Hypervalent Iodine Oxidations: Structure and Kinetics of the Reactive Intermediates in the Oxidation of Alcohols and 1,2-diols by o-Iodoxybenzoic Acid (IBX) and Dess-Martin Periodinane. A Comparative 1H-NMR Study

Article abstract of DOI:10.1021/jo961044m

Alcohols and 1,2-diols oxidation by o-iodoxybenzoic acid (IBX) has been examined by 1H-NMR spectroscopy.Reversible formation of reactive intermediates, iodic esters 5, has been observed, and their structures in DMSO-d6 solution have been defined as 10-I-4 axial alkoxyiodinane oxides by comparison of the chemical shift difference data with those obtained for Dess-Martin periodinane (DMP)-alcoholate and -diolate adducts.The dichotomous behaviour exhibited by IBX and DMP with 1,2-diols can be explained in terms of the different architecture of the reactive intermediates involved in the oxidation.With aliphatic alcohols, kinetic evidences support a two-step reaction mechanism involving a fast pre-equilibrium step leading to 5, followed by a rate-determining disproportionation step.With electronically activated benzyl alcohol, the attainment of pre-equilibrium is largely dependent on initial water concentration as a consequence of a particularly high K₂ value.The influence of the alcohol structure on measured equilibrium (K_eq) and rate constants (K₂) and the effect of water on the overall reaction rate are discussed.

Full text of DOI:10.1021/jo961044m

9272
J . Org. Chem. 1996, 61, 9272-9279
Hyp er va len t Iod in e Oxid a n ts: Str u ctu r e a n d Kin etics of th e
Rea ctive In ter m ed ia tes in th e Oxid a tion of Alcoh ols a n d 1,2-Diols
by o-Iod oxyben zoic Acid (IBX) a n d Dess-Ma r tin P er iod in a n e. A
1
Com p a r a tive H-NMR Stu d y
Sergio De Munari, Marco Frigerio, and Marco Santagostino*
Prassis Istituto di Ricerche Sigma-Tau, Via Forlanini 3, 20019 Settimo Milanese, Milano, Italy
Received J une 3, 1996X
Alcohols and 1,2-diols oxidation by o-iodoxybenzoic acid (IBX) has been examined by 1H-NMR
spectroscopy. Reversible formation of reactive intermediates, iodic esters 5, has been observed,
and their structures in DMSO-d6 solution have been defined as 10-I-4 axial alkoxyiodinane oxides
by comparison of the chemical shift difference data with those obtained for Dess-Martin periodinane
(DMP)-alcoholate and -diolate adducts. The dichotomous behavior exhibited by IBX and DMP
with 1,2-diols can be explained in terms of the different architecture of the reactive intermediates
involved in the oxidation. With aliphatic alcohols, kinetic evidences support a two-step reaction
mechanism involving a fast pre-equilibrium step leading to 5, followed by a rate-determining
disproportionation step. With electronically activated benzyl alcohol, the attainment of pre-
equilibrium is largely dependent on initial water concentration as a consequence of a particularly
high k2 value. The influence of the alcohol structure on measured equilibrium (Keq) and rate
constants (k2) and the effect of water on the overall reaction rate are discussed.
In tr od u ction
DMSO closely parallels the reactivity pattern of DMP in
chlorinated solvents, some differences are observed in the
oxidation of polyfunctional alcohols. We have shown that
IBX cleanly oxidizes alcohols in the presence of amino
and sulfide functional groups,6 which are not usually
tolerated by DMP. While DMP displays no selectivity
in competitive oxidations of saturated alkanols,2b site
selectivity has been reported in IBX oxidation of poly-
alcohols.6-8 A major difference is observed in the oxida-
tion of 1,2-diols. Thus, while DMP generally cleaves the
glycol C-C bond,2b,9 IBX oxidizes them to R-ketols or
R-diketones.5,10 Significantly, another 10-I-4 species,
1-hydroxy-1,3-dihydro-3,3-bis(trifluoromethyl)-1,2-benzio-
doxole 1-oxide (3), performs the clean conversion of
R-hydroxylactols to R-hydroxylactones.9a,b
The oxidizing properties of hypervalent iodine(V) com-
pounds are becoming increasingly appreciated by organic
chemists.1 The widespread utilization of 12-I-5 Dess-
Martin periodinane (DMP, 1,2 namely 1,1,1-triacetoxy-
1,1-dihydro-1,2-benziodoxol-3(1H)-one), for the efficient
oxidation of alcohols to carbonyl compounds testifies for
this trend. Its direct precursor, the polymeric, highly
insoluble 10-I-4 iodinane oxide 2 (1-hydroxy-1,2-benzio-
doxol-3(1H)-one 1-oxide, o-iodoxybenzoic acid, IBX3) was
first synthesized in 1893,4 but until recently little was
known about its chemical properties.
In this paper, we present kinetic and spectroscopic data
which may shed some light on the mechanistic aspects
that control the observed selectivity of IBX and clarify
the origin of the dichotomous behavior exhibited by 10-
I-4 and 12-I-5 species in the oxidation of 1,2-diols.
(4) (a) Hartman, C.; Meyer, V. Chem. Ber. 1893, 26, 1727. Other
syntheses of IBX have been reported in the literature: (b) Greenbaum,
F. R. Am. J . Pharm. 1936, 108, 17. (c) Banerjee, A.; Banerjee, G. C.;
Dutt, S.; Banerjee, S.; Samaddar, H. J . Indian Chem. Soc. 1980, 57,
640. (d) Banerjee, A.; Banerjee, G. C.; Ghattacharya, S.; Banerjee, S.;
In 1994, we reported that IBX can be readily dissolved
in DMSO and pointed out that IBX itself functions as a
valuable oxidant toward a variety of alcohols.5 Although
with simple primary and secondary alcohols, IBX in
Samaddar, H. J . Indian Chem. Soc. 1981, 58, 605. For
a more
convenient preparation of IBX, see ref 2b.
(5) Frigerio, M.; Santagostino, M. Tetrahedron Lett. 1994, 35, 8019.
(6) Frigerio, M.; Santagostino, M.; Sputore, S.; Palmisano, G. J . Org.
Chem. 1995, 60, 7272.
(7) Corey, E. J .; Palani, A. Tetrahedron Lett. 1995, 36, 3485.
(8) During the preparation of this article, kinetic evidences have
been provided which explain the observed selectivity of IBX in the
oxidation of 1,4-diols to γ-lactols: Corey, E. J .; Palani, A. Tetrahedron
Lett. 1995, 36, 7945.
(9) Isolated examples of the variable cleaving ability of DMP on 1,2-
dihydroxy compounds have appeared in the literature: (a) Grieco, P.
A.; Collins, J . L.; Moher, E. D.; Fleck, T. J .; Gross, R. S. J . Am. Chem.
Soc. 1993, 115, 6078. (b) VanderRoest, J . M.; Grieco, P. A. J . Am. Chem.
Soc. 1993, 115, 5841. (c) Pancrazi, A.; Anies, C.; Collemand, J .
Tetrahedron Lett. 1995, 36, 7771.
(10) Over 15 diols were tested with IBX in our laboratories, and
only (+)-pinanediol gave some percentage of oxidative cleavage product
(27% in DMSO at room temperature, 1.1 equiv of IBX, 0.4 M). This
mode of action is probably a manifestation of the ring strain in this
diol.
X Abstract published in Advance ACS Abstracts, December 1, 1996.
(1) For general reviews, see: (a) Nguyen, T. T.; Martin, J . C. In
Comprehensive Heterocyclic Chemistry; Katritzky, A. R., Rees, C. W.
Eds.; Pergamon Press: Oxford, 1984; Vol. 1, pp 563-572. (b) Varvoglis,
A. The Organic Chemistry of Polycoordinated Iodine; VCH: New York,
1992; pp 379-405. (c) Koser G. F. In The Chemistry of Functional
Groups, Supplement D; Patai, S., Rappoport, Z., Eds.; J ohn Wiley &
Sons: New York, 1983; Chapter 18. (d) Varvoglis, A. Synthesis 1984,
709.
(2) (a) Dess, D. B.; Martin, J . C. J . Org. Chem. 1983, 48, 4155. (b)
Dess, D. B.; Martin, J . C. J . Am. Chem. Soc. 1991, 113, 7277. For two
improved procedures for the preparation of DMP, see: (c) Ireland, R.
E.; Liu, L. J . Org. Chem. 1993, 58, 2899. (d) Meyer, S. D. M.; Schreiber,
S. L. J . Org. Chem. 1994, 59, 7549.
(3) The acronyms IBX and IBA, for 2-iodoxybenzoic acid and
2-iodosobenzoic acid, respectively, were coined by Katritzky. See:
Katritzky, A. R.; Duell, B. L.; Gallos, J . K. Org. Magn. Reson. 1989,
27, 1007.
S0022-3263(96)01044-4 CCC: $12.00 © 1996 American Chemical Society

Hypervalent Iodine Oxidants
Resu lts a n d Discu ssion
J . Org. Chem., Vol. 61, No. 26, 1996 9273
Ta ble 1. Equ ilibr iu m Con sta n ts Keq for F or m a tion of
th e IBX-Alcoh ola te Com p lex in DMSO-d 6 Solu tion s a n d
Ra te Con sta n t k2 for Disp r op or tion a tion Rea ction
Detection of In ter m ed ia tes in IBX Oxid a tion s.
Activated alkoxyperiodinane intermediates have been
observed in the reaction of alcohols with DMP2a,b,11a (vide
infra) and a number of other 12-I-5 species.2a,11b-e Con-
versely, there is no report of detection of analogous
complexes with 10-I-4 hypervalent species.12 We have
a
entry
alcohol
methanol
Keq
k2a (s-1
)
1
2
3
4
5
6
7
8
9
0.040
0.050
0.037
0.047
0.035
0.017
0.027
0.002
0.002
0.059
0.006
0.007
0.005
0.009
0.011
0.022
0.234
ethanol
isopropyl alcohol
isobutyl alcohol
neopentyl alcohol
2,4-dimethyl-3-pentanol
benzyl alcohol
tert-butyl alcohol
tert-pentyl alcohol
pinacol
1
examined the reaction of IBX with a few alcohols by H-
NMR spectroscopy and have observed formation and
decay of reactive intermediates.6 The obvious importance
of understanding the role and the structure of these
transient species has prompted us to carry out a system-
atic NMR analysis on a variety of simple alcohols and
diols. To begin our studies, we first examined the
reaction of IBX with nonoxidizable substrates. After
combination of 2 and t-BuOH in a 1:1 molar ratio at 23
°C in DMSO-d6, a small singlet, whose intensity did not
change in time, appeared at 1.50 ppm in the 1H-NMR
spectrum. The signal was assigned to a tert-butoxy group
tethering an iodinane oxide moiety as in 1-tert-butoxy-
1,2-benziodoxol-3(1H)-one 1-oxide. This conclusion was
bolstered by the observation that the mixed acetic
anhydride of IBX, 1-acetoxy-1,2-benziodoxol-3(1H)-one
1-oxide (Ac-IBX, 4),2b,d,13 reacts with t-BuOH to provide
the same compound in high yield.14 Treatment of IBX
with pinacol under the aforementioned conditions re-
sulted in a solution which exhibited, besides the known
resonances for the oxidant5 and the diol, a series of four
10
a
Due to the low relative intensity of the adduct signals, the
precision of the 1H-NMR integrals of 5 is very low. Consequently,
also Keq and k2 values are imprecise (ca. (20%).
Sch em e 1
1
peaks in the high-field region of the H-NMR spectrum,
seems to be a general characteristic of 1,2-diols.17 We
next turned our attention to the case of oxidizable
alcohols. As expected, reaction of IBX and ethanol (1
equiv) proceeds through the intermediacy of an ethoxy-
iodinane oxide whose intensity decreases rapidly in time
as the oxidation goes on. This underlines the prime role
of alkoxyiodinane oxides 5 in the oxidation process either
as products of the equilibrium between the alcohol and
the oxidant or as the reactive species which dispropor-
tionate to IBA3 and carbonyl derivative through a reduc-
tive elimination of the iodosoarene moiety (Scheme 1).
This behavior holds true for all the alcohols discussed
herein. The results of these NMR studies are sum-
marized in Table 2 (columns 2-4, alcohols) and Table 3
(diols) as a collection of relative shifts data for the
observed intermediates 5. A few points are noteworthy.
(1) IBX does not undergo complete ligand exchange with
alcohols. The equilibrium constants for formation of
adducts 5 are reported in Table 1 and were calculated
using the formula Keq ) ([5][H2O])/([IBX][ROH]) (see the
Experimental Section). (2) Even employing excess of
ligand, only one adduct type is observed during the
oxidation of symmetric alcohols and diols. (3) The
coexistence of unbound alcohol, oxidation products, and
alkoxyiodinane oxide introduces a significant complexity
in pursuing the complete assignment of the 1H-NMR
spectra. Moreover, due to the dissymmetrical nature of
IBX,18 chiral alcohols and diols give rise to diastereoiso-
mers and complexes derived from alcohols which contain
enantiotopic groups originate proton NMR spectra which
symptomatic of a pinacolate species with a lower sym-
metry than that of pinacol itself. Again, upon mixing Ac-
IBX and pinacol, we observed one adduct, which showed
the same 1H- and 13C-NMR signals.15 In both experi-
ments with IBX, the intensity of the signals of the
alkoxyiodinane oxides turned out to be directly propor-
tional to the alcohol and IBX concentrations, while it was
largely diminished by added water. The results dis-
cussed so far account for an equilibrium leading to
alkoxyiodinane oxide 5 with concomitant release of a
water molecule through a process of ligand exchange at
iodine, as already suggested by Dess and Martin (Scheme
1).2b The calculated values for the equilibrium constants
are 0.002 for t-BuOH and 0.059 for pinacol (Table 1). The
greater affinity of pinacol for IBX is probably due to the
presence of the 1,2-diol functionality. Resonably, the
second, unbound alcohol moiety of the diol is set in close
proximity to the iodine atom, and ligation is therefore
entropically favored.16 This process may eventually
result in an intramolecular transesterification. This
(11) (a) Linderman, R. J .; Graves, D. M. J . Org. Chem. 1989, 54,
661. (b) Kokunov, Y. V.; Sharkov, S. A.; Buslaev Y. A. Koord. Khim.
1982, 8, 55. (c) Oates, G.; Winfeld, J . M. J . Chem. Soc., Dalton Trans.
1974, 119. (d) Frohn, H. J .; Pahlmann, W. J . Fluorine Chem. 1984,
24, 219. (e) Frohn, H. J .; Pahlmann, W. J . Fluorine Chem. 1985, 28,
191.
(12) In the oxidation of alcohols by 3, no evidence for intermediates
was obtained when the reaction was monitored by 1H-NMR. See ref
2b.
(13) DMSO-d6 solutions of AcOIBX 4 were obtained by partial
hydrolysis of DMP with wet DMSO-d6. 1H-NMR (DMSO-d6): δH 2.20
(s, 3H, CH3COO), 7.93 (br t, 1H, J ) 7.2 Hz, H-6), 8.09 (m, 2H, H-4
and H-5), 8.49 (br d, 1H, J ) 7.2 Hz, H-7).
(16) We consider probable the cyclization of the open-chain adduct
9 to the unstable 12-I-5 spirobicyclic dialkoxyhydroxyperiodinane 10
and a fast reversion to the 10-I-4 adduct.
(17) High percentages of iodic esters derivatives have been observed
in qualitative preliminary experiments. Keq values not calculated.
(18) IBX has C1-symmetry, each crystal containing only one enan-
tiomer. For a proposed convention for the designation of absolute
configuration in optically active pentacoordinated species, see: Martin,
J . C.; Balthazor T. M. J . Am. Chem. Soc. 1977, 99, 152.
(14) Selected 1H- and13C-NMR resonances in DMSO-d6 for the IBX-
tert-butyl alcohol addduct. The values for the corresponding signal of
the free alcohol are reported in parentheses: δH 1.50, (1.12, Me); δC
31.7 (31.3, Me), 78.5 (67.0, CO).
(15) Selected 1H- and13C-NMR resonances in DMSO-d6 for the IBX-
pinacol adduct. The values for the corresponding signals of the free
alcohol are reported in parentheses: δH 1.22, 1.27, 1.37, 1.39 (1.07,
Me); δC 24.8, 25.6, 25.8, 26.0 (24.9, Me), 76.0 (73.6, COH), 85.2 (IOC).

9274 J . Org. Chem., Vol. 61, No. 26, 1996
De Munari et al.
Ta ble 2. 1H-NMR Ch em ica l Sh ift Differ en ce (∆δ)a Da ta for th e IBX-Alcoh ola te 5a x in DMSO-d 6 a n d for th e Axia l a n d
Equ a tor ia l DMP -Alcoh ola te Isom er s 6a x, 6eq in CDCl3 Solu tion s
5a x
6a x
6eq
R
Rb
0.66
0.72
0.71
â
γ
R
â
γ
R
â
γ
ax/eqc
methyl
ethyl
propyl
isopropyl
sec-butyl
0.96
1.01
0.96
1.12
1.21
0.65
0.74
5.7
6.3
7.4
8.1
4.5
0.24
0.27
0.17
0.27
0.19
0.26g
0.20h
-0.04
-0.06
0.12
0.10
0.18
0.08
0.07
0.66, 0.67d
0.88
-0.13
0.91
0.28, 0.30e
0.04, -0.06e
0.00g
0.95, 0.97f
0.29g
0.94
-0.12, -0.13f
h,i
0.05, 0.06f,h
neopentyl
isobutyl
tert-butyl
tert-pentyl
0.71
0.73
1.06
0.97
0.12
0.09
0.63
-0.06
11.6
4.6
4.4
0.33
0.38
0.15, 0.13e
0.24
0.63, 0.70e
i
-0.14, -0.15e
0.36
0.14
0.34g
i
0.31g
0.38h
0.11
0.07g
-0.15
3.5
0.43, 0.44e
0.22, 0.19e,h
∆δ ) δ(complex) - δ(alcohol). Column headings refer to the position of the probe protons relative to the oxygen atom. c Ratio between
a
b
axial and equatorial isomers. Diastereotopic methylene hydrogens. e Diastereotopic methyl groups. f Two diastereomeric complexes are
forme3d. Methylene hydrogens. Methyl group. Overlapping signal.
d
g
h
i
Ta ble 3. 1H-NMR Ch em ica l Sh ift Differ en ce Da ta for th e
Sch em e 2
IBX-Diola te Com p lex Ser ies in DMSO-d 6 Solu tion s
of the alcohol, the ligand exchange reaction is quantita-
tive. In accord with the existing literature, the major
adduct type observed, 6a x, appeared to bind the alkoxy
group axially.19 (2) In all cases, evidence was found for
a second monoaddition adduct type with asymmetric
structure, 6eq, in which the alkoxy group binds at the
equatorial11a position. This arrangement was confirmed
by the observation of a uniform upfield shift (-0.25 ppm)
for the alkoxy R-protons of 6eq relatively to the corre-
sponding signals for the axial isomer 6a x (Table 2,
colums 8 and 5, respectively).20 (3) With diols, complete
double ligand exchange is observed to produce chiral
spirobicyclic intermediates.21 In these adducts, the iodine
atom is asymmetric. Thus, only symmetrically substi-
tuted diols, devoid of stereogenic centers, give one adduct
(and its enantiomer). In all the other cases, mixtures of
diastereoisomers and constitutional isomers are formed
(see Table 4).
Str u ctu r e of Mon od en ta te Liga n d Ad d u cts. Two
adduct types with C1-symmetry can reasonably be ex-
pected when monodentate ligands, such as simple alco-
hols, react with IBX with formation of water: (1) complex
5a x, and its enantiomer, with a significantly electropos-
itive equatorial oxide ligand and an electronegative
alkoxy group occupying the apical ligand site, and (2)
complex 5eq, and its enantiomer, with an opposite and
energetically unfavored ligand arrangement.22 Struc-
tures 7 and 8, with the lone pair electrons in a position
∆δa
IOC-
parent diol
ethylene glycol
Rb CH-OH
â
γ
0.85
0.29
pinacol
0.30, 0.32c 0.28, 0.15c
0.32, 0.32d 0.13, 0.18d
(R,R)-2,3-butanediol
1,2-propanediol
(2-iodoxy)
(1-iodoxy)
cis-1,2-cyclohexanediol
0.81
0.21
0.95
0.88
1.02
e
0.27, 0.29d
0.13, 0.15d
0.33
0.28
0.25
e
e
e
e
trans-1,2-cyclohexanediol 0.85
a
b
∆δ ) δ(complex) - δ(alcohol). Column headings refer to the
position of the probe protons relative to the aryliodoxy group.
c Diastereotopic methyl groups. Two diastereoisomers are formed.
d
e Overlapping signals.
are often complicated also by diastereotopy. (4) Asym-
metrically substituted 1,2-diols produce statistical mix-
tures of constitutional isomers, evidencing the low sen-
sitivity of the complexation step to steric hindrance. In
order to unveil the stereochemistry at the iodine atom of
IBX-alcoholate intermediates, comparative analysis with
the intermediates involved in DMP oxidations proved to
be a fundamental step.
Detection of In ter m ed ia tes in DMP Oxid a tion s.
As mentioned above, it has been shown by 1H-NMR
analysis that DMP reacts very rapidly with 1 equiv of
alcohol to give 12-I-5 diacetoxyalkoxyperiodinanes. When
more than 1 equiv of alcohol (or a diol) is employed,
double displacement takes place, producing acetoxydi-
alkoxyperiodinanes (Scheme 2).2b
We have widened the survey already present in the
literature for DMP to comprise the alcohols and diols
tested with IBX in order to obtain two series of data
(Table 2, columns 5-10, and Table 4 for alcohols and
diols, respectively), to be compared with those reported
for the corresponding IBX adducts (Table 2, columns 2-4,
and Table 3). Before we describe the results of the
comparative study, a few aspects relative to DMP adducts
deserve some comments. (1) Regardless of the structure
(19) Displacement of the axial acetate, which lies in the plane of
symmetry of DMP, does not confer stereogenicity on the iodine atom,
while substitution of one of the enantiotopic equatorial acetates by a
different group originates a chiral adduct molecule. For a discussion
about chirality in octahedral complexes, see: Cahn, R. S.; Ingold, C.
K.; Prelog, V. Angew. Chem., Int. Ed. Engl. 1966, 5, 385.
(20) The ratio of axial to equatorial substitution isomers (Table 2,
last column) did not vary notably throughout the oxidation process,
indicating equal oxidation rates or fast interconversion.
(21) DMSO-d6 does not hinder the double displacement process.
DMP reacts with pinacol in this solvent to give quantitatively one
compound which shows an NMR pattern analogous to that observed
in CDCl3. Selected 1H-NMR resonances in DMSO-d6 for the DMP-
pinacol adduct and relative shifts from pinacol signal are δH 0.72 (∆δ
-0.36), 1.08 (0.00), 1.22 (0.14), 1.35 (0.27).

Hypervalent Iodine Oxidants
J . Org. Chem., Vol. 61, No. 26, 1996 9275
Ta ble 4. 1H-NMR Ch em ica l Sh ift Differ en ce Da ta for th e DMP -Diola te Com p lex Ser ies in CDCl3 Solu tion s
∆δa
b
parent diol
ethylene glycol
Rax
Req
0.67, 0.54c
âax
âeq
0.84, 0.78c
pinacol
0.18, 0.04d
-0.10
0.22
-0.10, -0.47d
0.22
0.02
(R,R)-2,3-butanediole
0.35
0.38
0.09
-0.21
1,2-propanediol
(2-iodoxy)e
0.22
0.48
1.22, 0.53c
1.07, 0.50c
0.50
0.50
0.59
-0.08
-0.33
0.14
-0.01
(1-iodoxy)e
1.34, 0.03c
1.34, -0.21c
0.85
0.29
0.30
cis-1,2-cyclohexanediol
f
f
f
f
f
f
trans-1,2-cyclohexanediole
0.32
0.28
a
b
∆δ ) δ(complex) - δ(alcohol). Column headings refer to the position of the probe protons relative to the aryliodoxy group.
c Diastereotopic methylene protons. Diastereotopic methyl groups. e Two diastereoisomers are formed. f Overlapping signals.
d
12-I-5 alkoxydiacetoxyperiodianes 6a x, cooperation of the
above-mentioned contributions invariably leads to strongly
positive ∆δ values. Comparison of the ∆δ data reported
in Table 2 for IBX and DMP complexes does enable us
to decide between the two more probable situations. ∆δ
values for the same alkoxy ligand are significantly
similar, even if the solvent is different, and diminish
regularly with increasing distance from the iodine atom,
always remaining positive. An average ∆δ of +0.77 is
associated with protons R to the oxygen atom, +0.32 with
the â position, and +0.14 with the γ position in IBX
different from the equatorial or the electronegative
iodoxolone ring linking two equatorial positions, were not
complexes (Table 2, columns 2-4). In the axial DMP
alcoholate series, averaged ∆δ values of +1.02, +0.27,
and +0.09, respectively, are observed (Table 2, columns
5-7). The enhanced deshielding effect at the R position,
uniformly associated with protons in DMP axial com-
plexes, possibly reflects the higher electronegativity of
the iodine atom in 12-I-5 complexes 6a x. Substantially
different is the pattern of shielding and deshielding
effects (averaged ∆δ, +0.73 for R, +0.06 for â, and -0.13
for γ protons) observed for equatorial DMP-alcoholate
series (Table 2, columns 8-10), substantiating the di-
verse ligand arrangement around the iodine atom in
complexes 6eq. Finally, downfield signals for aromatic
protons ortho to iodine, peri to apical I-O- charge dipole,
as would be expected26 for H-7 in 5eq-type adducts, are
not observed. These results strongly indicate that axial
ligation, predominantly obtained upon coordination of
monodentate ligands with DMP, does, indeed, exclusively
take place with IBX to produce 5a x-type complexes.
Str u ctu r e of Bid en ta te Liga n d Ad d u cts. Having
obtained cogent evidences indicating axial ligation in IBX
adducts of monodentate alcohol ligands, we set up to
investigate the behavior of IBX with potentially chelating
ligands. With 1,2-diols, the initial displacement of the
apical hydroxy ligand of IBX is expected to produce a 1-(â-
hydroxyalkoxy)-1,2-benziodoxol-3(1H)-one 1-oxide (9).
considered on the basis of electronegativity rules for
hypervalent compounds23 and a number of X-ray crystal-
lographic studies on related species.2b,24 Two important
factors are expected to influence the chemical shift of the
probe protons upon complex formation: (1) the magnetic
anisotropy of the benzene ring and (2) the iodoxylation
shift, analogous to the well-known acylation shift of
alcohols.25 If the alkoxy ligand resides in the aryl
deshielding region, as in 5a x adducts as well as in axial
(22) Although a 10-I-4 hypervalent species with an apical oxide
ligand has been isolated and fully characterized,2b this structural
feature is expected to introduce significant destabilization. Calculations
on trigonal bipyramidal 10-P-5 phosphorane oxide anions showed the
isomer with an apical oxide ligand to be 15.5 kcal/mol less stable than
the isomer with an equatorial oxide ligand. See: Deakyne, C. A.; Allen,
L. C. J . Am. Chem. Soc. 1976, 98, 4076 and references therein.
(23) (a) Gorenstein, D.; Westheimer, F. M. J . Am. Chem. Soc. 1970,
92, 634. (b) Gorenstein D. J . Am. Chem. Soc. 1970, 92, 644. (c) Musher
J . I. Angew. Chem., Int. Ed. Engl. 1969, 8, 54.
(24) For 10-I-4 species, see: (a) Viess, W. J .; Baird, H. W. Chem.
Commun. 1967, 1903. (b) Gilbert, D. D. Nucl. Sci. Abstr. 1973, 28,
26892. (c) Dess, D. B.; Wilson, S. R.; Martin, J . C. J . Am. Chem. Soc.
1993, 115, 2488. For isostructural 10-S-4, 10-Se-4 and 10-Te-4 species,
see: (d) Perozzi, E.F.; Martin, J . C.; Paul, I. C. J . Am. Chem. Soc. 1974,
96, 6735. (e) Paul, I. C.; Martin, J . C.; Perozzi, E. F. J . Am. Chem.
Soc. 1972, 94, 5010 and references cited therein.
(25) J ackman, L. M.; Sternhell, S. Applications of Nuclear Magnetic
Resonance Spectroscopy in Organic Chemistry, 2nd ed.; Pergamon
Press: Oxford, 1969; p 176.
(26) Aromatic hydrogens held in proximity to an I-O- charge dipole
are strongly deshielded. Dess, D. B.; Wilson, S. R.; Martin, J . C. J .
Am. Chem. Soc. 1993, 115, 2488 and references therein quoted.

9276 J . Org. Chem., Vol. 61, No. 26, 1996
De Munari et al.
Sch em e 3
second reaction pathway is less probable but frequently
observed.28 With 10-I-4 IBX, the oxidation of diols always
proceeds through an open-chain intermediate (9), whose
disproportionation occurs without C-C bond cleavage
and is likely to involve intramolecular abstraction of the
R-hydrogen by the strongly nucleophilic oxide ligand.29
A second, minor reaction pathway is available and
originates cleavage products. Anyway, this is very rarely
active10 and is dominant only in the special case of tert,-
tert-1,2-diols. Reasons why the open-chain 10-I-4 inter-
mediate does not cyclize to a 12-I-5 species are not yet
clear. Possibly, thermodynamic instability of spirobicy-
clic 1,1-dialkoxy-1-hydroxyperiodinanes can account for
the observed behavior.30 In fact, the contemporaneous
presence of two relatively electron-rich ligands (alkoxy
and hydroxy groups) at the terminal sites of the hyper-
valent bond developed in the cyclization is expected to
render the spirobicyclic dialkoxyhydroxyperiodinane 10
much more unstable than 11, where the acetoxy ligand
stabilizes the equatorial hypervalent bond.31
Kin etics of Alcoh ol Oxid a tion s by IBX. As is
clearly evidenced by the reaction mechanism depicted in
Scheme 1, water plays a fundamental role. In fact, the
detectability of intermediate 5a x is strongly dependent
on water concentration, and the inverse dependence of
the observed oxidation rate from [H2O] suggests that the
rate-determining step is the disproportionation of the
IBX-alcoholate adduct.8 Moreover, in the case of oxidiz-
able alcohols, the Keq value was fairly constant ((10%
RSD) during the reaction course, indicating an effectively
fast pre-equilibrium step. This hypothesis is fully sup-
ported by kinetic studies. Using the steady state ap-
proximation (d[5]/dt ) 0),32 alcohol consumption is de-
scribed by
Double coordination may occur by intramolecular reac-
tion of the â-hydroxy group with the electrophilic iodine
atom (Scheme 3). In this event, a 12-I-5 spirobicyclic
periodinane (10) is produced, whose structure closely
resembles the double displacement products observed
upon reaction of DMP with bidentate ligands. The
second step of the complexation pathway was expected
to be facile on the basis of the recognized proclivity of
10-I-4 hypervalent species to obtain a pentacoordinated
state around the iodine atom.27 Comparative analysis of
NMR values presented in Tables 3 and 4 again proved
to be adequate for unraveling the actual situation which
takes place during the oxidation of diols. In spirobicyclic
intermediates of DMP, the relative rigidity of the frame-
work emphasizes chemical shift differences between
diastereotopic atoms or groups (Table 4). Strong dia-
magnetic shielding contributions are expected to play a
particularly significant role for groups, bonded to either
axial or equatorial substituent, above the face of the
aromatic ring, often overwhelming even the strong
contact deshielding contributions for R protons. Con-
versely, groups far away from the aromatic ring should
experience less important diamagnetic contributions.
Reasonably, the apical substituent, which is roughly
coplanar with the aromatic ring, should be the most
downfield-shifted. Moreover, changes in conformation
due primarily to steric interactions with the iodine lone
pair electrons can contribute in altering this qualitative
prediction, as in the case of 1,2-propandiol (Table 4).
If the intermediates observed in IBX oxidation pos-
sessed the 12-I-5 pseudooctahedral structure 10, we
should observe the same pattern of shielding and deshield-
ing effects such as data in Table 4 provide. Indeed,
downfield-shifted values are uniformly observed in Table
3, suggesting that, in the preferred conformation, all the
alkoxy protons are held in the deshielding region of the
benzene ring. This is possible only for monoesterified,
axially bonded diols. In fact, the NMR data reported in
Table 3 compare extremely favorably with the data in
Table 2 (columns 2-4), confirming beyond any doubt the
intermediacy of the 10-I-4 species in IBX oxidation of
diols. In the light of these results, a rationale which
explains the dichotomy observed with 10-I-4 and 12-I-5
species in the oxidation of 1,2-diols is offered, based on
the different architecture of the reactive intermediates
(Scheme 4). With 12-I-5 DMP, reaction with chelating
ligands produces a cyclic iododioxolane (11) with a double
fate. It breaks down to cleavage products, reasonably
via a favored two-electron process, or decomposes with
cleavage of the CR-H bond to oxidation products. This
-d[ROH]/dt ) k2k1[IBX][ROH]/(k-1[H2O] + k2) (1)
At low and equimolar concentrations of reactants (e.g.,
[IBX]0 ≈ [ROH]0 ≈ 0.04 M), in the early stage of the
reaction, we may approximate [H2O] ≈ [H2O]0. Moreover,
in the pre-equilibrium hypothesis, we may neglect k2 in
comparison with k-1[H2O], and consequently eq 1 can be
further rearranged and integrated as follows:
-d[ROH]/[ROH]2 ) k2(Keq/[H2O]0) dt
1/[ROH] - 1/[ROH]0 ) k2(Keq/[H2O]0)t
(2)
(3)
In the presence of a large excess of water (>10 equiv),
the reaction rate is pseudo-second-order, with high
percentages of conversion. This is demonstrated by the
(28) For examples of reactions in which oxidation without cleavage
is the only observed pathway, see: (a) Wary, G.; Faser, R. Can. J .
Chem. 1994, 72, 69. (b) Broka, C. A.; Ruhland, B. J . Org. Chem. 1992,
57, 4888.
(29) The nucleophilic characteristics of oxide ligand are manifested
in the high catalytic activity displayed by hypervalent iodoso and
iodoxy compound in phosphoric and carboxylic esters hydrolysis. (a)
Moss, R. A.; Alwis, K. W.; Shin J . J . Am. Chem. Soc. 1984, 106, 2651.
(b) Moss, R. A.; Alwis, K. W.; Bizzigotti, G. O. J . Am. Chem. Soc. 1983,
105, 681. (c) Katritzky, A. R.; Duell, B. L.; Durst, H. D.; Knier, B. L. J .
Org. Chem. 1988, 53, 3972.
(30) A series of exploratory experiments indicates also the possibility
of interaction of DMSO molecules with the hypervalent iodine. This
can contribute in stabilizing the open-chain adduct. Nucleophilic
stabilization of hypervalent compounds by solvent molecules has been
frequently observed: (a) Yamamoto, Y.; Chen, X.; Akiba, K. J . Am.
Chem. Soc. 1995, 117, 7906. (b) Yamamoto, Y.; Chen, X.; Kojima, S.;
Ohdoi, K.; Kitano, M.; Akiba, K. J . Am. Chem. Soc. 1995, 117, 3922.
(c) Kawakami, T.; Sugimoto, T.; Shibata, I.; Baba, A.; Matsuda, M.;
Sonoda, N. J . Org. Chem. 1995, 60, 2677 and references therein.
(27) In IBX and related species, intermolecular contacts (secondary
bonds) have been shown to be strongly operative either in the solid
state or in solution, leading to dimeric or polymeric structures. IBX is
essentially pentacoordinated in the solid state, see: (a) Gougoutas, J .
Z. Cryst. Struct. Commun. 1981, 10, 489. Dimer formation in aceto-
nitrile solutions has been observed for 3.2b Aggregation phenomena
have been suggested for 4 in CDCl3 solutions.2d

Hypervalent Iodine Oxidants
J . Org. Chem., Vol. 61, No. 26, 1996 9277
linearity of the plot 1/[ROH] vs time, as exemplified in
Figures 1 and 2 for i-PrOH and PhCH2OH, respectively.
K
eq and k2 values reported in Table 1 were obtained from
kinetic runs carried out under experimental conditions
where the initial concentration of the intermediate is in
the order of 1% of reactants and monitoring the oxidation
reaction within 3% conversion (see the Experimental
Section). Good linear relationships were obtained upon
plotting the reciprocal of alcohol concentration as a
function of the variable (Keq/[H2O]0)t. Fitting the data
to eq 3 gave directly the rate constant values k2. The
observed influence of steric hindrance in determining the
acceleration of the intermediate decomposition can be
interpreted, as already suggested in the literature for the
chromic acid oxidation of secondary alcohols,33 either as
the result of steric strain relief in the transition state or
in terms of a preferred conformation about the I-OR
bond that favors the intramolecular abstraction of the
R-protons by the equatorial oxide ligand. This effect is
evident in the case of 2,4-dimethyl-3-pentanol (Table 1,
entry 6), which is oxidized faster than ethanol in a
competitive experiment, in spite of its lower Keq value
(relative observed oxidation rate, ca. 1.6).
F igu r e 1. Pseudo-second-order plot for the oxidation of
isopropyl alcohol with IBX ([i-PrOH] ) [2] ) 0.045 M in
DMSO-d6; [H2O] 0.51 M). The reaction was monitored during
16 h (48% conversion). Solid line is from linear regression
analysis (see text).
Kin etics of Ben zyl Alcoh ol Oxid a tion by IBX. In
the case of benzyl alcohol, the assumption k2 ,k-1[H2O]
is no more valid in the reaction conditions described
above, as demonstrated by the nonlinear dependence of
the kobs on [H2O] (Figure 3). The observed oxidation rate
for PhCH2OH is much larger than that for simple
(31) Significantly, the decomposition of the pinacolate complex of
DMP is catalyzed by the addition of 1 equiv of alcohol. This is believed
to form unstable trialkoxyperiodinanes, which decompose by a dis-
sociative mechanism to periodonium ions and then to oxidation
products.2b A very recent paper discloses the tendency of the 12-I-5
trihydroxyperiodinane 12, pseudooctahedral in the solid state, to lose
one molecule of water when dissolved in CDCl3. This process restores
the 10-I-4 structure and hence the observed stereogenicity of the iodine
atom. See: Stickley, S. H.; Martin, J . C. Tetrahedron Lett. 1995, 36,
9117.
F igu r e 2. Typical pseudo-second-order plot for the oxidation
of benzyl alcohol with IBX ([PhCH2OH] ) [2] ) 0.052 M in
DMSO-d6; [H2O] 1.45 M). The reaction was monitored during
1.25 h (53% conversion). Solid line is from linear regression
analysis (see text).
aliphatic alcohols, and the pre-equilibrium is not attained
at low relative concentration of water. In fact, very low
percentages (ca. 0.5%, ∆δ +0.65) of the intermediate
1
species were observed by H-NMR spectroscopy only in
concentrated solutions ([IBX] ≈ [ROH] ≈ 0.5 M). There-
fore, different tentative experiments had to be carried
out in order to determine the values for the equilibrium
constant Keq and the rate constant k2. Keq was estimated
from a series of single-scan spectra taken at 10 s intervals
from a 0.35 M solution of the reactants in DMSO-d6
containing 2M H2O.34 A value of Keq ) 0.027 was
obtained (0.4% of iodic ester intermediate).
On a similar basis, the contrasting reactivity of aryltrialkoxysulfurane
13 and diaryldilakoxysulfurane 14 is primarily a reflection of ligands’
electronic characteristics. Thus, while spirobicyclic 10-S-4 sulfuranes,
possessing an apical, strongly electron-withdrawing bis(trifluorometh-
yl)alkoxyl ligand, obey polarity rules and are easily synthesized from
13 by double ligand exchange (Astrologes, G. W.; Martin, J . C. J . Am.
Chem. Soc. 1977, 99, 4390), 14 does not form a cyclic product with
diols, to avoid the destabilizing influence of an aryl group at the apical
ligand site (Martin, J . C.; Franz, J . A.; Arhart, R. J . J . Am. Chem.
Soc. 1974, 96, 4604).
(32) March, J . Advanced Organic Chemistry, 4th ed.; J ohn Wiley &
Sons: New York, 1992; p 221.
(33) Kwart, H.; Francis, P. S. J . Am. Chem. Soc. 1959, 81, 2116.
At constant [H2O] and equimolar concentrations of
reactants, eq 1 can be solved to give the following

9278 J . Org. Chem., Vol. 61, No. 26, 1996
De Munari et al.
Sch em e 4
has been determined by 1H-NMR spectroscopy. The
initial presence of water is critical for the detectability
of the intermediate species and influences the overall
reaction rate. The opposite outcome in the oxidation of
diols with IBX and DMP is the result of the different
structure of the reactive intermediates (Scheme 4). In
fact, while DMP gives spirobicyclic periodinane adducts
11, IBX binds reversibly with 1,2-diols, originating open-
chain iodic monoesters 9, probably reflecting the different
electronic characteristics of the ligands in the oxidants.
Apart from diols, which strongly stabilize the intermedi-
ate complex, the Keq values calculated for a series of
monodentate aliphatic alcohols demonstrate the low
proclivity of tertiary alcohols toward the esterification
(Keq ≈ 0.002), while steric factors are less clear-cut for
primary and secondary alcohols. Only in the case of the
highly hindered 2,4-dimethyl-3-pentanol was the equi-
librium constant (Keq ) 0.017) significantly lower than
the values obtained for less hindered alcohols (ca. 0.04).
Apart from benzyl alcohol, in which the electronic influ-
ence of the aromatic group is largely predominant (k2 )
0.234 s-1), the opposite trend is observed for the dispro-
portionation constants k2 (e.g., 0.022 vs 0.005 s-1 for 2,4-
dimethyl-3-pentanol and isopropyl alcohol, respectively).
The overall observed oxidation rate is thus a balance of
these effects. Therefore, attention must be used in
foreseeing and interpreting the relative oxidation rates
in polyalcohols.
F igu r e 3. Dependence of kobs (M-1 s-1) on [H2O] (M-1) for the
oxidation of benzyl alcohol with IBX (ca. 0.04 M). Solid line is
from nonlinear regression analysis (see text).
equations:
1/[ROH] - 1/[ROH]0 ) kobs
t
(4)
(5)
Exp er im en ta l Section
kobs ) k2k1/(k-1[H2O] + k2)
Ca u tion ! IBX has been reported to detonate upon heavy
impact or heating over 200 °C.35 Dess and Martin reported2b
that heating and striking IBX with a hammer did not cause
any detonation, and in our hands,6 using IBX at temperatures
between 20 and 70 °C, no hazard has been experienced.
To calculate values of the rate constants, a series of
kinetic runs were carried out, varying the concentration
of water in the range 0.2-2.7 M (for an example, see
Figure 2). The concentration of reactants used was ca.
0.04 M. Nonlinear least-squares fitting of the experi-
Gen er a l. IBX was prepared according to the reported
method.2b Its purity was 93%, the remaining part being IBA36
(1H-NMR). DMP was prepared as described in ref 2d. DMSO-
d6 (CIL, Cambridge Isotope Laboratories) was distilled under
reduced pressure prior to use and stored over activated
molecular sieves (residual water, 0.134 M, Karl Fisher deter-
mination). CDCl3 (CIL) was distilled from anhydrous K2CO3
and stored over activated molecular sieves (ca. 3 mM residual
water). Mesitylene was present in both cases at 0.05 M
concentration as an internal standard. 1H- (13C-)NMR spectra
were recorded at 300.13 (75.39) MHz in DMSO-d6 solutions,
using DMSO-d5 (-d6) as internal referencing for chemical shifts
mental data to eq 12, using the value Keq ) k1/k-1
)
0.027, gave the following result: k1 ) 0.069, k2 ) 0.234
(Figure 3). Therefore, the disproportionation of the iodic
ester 5 derived from IBX and benzyl alcohol is about 40
times faster than in the case of simple aliphatic alcohols
and 10 times faster than the decomposition of the adduct
obtained from 2,4-dimethyl-3-pentanol.
Con clu sion s
1
(δ 3.49 for H, δC 39.5 for 13C). Elemental analyses and water
We have shown that the oxidation reaction of alcohols
by IBX is well described by a two-step mechanism, the
first of which is a fast pre-equilibrium, at least in the
case of electronically unactivated alcohols, and produces
transient axial 10-I-4 iodic esters 5a x, whose structure
(Karl Fisher) determination were carried out by Redox, Co-
logno Monzese (Milano, Italy).
(35) Plumb, J .; Harper, D. J . Chem. Eng. News 1990, J ul 16, 3.
(36) Alcohols react reversibly also with IBA to form an alkoxyiodi-
nane. This second equilibrium is characterized by a very slow onset
rate (.12 h for 0.04 M solutions in DMSO-d6) and can be neglected in
the experimental conditions adopted for the kinetic experiments herein
described.
(34) Water concentration was increased until the intermediate signal
became constant. These experimental conditions were the result of a
compromise between sensitivity and pre-equilibrium condition.

Hypervalent Iodine Oxidants
J . Org. Chem., Vol. 61, No. 26, 1996 9279
In ter m ed ia tes Detection . In a typical experiment, 1
equiv of alcohol was added via microsyringe to a 0.2 M solution
of IBX in DMSO-d6 (or 0.8 equiv of alcohol to a 0.1 M solution
of DMP in CDCl3). 1H-NMR spectroscopy was used to monitor
formation of intermediates and oxidation products within the
first minute of the reaction. However, DMP-diolate adducts
are much more stable and long-lasting species (for example,
DMP-trans-1,2-cyclohexanediol adduct is still present in more
than 50% yield after 18 h at room temperature).
tion of the various species [i] was obtained as follows: [i] )
fiAi[std]/Astd, where [i] ) [5], [OX], [IBX]; [std] ) 0.05 M
mesitylene; [OX] is the oxidation product; Ai is the NMR
integral value for 1H of the corresponding molecule; fi is the
relative correction factor for the area value Ai, obtained from
a separate experiment with a long relaxation delay (60 s) and
used to take into account the difference in relaxation times
between the peak of interest and the signal of the internal
standard (mesitylene aromatic hydrogens). The equilibrium
constants for oxidizable alcohols were calculated at each point
Kin etic Mea su r em en ts. All of the oxidation reactions
were followed by monitoring the signal intensities by 1H-NMR
spectroscopy, i.e., the aldehyde proton in the case of primary
alcohols and a suitable methyl group for the secondary ones.
The oxidation products were unambiguously identified at the
end of the reactions by comparison with the spectra obtained
from authentic materials. In a typical kinetic experiment, 7
mg of IBX (93%, 0.023 mmol) was dissolved in 0.5 mL of
DMSO-d6 containing 0.025 of mmol mesitylene and 0.067
mmol of H2O; 1 equiv of alcohol (neat or DMSO-d6 solution)
was then added in the NMR tube via microsyringe. After the
usual lock and field homogeneity optimization procedures
(usually 30-40 s), a series of 21 spectra was automatically
registered every 28 s with the following parameters: 10 scans
were collected for each spectrum (number of points, SI ) 16K;
acquisition time, AQ ) 2.015 s; spectral width, SW ) 4065
Hz; relaxation delay, RD ) 0 s). NMR data were transferred
via NMRLINK to a 486 PC and analyzed with the WIN-NMR
Bruker software. The FIDs were weighed for higher signal-
to-noise ratio (LB ) 0.5) and Fourier transformed, and the
resulting spectra were manually integrated with the tangential
baseline option after suitable phase correction. The concentra-
of the kinetic experiment from the following formula: Keq
)
([5][H2O])/([IBX][ROH]), where [ROH] ) [ROH]0 - [5] - [OX].
The actual concentration of water was calculated taking into
account the initial water content of DMSO-d6 and that formed
during the oxidation reaction, i.e., [H2O] ) [H2O]0 + [5] + [OX];
[H2O]0 ) 0.134 M. Statistical calculations and curve fitting
were carried out with the Statistica program, Statsoft.
Ack n ow led gm en t. Appreciation is expressed to
Mrs. Simona Sputore for preparing batches of Dess-
Martin periodinane and to Dr. Piero Melloni for sup-
porting this work.
1
Su p p or tin g In for m a tion Ava ila ble: Copies of H-NMR
spectra (300 MHz) of IBX and DMP complexes discussed in
Tables 2-4 (30 pages). This material is contained in libraries
on microfiche, immediately follows this article in the microfilm
version of the journal, and can be ordered from the ACS; see
any current masthead page for ordering information.
J O961044M