Acid Activation in Phenyliodine Dicarboxylates: Direct Observation, Structures, and Implications

Article abstract of DOI:10.1021/jacs.6b07999

The use of the hypervalent iodine reagents in oxidative processes has become a staple in modern organic synthesis. Frequently, the reactivity of λ³ iodanes is further enhanced by acids (Lewis or Br?nsted). The origin of such activation, however, has remained elusive. Here, we use the common combination of PhI(OAc)₂ with BF₃·Et₂O as a model to fully explore this activation phenomenon. In addition to the spectroscopic assessment of the dynamic acid-base interaction, for the first time the putative PIDA·BF₃ complex has been isolated and its structure determined by X-ray diffraction. Consequences of such activation are discussed from a structural and electronic (DFT) points of views, including the origins of the enhanced reactivity.

Full text of DOI:10.1021/jacs.6b07999

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Communication
Acid activation in phenyliodine dicarboxylates:
direct observation, structures and implications
Susana Izquierdo, Stéphanie Essafi, Iker del Rosal, Pietro Vidossich, Roser
Pleixats, Adelina Vallribera, Gregori Ujaque, Agustí Lledós, and Alexandr Shafir
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.6b07999 • Publication Date (Web): 08 Sep 2016
Downloaded from http://pubs.acs.org on September 9, 2016
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Acid activation in phenyliodine dicarboxylates: direct observation,
structures and implications
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Susana Izquierdo,a Stéphanie Essafi,b Iker del Rosal,b Pietro Vidossich,b Roser Pleixats,b Adelina
Vallribera,b Gregori Ujaque,b Agustí Lledós,*b Alexandr Shafir*a
aInstitute of Chemical Research of Catalonia (ICIQ), Barcelona Institute of Science and Technology, Av. Països Catalans 16,
43007, Tarragona, Spain; b Departament de Química and Centro de Innovación en Química Avanzada (ORFEO-CINQA),
Universitat Autònoma de Barcelona, 08193 Cerdanyola del Vallès, Spain.
Supporting Information Placeholder
ABSTRACT: The use of the hypervalent iodine reagents in
oxidative processes has become a staple in modern organic syn-
thesis. Frequently, the reactivity of λ3 iodanes is further enhanced
by acids (Lewis or Brønsted). The origin of such activation, how-
ever, has remained elusive. Here, we use the common combina-
tion of PhI(OAc)2 with BF3·Et2O as model to fully explore this
activation phenomenon. In addition to the spectroscopic assess-
ment of the dynamic acid-base interaction, for the first time the
putative PIDA·BF3 complex has been isolated and its structure
determined by X-Ray diffraction. Consequences of such activa-
tion are discussed from a structural and electronic (DFT) points of
views, including the origins of the enhanced reactivity.
Figure 1. Hypothetical activation of PhI(OAc)2 by a Lewis acid.
Kang and Gade proposed that HOTf might act as catalyst in olefin
dioxygenation with PhI(OAc)2, through the formation of the
[PhI(OAc)]+ cation.12 This species was actually detected by ESI+
spectrometry, yet it is already present in the mass spectrum of
non-activated PhI(OAc)2 in CH3CN13 and may thus arise from
MS-related ionization processes. Direct observation of this cation
under experimentally relevant conditions would certainly support
mechanistic hypothesis based on the enhanced reactivity of
[PhI(OAc)]+ cation. On this basis, we sought firmer structural
evidence for acid activation phenomenon by studying the ubiqui-
tous PIDA/BF3·Et2O combination.
The 1H NMR spectrum of PhI(OAc)2 was recorded in CDCl3 with
and without BF3·Et2O present. The addition of the Lewis acid (1
equiv) caused a downfield displacement (~0.1 ppm) of the aro-
matic resonances, consistent with the formation of a more elec-
tron-deficient species (Figure 2). Free Et2O was also observed,
confirming the liberation of the BF3 unit. Portionwise addition of
BF3·Et2O caused a gradual displacement of the o-Ph resonance
from 8.08 ppm up to 8.19 ppm, with the latter value reached at
approx. 1.2 equiv (Figure 2); a parallel change was observed for
the meta and para hydrogens and for OAc.
Although known for over a century,1 organoiodine(III) reagents
have gained significant importance in recent years, becoming an
important go-to tool in a number of synthetic processes.2,3 Among
the most commonly used iodine(III) reagents are phenyliodine(III)
dicarboxylates, obtained either through oxidation of iodobenzene,
or by treating the polymeric iodosobenzene PhI=O with the corre-
sponding carboxylic acid (Equation 1). Phenyliodine diacetate,
PIDA, and phenyliodine bis(trifluoroacetate), PIFA are the most
prominent members of this family.
While λ3 iodanes may be quite reactive, their reactivity is fre-
quently further enhanced by an acid additive, either Lewis or
Brønsted. Indeed, hundreds of transformations have been reported
requiring the inclusion of such activators, often chosen from
among BF3·Et2O, HOTf, Me3SiOTf or Me3SiBr. Combinations of
PIDA or PIFA with BF3·Et2O have proven particularly versatile,
as seen in the formation of λ3-diaryliodanes4 and the oxidation of
alcohols,5 the dehydrogenative arene-arene coupling,6 arene func-
tionalization,7 olefin diacetoxylation,8 or a variety of rearrange-
ment9 and C-O, C-N and C-S cyclization reactions.10
H3C
O
m
CH3
6H
o
O
O
p
I
O
CH3
o
p
m
BF3—Et2O added
6H
8.21
8.19
H3C
O
8.16
orthoꢀH
BF3—Et2O
O
+
O
I
In our own research, and building upon earlier findings by Kita et
al., the PIFA/BF3·Et2O combination was used for direct dehydro-
genative synthesis of polynaphthalenes.11 Importantly, no cou-
pling took place in the absence of the Lewis acid. Surprisingly,
despite its recognized importance, the role played by the acid
additives in iodine(III) chemistry is seldom addressed, beyond the
general assumption of the formation of a more reactive PhI(OAc)+
cation (Figure 1).
O
8.11
8.06
CH3
H
equiv BF3—Et2O
(ppm)
0
1
2
3
4
1
Figure 2. H NMR spectra of PIDA with and without BF3·Et2O,
and 1H NMR titration plot (δortho) of PIDA with BF3·Et2O.
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No further displacement was observed with additional portions of
1
2
the Lewis acid, which is in line with a 1:1 stoichiometry in the
1
PIDA-BF3 adduct. The continuous displacement of the H NMR
resonances suggests a rapid BF3 hopping between molecules of
PIDA, leading to a weight-averaged chemical shift. Furthermore,
the presence of a single acetate resonance (6H) suggests either a
symmetrical species, or a rapid BF3 exchange between the two
acetate sites. The latter scenario was confirmed by cooling a 1:1
3
4
5
6
7
8
o
PIDA/BF3 solution to -53 C, which rendered the two distinct
OAc (3H and 3H) signals clearly distinguishable (Figure 3).
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Scheme 1. Synthesis and structure of PhI(OAc)2·BF3.
For further insight, two additional analogs were prepared, the
monofluoroacetate PhI(OCOCH2F)2, 117 and bis-difluoroacetate
PhI(OCOCHF2)2, 2. Both were obtained through the oxidation of
iodobenzene with Oxone® in the presence of the corresponding
carboxylic acid (Scheme 2).18 In the case of 1, the addition of
2.4 2.3 2.2 2.1
Figure 3. Variable temperature 1H NMR spectrum of the 2:1
mixture of PIDA and PIDA·BF3. At -50 °C the coexistence of the
two species is clearly distinguishable.
1
BF3·Et2O caused a displacement of the NMR signal as already
observed for PhI(OAc)2, indicating sufficient basicity to form a
1·BF3 adduct. When conducted in CH2Cl2, this addition caused
the formation of a white crystalline 1·BF3; both 1 and 1·BF3 were
characterized by single crystal X-Ray diffraction (Scheme 2).
Once again, the adduct can be described as a weakly bound ion
1
Due to fast BF3 hopping, a single time-averaged set of H NMR
resonances is observed for a 2:1 mixture of PIDA and BF3·Et2O,
expected to contain an equimolar PIDA / PIDA·BF3 mixture.
o
Nevertheless, at -50 C the pattern was resolved into two sets of
-
pair between [PhI(O2CCFH2)+ and the FH2CCOO·BF3 anion. In
signals, one for PIDA and the other for PIDA·BF3 (Figure 4).
From the coalescence temperature (~260 K) the ꢀG‡ barrier for
BF3 hopping was estimated to be ~9 kcal/mol (see Support. Info).
contrast, the bis-difluoroacetate 2 behaved much like PIFA, and
gave no indication by 1H NMR of interacting with BF3·Et2O.
Figure 4. Coexistence of the clearly distinguishable PIDA and
PIDA·BF3 at -53 oC.
Having assessed the nature of a putative PhI(OAc)2·BF3 complex
by solution NMR, we sought to access this species synthetically.
It was found that the addition of 1.5 equiv of BF3·Et2O to a solu-
tion of PhI(OAc)2 in a 1:1 hexane/CH2Cl2 mixtures led, after 1 h,
to the appearance of a white precipitate, which was isolated by
filtration under N2 atmosphere. The 1H and 19F NMR of this solid
confirmed the formulation as PhI(OAc)2·BF3, isolated in an 87%
yield (Scheme 1). For the first time, crystals suitable for X-Ray
diffraction were obtained as colorless needles from a CH2Cl2
solution via a slow diffusion-exchange with n-hexane. The struc-
ture presents discreet units of PhI(OAc)2·BF3 with the BF3 moiety
bound to the distal O atom of one of the OAc ligands. Comparison
Scheme 2. The range of phenyliodine dicarboxylates explored,
along with the synthesis and X-Ray structure of 1·BF3. Calcu-
lated ꢀG for the formation equilibrium.
This data are indicative of an acid-base equilibrium, whereby the
λ3-iodane and the Et2O molecule compete for the BF3 unit, with
the equilibrium shifted toward the BF3 adduct for the more basic
PIDA and 1. In contrast, for 2 as well as PIFA, this equilibrium is
shifted far to the left (Scheme 2). DFT calculations support this
interpretation, with calculated Gibbs energy for the equilibria in
Scheme 2 decreasing in the order +8.1 kcal mol-1 (CF3), 0.0
(CHF2), -3.0 (CH2F) and -6.5 (CH3). Nevertheless, even for PIFA,
there would be a finite small concentration of the BF3-activated
species, possibly responsible for the increased reactivity. For the
mildly basic 1, NMR titration allowed contrasting the computa-
tional estimate with the experimental measure (Figure 5). The
observed chemical shift is a weighted average of chemical shifts
of the free 1 and 1·BF3 (Equation a in Fig. 5). Therefore, δobs
provides a direct measure of the extent of reaction, x, which, in
turn, depends directly on the equilibrium constant K (Equation b
in Fig. 5). By fitting the theoretical δ curves, obtained by solving
equations a and b in Figure 5,19 to the experimental chemical
shifts δexp, an optimal values of K = 3.3 and ꢀGexp = -1.1 kcal/mol
were obtained (Figure 5).
14
with the structure of PhI(OAc)2 reveals a geometrically analo-
gous arrangement around the λ3 iodine and a similar CPh-I bond
length (2.099 Å). However, the new adduct features the elonga-
tion of the I-O bond from 2.15 Å (average in PIDA) to 2.28 Å for
the OAc·BF3 group. Given the strong trans influence in λ3
iodanes,15 this lengthening is accompanied by the shortening of
the complementary I-OAc bond to 2.076 Å. These structural
features are consistent with the development of partially cationic
character, namely, with [PhI(OAc)]+. We then proceeded to ex-
tend this study to other iodanes / acid systems. Surprisingly, no
interaction between phenyliodine bis(trifluoroacetate), PIFA, and
BF3·Et2O was observed by NMR16 even in the presence of 8 equiv
of BF3·Et2O. This reactivity difference between PIDA and PIFA
appears to stem from the much lower basicity of PIFA.
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K
PhI(O2CCH2F)2 + BF3·Et2O
PhI(O2CCH2F)·BF3 + Et2O
1
m-x
n-x
x
x
2
3
8.22
m = [PhI(O2CR)2] init
n = [BF3·Et2O] init
4
5
6
7
8
9
10
11
12
8.20
8.18
8.16
8.14
x = extent of reaction
δ
ortho measured
δ1·(m-x) + δ1·BF3·x
δ
ortho calculated (K = 3.3)
(a)
(b)
δobs
=
m
x2
(m-x)·(n-x)
K =
Figure 6. DFT calculated LUMO energies (eV) for several
PhI(OAc)-X species.
0
2
equiv BF3·Et2O
4
6
8
We then verified the synthetic relevance of the isolated activated
species by testing its reactivity in transformations known to pro-
ceed in the presence of the PIDA/BF3·Et2O combinations. Thus,
the oxidative cyclization of the N-allyl benzamide 3 to oxazoline
4,23 proceeded smoothly both with a mixture of PIDA/BF3·Et2O
and with the preformed PIDA·BF3; importantly, no reaction took
place with PIDA alone (Scheme 4).
Figure 5. Dependence of the δortho for 1 on the amount of
BF3·Et2O added; m = [PhI(O2CR)2]init; n = [BF3·Et2O]init; x is
extent of reaction.
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We complemented our study by treating PIDA with TMSOTf,
commonly employed in iodine(III) activation. The reaction af-
forded PhI(OAc)(OTf) (76% yield), a species previously obtained
by Stang and coworkers from PhI=O, and recently observed (MS,
1H NMR) by the groups of Gade12 and Dutton (Scheme 3).20
While the compound is highly unstable, Ochiai, Miyamoto and
co-workers did characterized its hydrolysis (aqua) product in the
presence of [18]crown-6.21 Now, X-Ray quality crystals of this
O
IX
additive
OAc
2
O
N
+
Ph
Ph
N
H
I
CH Cl room temp, 1h, -Ph
2
4
2,
3
I
Ph (OAc)
0%
99%
I
Ph (OAc) ·BF
2 3
96%
--
2
PhI(OAc) + BF ·Et O
3
2
2
o
Scheme 4. The effect of acid activation on the formation of the
oxazoline 4 from 3 with PIDA.
reagent were obtained by storing a CH2Cl2 solution at -25 C
under argon. The structure is consistent with a weakly bound ionic
pair between PhI(OAc)+ and OTf-, with a rather long I-OTf dis-
tance (2.35 Å) and the I-OAc bond of 2.056 Å, which is even
shorter than in the BF3 adduct. Incidentally, attempts at crystalli-
zation also produced a second set of crystals, now corresponding
to the dimeric [PhIOIPh](OTf)2, i.e. the Zefirov’s reagent, often
employed as a HOTf-activated PhIO equivalent.22 This has al-
lowed for the solid state structure of this reagent to be determined
for the first time (Scheme 3).
We also tested an interesting usage of PIDA as a C6H5I building
block via ortho propargylation. In the original report by Ochiai et
al.24 described the formation of the ortho-propargyl iodobenzene
from PhI(OAc)2 and propargylsilane in the presence of BF3·Et2O.
Hence, the coupling was tried using propargylsilanes bearing the
terminal R=H (5a) and R=cyclohexyl (5b) groups. As seen in
Scheme 5, while PIDA itself was unreactive, respectable yields of
the corresponding ortho-propargyl iodobenzenes 6a and 6b were
indeed obtained either by introducing BF3·Et2O (1 equiv) or by
using the pre-formed PIDA·BF3 and PhI(OAc)(OTf);25 this be-
havior argues in favor of the synthetic relevance of the newly
prepared Lewis-acid activated complex.
ad ditive
AcO
IX
I
2
Me Si
3
R
+
I
R
CH Cl
2
2
R
o
H
-20 C, 1h
·
5
6
via [3,3]
PhI(OAc)
PhI(OAc)
2
PhI(OAc) ·BF
2
PhI(OAc)(OTf)
---
2
3
additive
---
0%
0%
BF ·Et O
3 2
---
AcO
δ+
R =H, 6a
82%
69%
72%
57%
86%
42%
I
R
6b
R =Cy,
SiMe
3
Scheme 3. Formation and X-Ray structure of PhI(OAc)(OTf)
and the dimeric Zefirov’s reagent.
Scheme 5. The effect of acid activation on the ortho-
propargylation of PhI(OAc)2.
As mentioned in the introduction, acid activation is supposed to
promote the formation of species with enhanced [PhI-OAc]+
cation character. From a molecular orbital point of view, activa-
tion lowers the energy of LUMO, rendering the resulting species a
stronger Lewis acid and oxidant. Within the three-level hyperva-
lent bonding model,2,3 the LUMO in PIDA is a p-type orbital
centered on iodine and aligned with the O-I-O vector. DFT calcu-
lations show a clear correlation between LUMO energies for a
range of the PhI(OAc)-X species and the coordinating ability of
the X- anion (Figure 6). In PIDA, the LUMO orbital is at -1.9 eV,
and this energy is lowered to different extents by converting one
of the acetate ligands into a less coordinating X anion. Binding of
BF3 generates X =OAc·BF3 and lowers the LUMO energy to -
2.59 eV, while in the PhI(OAc)(OTf) complex this energy is -2.77
eV. Simply put, acid activation tends to generate a species more
akin the cationic [PhI(OAc)]+ with the LUMO energy of -4.19 eV.
We also investigated the significant rate acceleration for the reac-
tion between PhI(OAc)2 and mesitylene ushered by BF3·Et2O.
When PIDA alone was used in CDCl3, no reaction was detected at
25 oC after 60 min. The addition of BF3·Et2O led to an immediate
(<10 sec) quantitative (NMR) formation of the corresponding
diaryl iodane Ph(Mes)I-OAc (Scheme 6)
AcO
Me
I
(OAc)2
Lewis acid:
-- <1%
BF3 >95%
I
Me
H
+
CDCl3, rt
60 min
Me
Me
Me
Me
Scheme 6. The effect of BF3 activation on the formation of a
diaryl λ3 iodane.
These results argue in favor of synthetic relevance of the newly
prepared Lewis-activated complex, suggesting, in both cases, that
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a cationic [PhI(OAc)]+ character facilitates the crucial interaction
between the iodine(III) center and the substrates π system.
1
Notes
The authors declare no competing financial interests.
2
3
4
5
6
7
8
9
A DFT mechanistic study of the reactivity of PIDA towards me-
sitylene was undertaken to unravel the effect of the Lewis additive
assuming an SEAr process (Figure 7). For the reaction to take
place, mesitylene required cis binding to the Ph ligand (the
strongest trans-directing ligand). This was made possible by a
movement of the OAc to a position trans to Ph, which, in the
absence of a Lewis acid, proceeds with a barrier of 19.8 kcal mol-1
(TS-I-II, Fig. 6). In contrast, binding of the BF3 group greatly
facilitates the “slipping” of the resulting anion (TS-I-II-BF3
Figure 6). The subsequent binding of mesitylene is favorable. The
reaction is completed by the acetate-assisted C-H deprotonation to
restore the aromaticity of the mesitylene ring. This step is also
favored by BF3 (TS-III-IV). Thus, in this case BF3 promotes the
reactivity at two levels: by favoring the intramolecular pre-
arrangement of the λ3-iodane and by lowering the activation
barrier of the bond breaking event.
ACKNOWLEDGMENT
This work was funded by Fundació ICIQ, MINECO (CTQ2013-
46705-R, CTQ2014-54071-P, CTQ2014-53662-P, 2014-2018
Severo Ochoa Excellence Accreditation SEV-2013-0319 and
CTQ2014-51912-REDC) and the Generalitat de Catalunya (2014
SGR 1192, 2014 SGR 1105). The CELLEX Foundation is grate-
fully acknowledged for a post-doctoral contract to S. I. and for
support through the CELLEX-ICIQ HTE platform.
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In summary, the phenomenon of acid activation of simple λ3
iodane has been studied for the model PhI(O2CCR)2 by NMR,
DFT and through synthetic approaches, including the isolation
and single crystal characterization of the two key species,
PhI(OAc)·BF3 and PhI(OAc)(OTf).26 Surprisingly, no interaction
between PIFA and BF3·Et2O was detected by NMR. Lowering of
the LUMO energy is proposed as key for the activation phenome-
non. As a word of caution, it is important to emphasize that, de-
pending on the reaction, the role of acid additives may go beyond
the activation of the iodane species, through participation in fur-
ther phenomena, e.g. in radical caging, catalyst or substrate acti-
vation or fluoride transfer. Nevertheless, we expect that detailed
understanding of the effect exerted by acids on the hypervalent
iodine reagent will assist researchers in studying the mechanisms
involving such species and in the development of new stoichio-
metric and catalytic oxidative transformations.
́
́
S.; Tellitu, I.; Domınguez, E.; Moreno, I.; SanMartın, R. Tetrahedron Lett.
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T.; Tohma H. Chem. Commun. 1996, 2225-2226.
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3667.
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(14) Coordinates for PIDA from CSD (refcode IBZDAC12): Togo, H.;
Nabana, Y.; Yamaguchi, K. J. Org. Chem. 2000, 65, 8391–8394.
(15) a) Ochiai, M.; Sueda, T.; Miyamoto, K.; Kiprof, P.; Zhdankin, V.
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C. H. Inorg. Chem. 2012, 51, 967–977.
(16) An analogous PIFA-BF3 interaction has been invoked as key for
SET processes: Dohi, T.; Ito, M.; Yamaoka, N.; Morimoto, K.; Fujioka
H.; Kita, Y. Tetrahedron 2009, 65, 10797–10815.
(17) Merkushev, E. B.; Novikov, A. N.; Makarchenko, S. S.; Mos-
kal'chuk, A. S.; Glushkova, V. V.; Kogai, T. I.; Polyakova, L. G. Zh. Org.
Khim. 1975, 11, 1259-1263.
(18) Protocol adapted from Zagulyaeva, A. A.; Yusubov, M. S.;
Zhdankin, V. V. J. Org. Chem. 2010, 75, 2119−2122.
ASSOCIATED CONTENT
Supporting Information
NMR data, synthetic procedure, product characterization, single
crystal diffraction studies, DFT methodology employed and Car-
tesian coordinates and energies of all the optimized structures.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(19) See Supporting information for details.
(20) a) Zhdankin, V. V.; Crittell, C. M.; Stang, P. J.; Zefirov, N. S. Tet-
rahedron Lett. 1990, 31, 4821-4825; b) Aprile, A.; Iversen, K. J.; Wilson,
D. J. D.; Dutton, J. L. Inorg. Chem. 2015, 54, 4934−4939; for the related
ArI(OTf)2, also see: c) Farid, U.; Wirth, T. Angew. Chem. Int. Ed. 2012,
51, 3462 –3465; d) Hu, B.; Miller, W. H.; Neumann, K. D.; Linstad, E. J.;
DiMagno, S. G. Chem. Eur. J. 2015, 44, 6394 – 6398.
(21) a) Ochiai, M.; Miyamoto, K.; Yokota, Y.; Suefuji, T.; Shiro, M.
Angew. Chem. Int. Ed. 2005, 51, 75–78; b) Miyamoto, K.; Yokota, Y.;
Suefuji, T.; Yamaguchi, K.; Ozawa, T. Ochiai, M. Chem. Eur. J. 2014, 20,
5448–5452.
AUTHOR INFORMATION
Corresponding Author
*agusti@klingon.uab.es
*ashafir@iciq.es
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(22) Zefirov, N. S.; Zhdankin, V. V.; Dan’kov, Y. V.; Sorokin, V. D.;
(25) See Supporting information for details.
Semerikov, V. N.; Koz’min, A. S.; Caple R.; Berglund, B. A. Tetrahedron
Lett. 1986, 27, 3971–3974.
(23) Moon, N. G.; Harned, A. M. Tetrahedron Lett. 2013, 54, 2960–
2963.
(26) While this work was in preparation, the ability of fluorinated alco-
hols to activated PIDA via hydrogen bonding was reported: Colomer, I.;
Batchelor-McAuley, C.; Odell, B.; Donohoe, T. J.; Compton, R. G. J. Am.
Chem. Soc. 2016, 138, 8855–8861.
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(24) a) Ochiai, M.; Ito, T.; Takaoka, Y.; Masaki, Y. J. Am. Chem. Soc.
1991, 113, 1319-1323; b) for a mini-review on iodonio-Claisen rear-
rangements: Shafir, A. Tetrahedron Lett. 2016, 57, 2673–2682.
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