O-Iodoxybenzoic Acid (IBX) - Pka and Proton - Affinity Analysis
O-Iodoxybenzoic Acid (IBX) - Pka and Proton - Affinity Analysis
O-Iodoxybenzoic Acid (IBX) - Pka and Proton - Affinity Analysis
Chemie
Organic Oxidants
DOI: 10.1002/anie.200504156
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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 IO3 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 mol1) is quite
close to the experimental value for dichloroactetate (328 kcal
mol1).[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 mol1, 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 mol1) 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 mol1) than for IBA
converted ketone 9 into bicycle 10[21] (Scheme 1), we inves- (17·NMO 328 kcal mol1). 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
½21 AA21
pH ¼ pK 21
a þ log ¼ pK5a þ log ð1Þ
½21 A21 A
½IBX
pKIBX
a ¼ pHlog ð2Þ
½IBX
Scheme 3. UV/Vis spectral indicators used herein.
Angew. Chem. Int. Ed. 2006, 45, 2929 –2934 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim www.angewandte.org 2931
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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 mol1) 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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Communications
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[44] F. Terrier, P. Rodriguez-Dafonte, E. Le GuLvel, G. Moutiers,
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Angew. Chem. 2002, 114, 1444; Angew. Chem. Int. Ed. 2002, 41,
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