/1,3,5-benzenetriol/diethyl ether. Panel b) equilibrium process leading to the [Ph·–TiIII·–Eth]– diradical. Panel c) equilib-
rium processes leading to the [Ph·–TiIII·–Ph]– diradical and [Ph·–TiIII·–Ph·]– triradical. Level of theory: HF/6-31G* for reactants and
neutral complexes in panel a; ROHF/6-31G* for H2NO/6-31G*, CASSCF(8,8)/6-31G* for diradical structures ([Ph·–TiIII·–Eth]– and [Ph·–
TiIII·–Ph]–, either triplet or open-shell singlet states; in panels b and c) and CASSCF(11,11)/6-31G* for the triradical structure [Ph·–TiIII·
Ph·]– either quartet or doublet states (in panel c). ZPE correction has been included for each minimum energy structure.
–
H), 5.56 (s, 1 H, br. s, OH), 5.22 (s, 1 H, Ar-H), 4.39 (s, 1 H, br. s, For the first stage of the reaction we explore the stability of the
OH), 3.75 (s, 3 H), 3.71 (s, 6 H), 3.62 (s, 3 H), 2.2–1.0 (m, 18 H,
b.s.) ppm. UV/Vis (methanol): λmax = 255.6 nm.
possible complexes between TiCl4 with 1,3,5-triphenol and/or di-
ethyl ether. We employed a theoretical approach based on the
Hartree–Frock (HF) functional since the electronic ground states
of all these structures are closed-shell in nature. The extraction of
a proton from the Ph–TiIV–Eth or the Ph–TiIV–Ph complexes is
modeled by addition of a tertiary amine to these species to simplify
the calculations. Notice that in the present experimental set up the
reaction occurs without adding a base and the proton extraction
in anhydrous CH2Cl2 is performed by one molecule of 3,5-dimeth-
oxyphenol acting as a base to form complex 3 (neither CH2Cl2 nor
the ether can act as a proton acceptor). In the case of the Eth–
TiIV–Eth complex, it is not reactive in the presence of the base or
the H2NO species and will not be relevant for the rest of the mecha-
nism. However, the base extracts a proton from the phenol group
of the phenolic complexes to generate the anionic structures that
exhibit valence tautomerism, showing an accessible and stable di-
radical electronic state. In both cases, the open shell singlet is
0.3 kcal mol–1 more stable than the triplet state, which suggests that
the triplet and the open-shell singlet are quasi-degenerate (the
closed-shell singlet solution is significantly higher in energy: the
3A at UHF level is lower than the 1A RHF solution by almost
20 kcal mol–1). Indeed, the EPR spectrum at 4 K suggests that the
ground state of the diradical species is a triplet since the intensity
of the observed peaks decrease with temperature and the half-field
signal at g ≈ 4.392. Here, it is worth noting that in the case of the
original formylation process shown in Scheme 1 of the main text
the tautomeric equilibrium involving this anionic complex provides
the essential step to reach the products through an intramolecular
Ab Initio Calculations on the Model System: To provide a theoreti-
cal justification of the proposed mechanism several wave function
calculations were performed to show the stability of the intermedi-
ate diradical and triradical structures essential for this mechanism.
The electronic structure of these complexes and their molecular
structures were investigated by using a simplified molecular model
in vacuo representative for the description of the formation process
of the diradical TiCl4–phenolate complexes by means of ab initio
wave function electronic structure calculations. Hence, 3,5-di-
hydroxyphenol was adopted as a model system to represent 3,5-
dimethoxyphenol, the TEMPO radical was substituted by H2NO.
The addition of a tertiary amine to these species [trimethylamine,
N(Me)3], a base to model the proton extraction (see comment in
Scheme 3), has different effects as shown in Figure 1 (panels b and
c). Using this simplified model we investigate the stability of the
intermediate species (neutral, anionic, diradical and triradical) in-
volved in the initial equilibria and the following reactions with base
and TEMPO, shown in Scheme 3. A sketch of the resulting mini-
mum energy stable structures is reported in Figure 1.
All calculations presented herein have been carried out by em-
ploying the standard 6-31G* basis set and the GAMESS 2012
package.[13] The all electron basis sets correspond to the standard
basis sets reported by Pople and collaborators: [4s/2s] for H,
[10s4p1d/3s2p1d] for C, N, and O,[14] [16s10p1d/4s3p1d] for Cl[15]
and [22s16p4d1f/5s4p2d1f] for Ti.[16]
2116
www.eurjoc.org
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2015, 2111–2118

On the Mechanism of TiCl4-Mediated Phenolic Formylation
Figure 2. The most relevant natural orbitals (open shells) of the triplet state of [Ph·–TiIII·–Ph]– (left) and the quartet state of [Ph·–TiIII·
–
Ph·]– (right). Contour value for orbital isosurfaces is 0.03 |e|·bohr–3.
nucleophilic attack on the Cl substituent situated on the ether
group.
vide a plausible and consistent mechanism for the overall process
as described in Figure 1.
The relative stability of the two possible diradical species is clearly
favorable to the [Ph·–TiIII·–Ph]– complex that, overall, displaces the
previous equilibrium as long as the reaction proceeds. Notably, in
the case of the original formylation process shown in Scheme 1,
the tautomeric equilibrium involving the [Ph·–TiIII·–Eth]– anionic
complex provides the essential step to reach the products through
an intramolecular nucleophilic attack on the Cl substituent situated
on the ether group. The valence tautomerism between the two
forms of the anionic and diradical intermediates, namely [Ph·–
Acknowledgments
I. R.-T. thanks the Generalitat de Catalunya for a pre-doctoral fel-
lowship. Financial support from the Spanish Ministerio de Econ-
omía y Competitividad (MEC), projects CTQ2006-15611-C02-02,
CTQ2009-13797,
CTQ2011-22505,
CTQ2012-30930
and
CTQ2012-30751 and, in part, from the Generalitat de Catalunya
projects 2005SGR-00111, 2009SGR-1041, 2009SGR-1024,
2014SGR-2016 and XRQTC, is fully acknowledged.
TiIII·–Ph]– and [Ph–TiIV–Ph]– or [Ph·–TiIII·–Eth]– and [Ph–TiIV
–
Eth]– requires the use of a multi-reference approach as the complete
active space self-consistent field (CASSCF). From the natural or-
bital occupations between 1.98 and 0.02 of the triplet state it has
been established that the appropriate CASSCF wave function re-
quires 8 electrons in 8 orbitals. This fact precludes the application
of DFT methods based on a single Kohn–Sham determinant to
represent the electronic states of the reported TiCl4–enolate struc-
tures as discussed by us in previous papers. In addition, Schreiner
and co-workers have shown that, even for closed shell organic mol-
ecules, the accuracy of standard hybrid DFT potentials is question-
able.
[1] H. Gross, A. Rieche, G. Matthey, Chem. Ber. 1963, 96, 308–
313.
[2] T. M. Cresp, M. V. Sargent, J. A. Elix, D. P. H. Murphy, J.
Chem. Soc. Perkin Trans. 1 1973, 340–345.
[3] O. Garcıa, E. Nicolás, F. Albericio, Tetrahedron Lett. 2003, 44,
4961–4963.
[4] O. Garcia, J. M. Bofill, E. Nicolas, F. Albericio, Eur. J. Org.
Chem. 2010, 3631–3640.
[5] M. Góngora-Benítez, L. Mendive-Tapia, I. Ramos-Tomillero,
A. C. Breman, J. Tulla-Puche, F. Albericio, Org. Lett. 2012, 14,
5472–5475.
The same scheme leads to a CASSCF(11,11) active space to prop-
[6] A. Vilsmeier, A. Haack, Ber. Dtsch. Chem. Ges. 1927, 60, 119–
4
erly describe the triradical anion [Ph·–TiIII·–Ph·]–, either the A or
122.
the 2A states (the 2A state is 0.4 kcal mol–1 more stable than the 4A
state, suggesting that these states are almost degenerate). The most
relevant CASSCF(8,8) and CASSCF(11,11) natural orbitals (NOs)
of the triplet state of the diradical and the quartet state of the
triradical are those reported in Figure 2 with the corresponding
occupation numbers close to 1.00. The topology of these NOs al-
lows us to assign these orbitals to the nonbonding orbital of the
phenol rings combined with one Ti d orbital.
[7] J. C. Duff, E. J. Bills, J. Chem. Soc. 1932, 1987–1988.
[8] S. Gambarotta, C. Floriani, A. Chiesi-Villa, C. Guastini, J.
Am. Chem. Soc. 1983, 105, 7295–7301.
[9] I. de P. R. Moreira, J. M. Bofill, J. M. Anglada, J. G. Solsona,
J. Nebot, P. Romea, F. Urpí, J. Am. Chem. Soc. 2008, 130,
3242–3243.
[10] S. Beaumont, E. A. Ilardi, L. R. Monroe, A. Zakarian, J. Am.
Chem. Soc. 2010, 132, 1482–1483; P. J. Mabe, A. Zakarian, Org.
Lett. 2014, 16, 516–519; A. Gómez-Palomino, M. Pellicena,
J. M. Romo, R. Solà, P. Romea, F. Urpí, M. Font-Bardia,
Chem. Eur. J. 2014, 20, 10153–10159.
The triradical anion along with the diradical structures [Ph·–TiIII·
–
Ph]– and [Ph·–TiIII·–Eth]– are the key stable intermediates to pro-
Eur. J. Org. Chem. 2015, 2111–2118
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2117

E. Nicolás, F. Albericio, I. de P. R. Moreira, J. M. Bofill et al.
SHORT COMMUNICATION
[11] E. Damiani, P. Astolfi, M. Benaglia, A. Alberti, L. Greci, Free
Radical Res. 2004, 38, 67–72.
[12] H. Karoui, F. Le Moigne, O. Ouari, P. Tordo in Stable radicals:
Fundamentals and applied aspects of odd-electron compounds
(Ed.: R. G. Hicks), John Wiley & Sons, Chichester, UK, 2010,
pp. 173–230.
[13] M. W. Schmidt, K. K. Baldridge, J. A. Boatz, S. T. Elbert,
M. S. Gordon, J. H. Jensen, S. Koseki, N. Matsunaga, K. A.
Nguyen, S. Su, T. L. Windus, M. Dupuis, J. A. Montgom-
ery Jr., J. Comput. Chem. 1993, 14, 1347–1363.
[14] P. C. Hariharan, J. A. Pople, Theor. Chim. Acta 1973, 28, 213–
222.
[15]
[16]
M. M. Francl, W. J. Petro, W. J. Hehre, J. S. Binkley, M. S. Gor-
don, D. J. DeFrees, J. A. Pople, J. Chem. Phys. 1982, 77, 3654–
3665.
V. Rassolov, J. A. Pople, M. Ratner, T. L. Windus, J. Chem.
Phys. 1998, 109, 1223–1229.
[17] W. Boerjan, J. Ralph, M. Baucher, Annu. Rev. Plant Biol. 2003,
54, 519–46.
[18] C. Giulivi, N. J. Traaseth, K. J. A. Davies, Amino Acids 2003,
25, 227–232.
Received: November 30, 2014
Published Online: February 25, 2015
2118
www.eurjoc.org
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2015, 2111–2118