Angewandte

Chemie

Organic Oxidants

DOI: 10.1002/anie.200504156

o-Iodoxybenzoic Acid (IBX): pKa and Proton-

Affinity Analysis **

Michael J. Gallen, Rgis Goumont, Timothy Clark,

Franois Terrier, and Craig M. Williams*

o-Iodoxybenzoic acid (IBX; 1)[1, 2] is an important oxidant in

organic synthesis owing to the landmark contributions by

Nicolaou et al.[3–11] Some stunning examples include benzylic

oxidation,[7, 8] dehydrogenation of carbonyls and alcohols to
a,b-unsaturated enones,[3, 4, 7] and cyclic amination.[6, 9–11] Since
then, the synthetic community has witnessed many new
oxidation-based applications of this reagent by the Nicolaou
group and others; examples include the conversions of amines
into imines,[12, 13] of dithioketals,[12–14] dithioacetals,[12–14] and
oximes[15] into ketones and aldehydes, of alcohols into
esters,[16] as well as oxidative 1,3-transpositions,[17] aromatiza-
tions,[18] and demethylations.[19]

[*] M. J. Gallen, Dr. C. M. Williams

School of Molecular and Microbial Sciences
University of Queensland
Brisbane, 4072, Queensland (Australia)
Fax: (+ 61) 733-654-299
E-mail: [email protected]
R. Goumont, Prof. F. Terrier
Institut Lavoisier-Franklin
Universit> de Versailles
45 avenue des Etats Unis, 78035 Versailles cedex (France)
Prof. T. Clark
Computer-Chemie-Centrum
Friedrich-Alexander-UniversitBt Erlangen-NErnberg
NBgelsbachstrasse 25, 91052 Erlangen (Germany)
[**] We thank the University of Queensland and the Universit> de
Versailles for financial support.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.

Angew. Chem. Int. Ed. 2006, 45, 2929 –2934  2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim 2929
Communications
There are other IBX-mediated processes, however, that the two tautomers 12–15, and this led to a single anion for
are oxidative transformations only in part, for example, the both IBX and IBA (16 and 17, respectively), both of which
one-pot conversion of tetrahydropyranyl (THP) ethers 5 into have a partially opened five-membered ring at the I
O3 bond
aldehydes/ketones 6[20] and of silyl enol ethers 7 into enones (Supporting Information). The calculated gas-phase proton
8[5] (Scheme 1). Considering these processes and the obser- affinity for deprotonated IBX 16 (337 kcal mol
1) is quite
close to the experimental value for dichloroactetate (328 kcal
mol
1).[26–28] Deprotonated IBA 17 has an almost identical
calculated gas-phase proton affinity to 16 at the B3LYP/
LANL2dz + p level, but IBA is calculated to be a weaker acid
than IBX at the PW91/dnp level. The acidities in aqueous
solution were estimated by using standard SCRF-PCM
calculations[30] with default settings for Gaussian 03. They
gave a calculated energy change in aqueous solution for the
proton-exchange reaction CHCl2COO
+ 1!CHCl2COOH
+ 16 of only 0.52 kcal mol
1, which, when combined with the
pKa value of dichloroacetate in water (1.26), gave an
estimated aqueous pKa value for IBX of roughly 1.6.
Complexation of IBX (e.g. 3) or IBA with dimethyl
Scheme 1. IBX-mediated processes that are oxidative transformations sulfoxide (DMSO) (gas-phase proton affinities of 16·DMSO
only in part. and 17·DMSO are both 327 kcal mol
1) makes both com-
pounds stronger acids, as does complexation with NMO,
although the latter has a larger effect for IBX (gas-phase
vation in our own laboratories that IBX unexpectedly proton affinity of 16·NMO = 326 kcal mol
1) than for IBA
converted ketone 9 into bicycle 10[21] (Scheme 1), we inves- (17·NMO 328 kcal mol
1). Notably, the COOH tautomers of
tigated the possibility that IBX may exhibit physical proper- both IBX and IBA (13 and 15, respectively) are stabilized by
ties of note (other than oxidant and explosive[1b, 13, 22]). complexation with DMSO and to a lesser extent with NMO,
Given that both 5 and 7 are acid-sensitive, and that the but in both cases this stabilization is not large enough to make
formation of 10 can be prevented by using IBX·NMO (4; them the more stable of the two tautomers.
NMO = N-methylmorpholine N-oxide), which instead affords Solution-phase acidity determinations were performed in
11,[23] we investigated the acidity of IBX. Even though its both aqueous media and DMSO. An aqueous pKa value of
chemical name o-iodoxybenzoic acid implies that this mole- 2.40 for IBX was obtained by using standard potentiometric
cule must display a certain level of Brønsted acidity, in fact no titration methods. Determining a pKa value for IBX in DMSO
such information has been reported or considered in the (i.e. 3) was much more difficult as potentiometric measure-
literature.[24] ments[31] proved unsuitable. Furthermore, as the ionization of
A computational study of acidity (proton affinity) at the IBX does not induce absorbance changes in the UV/Vis
PW91/dnp and B3LYP/LANL2dz + p levels[25] were per- spectral region, buffers formed from the appropriate colorless
formed on IBX in the first instance, although the oxidative amine, carboxylic acid, or phenol were not used to determine
by-product 2-iodosobenzoic acid (IBA; 2) (from the one-step pKa values spectrophotometrically because an excessively
reduction of 1) and the more active oxidant 4 were also large number of potential buffers could be envisioned.[32, 33]
compared. Furthermore, because both IBX and IBA can exist However, in keeping with the indicator strategy, the alter-
in two tautomeric forms (12 and 13 (IBX), 14 and 15 (IBA); native approach of measuring the pH value of IBX buffer
Scheme 2), an understanding of their operating structures was solutions with reference to suitable indicators of known
required. pKMea
2 SO
values was pursued.
Geometry optimizations were performed starting from Considering the acidity of IBX in water (pK H a
2O
= 2.40)
deprotonated forms derived from the optimized structures of and the well-known fact that the acidity of oxygen acids[34–37]
strongly decrease on going from water to DMSO (e.g. the pKa
value of acetic acid is 4.75 in water and 12.3 in DMSO[33]), we
anticipated that the change in solvent would increase the
pKMea
2 SO
value of IBX by at least 5 pKa units.[34–37] The
ionization of 2,4-dinitrophenol (18; Scheme 3) (pKMe a
2 SO
=
[33]

5.12) in a 1:1 IBX buffer ([IBX] = [IBX ] = 0.012 m) was
therefore investigated.
The resulting UV/Vis spectrum was identical to that
obtained in a 1:1 1,4-diazabicyclo[2.2.2]octane (DABCO)
buffer ([DABCO] = [DABCOH+] = 0.012 m ; pH = 9.06),
leaving no doubt that the 1:1 IBX buffer is sufficiently basic
to allow complete ionization of 18, that is, pKIBX a  6.6. 4-
Nitrobenzyltriflone (19; pK = 9.46)[37a] was similarly studied
Scheme 2. Calculated structures for deprotonated IBX and IBA. in a 1:1 IBX buffer to obtain an upper limit for pK IBXa . In this

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 Angewandte
Chemie

was measured with a 1:1 DABCO buffer (pH = 9.06). From

½21

the pKa value of 21 and the observed variations in the ½21 ratio
A
A21
calculated as A21
A


, the pH values of each of the IBX buffer
solutions were readily obtained [Eq. (1)]. From these pH

½21
 A
A21
pH ¼ pK 21
a þ log ¼ pK5a þ log ð1Þ
½21 A21

A

values, the pKa of IBX·DMSO was then calculated at each pH

value [Eq. (2)]. This resulted in an average pK IBX
a of 6.65 

½IBX

pKIBX
a ¼ pH
log ð2Þ
½IBX
Scheme 3. UV/Vis spectral indicators used herein.

0.05 (Supporting Information). Even though the ionization of

case, no appreciable development of the absorbance of the 20 was far from complete in the most basic IBX buffer
carbanion of 19 (lmax = 475 nm) was observed, suggesting that employed, a similar pKa value (6.78  0.1) was derived from
pKIBX
a  8. Based on the two limits above, two indicators were the analysis of the absorbance variations observed for this
selected to determine accurately the pK Me a
2 SO
value of IBX, indicator along the IBX buffer series (Figure 1 and Support-
namely, 2,4,6-trinitrodiphenylamine (20; pKMe a
2 SO
= 8.01) ing Information). However, the observed consistency
(Figure 1) and 4’,2,4,6-tetranitrodiphenylamine (21; between the two pK IBX a values obtained provides evidence
pKMe
a
2 SO
= 6.07) (Figure 2).[32]
that the measurements in DMSO are not appreciably affected
by side phenomena such as homoconjugation.[34, 39, 40]
Extensive studies of solvent effects on the acidity of
common oxygen acids such as carboxylic acids, phenols,
oximes, or nitronic acids have shown that the transition from
water to DMSO decreases the acidity markedly.[32–37, 41, 42] The
pKa values of acetic acid and benzoic acid are 4.75 and 4.19,
respectively, in water at 25 8C,[43] but 12.3 and 11, respectively,
in pure DMSO.[33] Similarly, the pKa of phenol increases from
9.89 in water to 18.0 in DMSO.[33, 43] This effect of changing
from water to DMSO has long been attributed to a decrease
in the stability of the conjugate oxyanionic structures owing to
Figure 1. Ionization of 20 (pKa = 8.01) in DMSO:[38] a) to f) refer the loss of favorable hydrogen-bonding solvation.[33, 35–37, 41, 42]
successively to 1:2, 1:1, 2:1, 3:1, 4:1, and 5:1 IBX buffers; g) 1:1 In this context, the increase observed in the pKa value of IBX
butylamine buffer (pKa = 11.12).
from water to DMSO was to be expected. However, this
increase amounts to  4 pK units, which represents a rather
moderate change relative to a common reference such as
acetic acid (DpKa = 7.5). Within a family of structurally
similar oxyacids, the solvent effect has been found to be a
function of the acidity in aqueous solution.[37, 41] For example,
the pKa value of dichloroacetic acid is 1.48 in water[43] and 6.4
in DMSO,[33] that is, DpKa = 4.9, versus DpKa = 7.5 for acetic
acid. Similar increases in DpKa = pK aMe2 SO
pK H a
2O
with
increasing pK H a
2O
values have been found in phenol and
oxime systems and accounted for in terms of an increased
hydrogen-bonding solvation of the oxyanions with increasing
basicity.[37, 44] The greater the pKH a
2O
, the greater will be the
stabilization of the oxyanions by hydrogen-bonding solvation
in aqueous solution, and hence the greater will be the
Figure 2. Ionization of 21 (pKa = 6.07) in DMSO:[38] a) 0.1 m CF3SO3H; destabilization of these species on going to DMSO. Based on
b) to h) refer successively to 1:4, 1:3, 1:2, 1:1, 2:1, 3:1, and 4:1 IBX
these arguments, the 4-pK-unit decrease in acidity of IBX
buffers; i) 1:1 DABCO buffer (pKa = 9.06).
from water to DMSO seems in order, especially in compar-
ison to that of similarly acidic systems (i.e. dichloroacetic
Pronounced variations in the visible absorption of 21 acid) in aqueous solution.
(Figure 2) were observed in progressing along the buffer What impact does the acidity of IBX have on the currently
series with a nearly complete conversion of this substrate into accepted mechanism of oxidation reactions? In direct one-
the conjugate base of 21 in the most basic buffer used. The step oxidation processes the current mechanism is unaltered.
absorbance of the conjugate base of 21 in its pure form (A21
) However, in stepwise processes (one-pot, two or more steps)

Angew. Chem. Int. Ed. 2006, 45, 2929 –2934  2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim www.angewandte.org 2931
Communications
such as the conversion of THP ethers 5 into aldehydes/ IBX has an acidity in water similar to that of 2-nitrobenzoic
ketones 6, an acid-catalyzed conversion into the alcohol 22 acid (pK H
a
2O
= 2.18) and an acidity in DMSO similar to that of
followed by oxidation to the aldehyde/ketone 6 is now very dichloroacetic acid (pK Me
a
2 SO
= 6.4), thus implying that 1 and 3
likely the case. In fact, THP ether hydrolysis (acid cat.) in the are relatively acidic on the organic scale. This knowledge
presence of IBX (i.e. 23!24; Scheme 4) was observed by Rao should aid those wishing to utilize this important suite of
and co-workers,[20] but was, we believe, incorrectly attributed hyperiodine reagents 1–4 in future synthetic transformations.
to the presence of b-cyclodextrin.

Experimental Section
Calculations: Geometries were initially optimized[46] with Dmol3
using the dnp basis set[47] with DFT semi-core pseudopotentials[47, 48]
and the Perdew 91 (P91) exchange and correlation functionals.[49] The
geometries thus obtained were employed as starting points for
optimizations with Gaussian 03[50] using the LANL2dz basis set[51] and
Los Alamos pseudopotentials[52] augmented with a set of polarization
functions.[53] All LANL2dz calculations used the hybrid B3LYP
functional,[54] which includes contributions from Hartree–Fock
exchange with Becke[55] and Vosko, Wilk, and Nusair (VWN)[56]
Scheme 4. IBX-catalyzed THP deprotection. exchange functionals and the Lee, Yang, Parr (LYP) correlation
functional.[57] The structures obtained at the B3LYP/LANL2dz + p
level were confirmed to be local minima by the calculation of their
normal vibrations within the harmonic approximation.
In our case it would seem that IBX performs the expected
Aqueous titrations of IBX[1b] (1) were carried out on a Metrohm
dehydrogenation of ketone 9 to give enone 11, which then 796 Titroprocessor with an Ionode IJ44 pH electrode containing a
undergoes an acid-catalyzed ene reaction to afford 10 saturated KCl gel. The pH potentiometric titrations were made on
(Scheme 5). However, in the case of 7!8 (Scheme 6), it is solutions in a double-walled glass vessel maintained at 25.1  0.1 8C
very difficult to appreciate the effect that IBX acidity has on with an external water heater. Nitrogen was bubbled through the
this reaction, for example, protolysis to ketone 25, mainly solution to maintain an inert atmosphere. Efficient stirring of the
solution was obtained with a magnetic stirrer. The instrument was
because silyl enol ethers are so notoriously susceptible to
standardized against standard buffers of pH 4.00, 7.00, and 10.00 from
protolysis by strong or weak acids. Biolab with adjustments made for temperature. This standardization
procedure was repeated before each experiment, and a slope of 0.95–
1.00 was required from the Metrohm program for the Nernstian plot
before titration could proceed. Calibration was performed by titration
of Et4NClO4 (0.1m) in HClO4 (6 mm) with Et4NOH (0.096 m). A plot
of potential against pH provided a slope of
58.9 mV, close to the
expected theoretical value of
59.1 mV. The E8 and pKw values were
obtained for each aqueous titration and used in the pKa calculations,
as they deviated from those of pure water. The titration curves were
fitted with the TITFIT program.[58]
Titrations of IBX in DMSO: The procedure described by
Scheme 5. IBX-catalyzed ene reaction. Bordwell[33] and Crampton and Robotham[32] was used to determine
spectrophotometrically the pKa of IBX with reference to the various
selected indicators. UV/Vis spectra were taken on an HP 8453
spectrophotometer at 25  0.2 8C. DABCO and 18 of the highest
quality available commercially were used and were not purified.
Butylamine was distilled prior to use, whereas 21,[59] 19,[37a] and 20[60]
were prepared as reported. DMSO was heated at reflux over calcium
hydride, distilled, and the fractions at 32–35 8C (under 2-mmHg
pressure) were collected and stored under argon. All solutions of
Scheme 6. IBX dehydrogenation of silylenol ethers. indicators and IBX were freshly prepared in a glove box under argon.
We generated all the IBX buffers by adding DABCO to the
appropriate parent IBX solution, such that the molarity of the base
component (IBX
) was always 0.012 m. Butylamine and DABCO
What impact does the acidity of IBX have on synthetic buffers (1:1) were made by the introduction of trifluoromethanesul-
utility? In most cases the acidity of IBX (or IBA) has no fonic acid to generate the required concentration (0.012 m) of the acid
adverse effects on substrate or product as demonstrated in the forms.
current literature. Considering, however, that 4 prevents the
ene reaction (Scheme 5; giving 11 as the sole product) in cases Received: November 22, 2005
in which the substrate or product may be acid-sensitive, for Published online: March 27, 2006
example, when certain protecting groups are present, we
would recommend the use of 4 instead of 1 or 3.[45]

(pKH
In conclusion, the pKa value and proton affinity of IBX
has been determined by in silico (337 kcal mol
1) and in vitro
a
2O
= 2.40, pKMe
a
2 SO
= 6.65) methods, which suggest that
. Keywords: acidity · density functional calculations ·
o-iodoxybenzoic acid · oxidation · proton affinity

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 Angewandte
Chemie

energy correction) is remarkably close to the experimental

[1] a) C. Hartman, V. Meyer, Ber. Dtsch. Chem. Ges. 1893, 26, 1727; values of 328.4  2.1,[26] 327.3  2.1,[27] and 328.4  2.6 kcal
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1.[28] As expected, the calculated value decreases to
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course. the AH/A
pair; it occurs, for example, to a much greater extent
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Org. Lett. 2005, 7, 5155. detected for phenols (i.e. 2,6-dinitrophenol (pKa = 4.9) or 4-
[24] The structure and acidity of IBA have been discussed in chloro-2,6-dinitrophenol (pKa = 3.6)) in DMSO,[39b] the contri-
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