Aliphatic C-H Bond Iodination by a N-Iodoamide and Isolation of an Elusive N-Amidyl Radical

Article abstract of DOI:10.1021/acs.joc.7b00557

Contrary to C-H chlorination and bromination, the direct iodination of alkanes represents a great challenge. We reveal a new N-iodoamide that is capable of a direct and efficient C-H bond iodination of various cyclic and acyclic alkanes providing iodoalkanes in good yields. This is the first use of N-iodoamide for C-H bond iodination. The method also works well for benzylic C-H bonds, thereby constituting the missing version of the Wohl-Ziegler iodination reaction. Mechanistic details were elucidated by DFT computations, and the N-centered radical derived from the used N-iodoamide, which is the key intermediate in this process, was matrix-isolated in a solid argon matrix and characterized by UV-vis as well as IR spectroscopy.

Full text of DOI:10.1021/acs.joc.7b00557

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Article
Aliphatic C–H Bond Iodination by a N-Iodoamide
and Isolation of Elusive N-amidyl Radical
Alexander Artaryan, Artur Mardyukov, Kseniya Kulbitski, Idan Avigdori,
Gennady A. Nisnevich, Peter R. Schreiner, and Mark Gandelman
J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 08 May 2017
Downloaded from http://pubs.acs.org on May 8, 2017
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The Journal of Organic Chemistry
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Aliphatic C–H Bond Iodination by a N-Iodoamide and Isolation of
Elusive N-amidyl Radical
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Alexander Artaryan§, Artur Mardyukov†, Kseniya Kulbitski§, Idan Avigdori§, Gennady A.
Nisnevich§, Peter R. Schreiner,*, † and Mark Gandelman*,§
§Schulich Faculty of Chemistry, Technion-Israel Institute of Technology, Technion City, Haifa 32000, Israel
†Institute of Organic Chemistry, Justus-Liebig University, Heinrich-Buff-Ring 17, 35392 Giessen, Germany
ABSTRACT: Contrary to C–H chlorination and bromination, the direct iodination of alkanes represents a great challenge.
We reveal a new N-iodoamide which capable of a direct and efficient C–H bond iodination of various cyclic and acyclic
alkanes providing iodoalkanes in good yields. This is the first use of N-iodoamide for C–H bond iodination. The method also
works well for benzylic C–H bonds, thereby constituting the missing version of Wohl-Ziegler iodination reaction.
Mechanistic details were elucidated by DFT computations, and the N-centered radical derived from the used N-iodoamide,
which is the key intermediate in this process, was matrix-isolated in solid argon matrix and characterized by UV-Vis as well
as IR spectroscopy.
Scheme 2. A proposed mechanistic pathway and
relevant bond dissociation energies.
INTRODUCTION
Alkyl halides are some of the most important starting
materials in synthetic chemistry. Among them, alkyl
iodides are especially valuable as substrates for
subsequent functionalizations as they possess the weakest
carbon–halogen bonds. The most attractive synthetic
route to these compounds is the direct C–H bond
functionalization of unactivated hydrocarbons. While
direct halogenations with molecular fluorine through
bromine are well established, the corresponding
iodination is thermodynamically unfavorable.4 Moreover,
iodine-carbon bonds can be easily cleaved thermally or
photochemically, which puts substantial limitations on the
#
1
2
3
4
5
6
Bond type
C–H (sp3)
C–I (sp3)
BDE(avg.) kcal mol–1
98.71
reaction conditions for direct C–H bond iodinations.5
Several existing methods for the direct C–H bond
iodination are based on the use of strongly electrophilic
radicals instead of I-radicals.6-11 A serious limitation in the
reaction with iodine is that the formed hydrogen iodide
can reduce alkyl iodides back to the corresponding alkanes
56.51
56.82
43.5a
54.6a
N–I (NIS)
N–I (1-ITMH, 1)
N–I (3-ITMH)
N–H (succinimide)
because there is
formation of a strong bond between hydrogen and its
radical abstractor. The most significant iodination
a significant driving force for the
118.03
methods known to date are presented in Scheme 1.
aComputed at M06-2X/6-311G(d,p).
Scheme 1. Existing iodination methods (a)-(c), and the
approach pursued in this work.
The first radical iodination method and its modifications
employed tert-butyl hypoiodite (Scheme 1a), which is
highly unstable and must be prepared in situ.10 In an
alternative approach the propensity of perfluoroalkyl
radicals for hydrogen atom abstraction from
hydrocarbons12 was utilized.13
The reaction conditions require a mixture of the t-butyl
hydroperoxide/iron(III) redox system and perfluoroalkyl
iodide in hot acetic acid (Scheme 1b).
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Scheme 3. Optimization of the reaction conditions.
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1
2
3
4
5
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9
Yield %a,b
#
Conditions
“N–I”
1 h
3
2 h
4
1
2
neat
neat
5
3
7
8
6
4
1
1
1
1
1
1
1
1
1
1
1
9
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4
3
neat
4
4
neat
0
0
5
neat
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1
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6
neat
1
7
neat
86
85
-
86
81
8
8
neat – air
neat – dark
neat – H2Oc
CCl4
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10
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17
58
45
33
41
48
9
25
56
46
33
40
44
9
PhH
PhCl
PhF
PhCF3
CH2Cl2
DCE
0
3
aGC yield; Yields are calculated with respect to N-Iodoamide; 10% mol
b
c
H2O relative to 1
One of us developed a method in which the direct
iodination of alkanes is achieved in the absence of strong
oxidating agents. Thus, aliphatic hydrocarbons are
known Wohl-Ziegler reaction. Our mechanistic and
spectroscopic studies support the formation of an N-
centered radical derived from 1 as the key species in this
process. This hitherto elusive N-amidyl radical was
isolated in an argon matrix and characterized by IR and UV
analyses.
converted to the corresponding iodoalkanes upon reaction
with CHI3 (which provides the chain carrier species CI4
next to CH2I2 via disproportionation in situ) and solid
sodium hydroxide in a heterogeneous two-phase system
(Scheme 1c).14-16 While this reaction is useful and
operationally very simple and broadly applicable to
alkanes, iodination of benzylic positions (Wohl-Ziegler
reaction) proved unsuccessful. As such, methods for the
direct C–H iodination are still rare,17 and the development
of efficient synthetic approaches represents a formidable
challenge.
RESULTS AND DISCUSSION
Recently, we developed an efficient iododecarboxylation
utilizing DIH or NIS as both the radical initiator and the
iodine source.22 It was assumed that the in situ formed N-
centered radical homolytically cleaves the strong O–H
bond of the carboxylic acid group (BDE(AcO–H)) = 112.0
kcal mol–1;1 BDE = bond dissociation energy) as a key step
in the reaction. We sought to apply this idea to the radical
iodination of alkanes with N–I amides, as the average
BDEs for their C–H bonds are similar to those of O–H-
bonds in carboxylic acids [BDE(C–H)avg.= 98.7 kcal mol–1].1
A plausible radical chain reaction is depicted in Scheme 2.
Presumably, the thermodynamic driving force for this
process is the weaker N–I bond in the iodo-amide as
compared to the newly formed C–I bond of the product.
Contrary to NCS, NBS, and their derivatives, the BDE in NIS
is not compensated for by the formation of the alkyl
iodide. Indeed, our attempts to iodinate cyclohexane with
NIS resulted in very low yield of the desired product
(Scheme 3, entry 1). In an attempt to overcome this
problem, we searched for an iodoamide with an N–I BDE
lower than in NIS. We proposed that DIH could be a good
candidate for this reaction since its N–I BDEs are
considerably lower (38.1 kcal mol–1 for N1 and 48.7 kcal
mol–1 for N3).2 However, DIH proved inefficient for the
In this paper we describe
a novel, efficient, and
operationally convenient method for the iodination of
hydrocarbons with the single new reagent 1-iodo-3,5,5-
trimethylhydantoin (1-ITMH, 1),18 which is the only N-
Iodoamide that effectively enabled this transformation.
Remarkably, while the direct chlorination or bromination
of alkanes by N-bromo or chloro amides are well-
documented,19-21 the corresponding C–H iodination has not
been reported. Reagent 1, which fills this missing link,
behaves as both a powerful radical initiator and an iodine
donor. Our reagent can readily be prepared and, contrary
to some other iodoamides (e.g., 1,3-diiodo-5,5-
dimethylhydantoin (DIH, 3)), is quite stable and shows
good solubility in organic solvents. Reagent 1 is capable of
iodinating the C–H bonds in various cyclic and acyclic
alkanes. Moreover, 1 allows the direct conversion of
benzylic C–H bonds to the benzyl iodides, thus,
accomplishing the missing iodine-version of the well-
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Table 1. Iodination of some aliphatic hydrocarbons with 1.a
1
2
3
4
5
6
7
8
9
Time
[h]
#
1
Substrate
Product(s)
Yield %b
60c,f
2
1
2
3
4
62
60
73
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11
12
13
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15
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18
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22
23
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60
1
1
32c,f,g,h
5
1
dr 31:69
70c,f,g
6
7
2
7:35:58
24
59d
48c,e
8
2
9:42:22:27
aReaction conditions: neat, 100 oC, white LED irradiation (400-800 nm, 3W); Yields are calculated with respect to 1-ITMH;
b
cGC yield; dReaction performed with a 250 W incandescent light bulb; Isomer ratio determined by GC; Isomer ratio
determined by 1H NMR spectroscopy; gReaction performed in a closed tube; hReaction in a mixture of substrate with PhCF3 in a
1:1 ratio.
e
f
iodination of cyclohexane furnishing low conversion
(entry 2), which can be rationalized by its low solubility.23
An attempt to perform this reaction in polar solvents like
acetonitrile resulted in no product formation. In looking
commonly used N–I amides were much inferior to 1 in this
iodination process (entries 1–6).
After identifying
1 as an efficient reagent for C–H
iodination, we determined the key factors of this reaction.
The main conclusions are: (1) irradiation is necessary;
carrying out the reaction in the dark results in almost no
product (entry 9); (2) the process can be carried out under
aerobic conditions with no significant decrease in yield
(compare entries 7 and 8); (3) addition of large quantities
of water leads to inferior results, due to hydrolysis of the
N–I bond in 1 (entry 10);24 (4) performing this process in
solvents other than the neat alkane furnishes reduced
yields.
We were pleased to find that numerous alkanes undergo
efficient C–H iodination with our reagent under our
optimized conditions (Table 1). Thus, cycloalkanes can be
selectively converted to their corresponding monoiodo
derivatives in good yields within relatively short reaction
times (entries 1–5). Acyclic alkanes and haloalkanes also
undergo smooth iodination resulting in a mixture of
iodoalkanes, which is typical for radical halogenations
(entries 6–8).
for
a new reagent that could perform an efficient
iodination in non-polar solvents (e.g., alkanes) we decided
to create a more soluble derivative of DIH by replacing the
iodine on the N3 atom by a methyl group to reduce the
molecule’s overall polarity. Hence, we synthesized novel
N–I amide 1, which, indeed, exhibits much better solubility
in alkanes as compared to DIH.
Importantly, our DFT computations reveal that
1
possesses a relatively weak N–I bond of only 43 kcal mol–1
(Scheme 2). Moreover, differential scanning calorimetry
analysis shows significant thermal stability of 1.18 Its
counterpart, 3-ITMH (BDE (N–I) = 54.6 kcal mol–1) was
also prepared for comparison (vide infra).18
Gratifyingly, when 1 was irradiated in neat refluxing
cyclohexane with a 3 W white LED lamp (λ = 400–800 nm)
under N2 atmosphere, the desired iodocyclohexane was
obtained in 86% yield after 2 h (Scheme 3, entry 7). As
expected, 3-ITMH was much less active in this reaction,
and provided as poor a result as NIS (entry 6). Other
Notably, benzylic C–H bonds also can be iodinated with 1.
While bromination or chlorination of these bonds with
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2). The target iodides were obtained in moderate to good
Table 2. Iodine version of the Wohl-Ziegler reaction
1
2
3
4
5
6
7
8
yields within three hours. Even in the case of mesitylene,
where the aromatic ring is strongly activated towards
electrophilic aromatic substitution, the benzylic C–H
iodination product was obtained in 45% yield (entry 5),
together with 41% of 2-iodo-1,3,5-trimethylbenzene.
Note that the isolation of benzylic iodination products
from benzene solution proved to be challenging. Organic
iodides are frequently not the final targets, and are used in
synthesis as substrates for further functionalization via
facile nucleophilic displacement of iodide group.
Yield
%
Yield
9
#
1
Iodide
Ester
b
c
%
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Therefore, the organic iodides can be converted in situ to
the desired compounds followed by isolation. We
exemplified this scenario by in situ conversion of benzyl
iodides, obtained by our method, to the corresponding
42
63
39
58
51
56
benzyl
benzoates
via
facile
reaction
with
tetrabutylammonium benzoate (Table 2).
We were
pleased to find that these organic benzoates can be easily
isolated from these reaction mixtures by column
chromatography with only a slight decrease in product
yield.
We addressed the mechanistic features of this process as
well as the properties of 1 by both experimentally and
computationally. We assumed that, owing to its relatively
2
3
4
54
weak N–Hal bond,
1 readily undergoes N−l bond
homolysis25,26 in the first step of the mechanism (Scheme
2). This leads to formation of an elusive N-centered
radical, which represents a key species for understanding
the iodination reaction described above. We attempted to
isolate such species to examine the feasibility of its
formation and to understand the nature of such N-
centered radicals.
66d
Hioe et al.27 computed the radical stabilization energies
(RSE) for various N-centered radicals and demonstrated
that the attachment of a carbonyl group to the amino
radical significantly destabilizes such species and makes
them much more reactive. The addition of a second
carbonyl group next to the radical center increases the
destabilizing effect by reduction of the resonance
interactions between the carbonyl group and the nitrogen
lone pair.
5
45e
37
6
7
47
45
40
39
The matrix isolated ESR spectra of the succinimidyl and
phthalimidyl as well as the 1,8-naphthalimidyI radicals in
argon matrices have been reported.28,29 The succinimidyl
aReaction conditions: benzene, 120 °C, white LED
b
irradiation (3 W, white LED, 400–800 nm), 3 h; GC yield;
d
cYield of isolated product; In addition 16% of 1-iodo-2,4-
e
dimethylbenzene formed; In addition, 41% of 2-iodo-1,3,5-
trimethylbenzene formed.
NBS or NCS in CCl4 represents the well-known Wohl-
Ziegler reaction, the analogous process with NIS is not
possible due to its endergonicity (BDEs in kcal mol–1 of: N–
I(NIS) = 61.9, PhCH2–I = 46.7).1-3 As such, our process
constitutes the missing iodine-version of the Wohl-Ziegler
reaction that allows the direct preparation of benzyl
iodides with a simple N-haloamide.
While performing this reaction under our optimized
conditions for benzylic C–H bonds (see SI), we found that
the method is broadly applicable to a range of substrates
displaying different electronic and steric properties (Table
Figure 1. (a) IR spectrum of 1-ITMH computed at the M06-
2X/6-311++G(2p,2d) level of theory. (b) IR difference
spectra showing the photochemistry of 1-ITMH upon
irradiation with λ = 366 nm in argon at 10 K. Bands
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pointing downwards assigned to 1-ITMH disappear and
bands pointing upwards assigned 5 and 6 appear after 20
min irradiation time.

Page 5 of 10
The Journal of Organic Chemistry
the formation of 27 and 28 starting from radical 23
1
2
3
4
5
6
7
8
9
10
(Figure 2).
Although it is not clear if this is a photochemical or a hot
ground state reaction, only ground state reactions were
investigated. We suggest that the elusive radical 23,
formed by N–I homolysis of 1, can decompose through
several pathways. The first reaction path implies the
cleavage of the C–N bond in 23 to produce radical 24 via
TS1 (Figure 2). The barrier is 24.5 kcal mol–1 (including
the zero-point vibrational energy correction, ZPVE,
denoted as ∆H0). The other pathway for producing 27
and28 proceed through radical 25, which forms from 23
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23
24
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Figure 2. Energy profile (∆H0) in kcal mol–1 of the reactions
of radical 23 at the M06-2X/6-311++G(2d,2p) level of theory
via TS2 (∆H0 =29.9 kcal mol–1). Subsequent C–C bond
‡
fission to 27 and 28 is accompanied by an activation
barrier (TS4) of 35.7 kcal mol–1. The rearrangement of 23
to 26 is also endothermic by +13.4 kcal mol–1 with
activation barrier of 42.7 kcal mol–1, respectively (M06-
‡
2X/6-311++G(2d,2p), ∆H0 ). However, radical 23 was not
observed in our matrix isolation experiments under
photochemical conditions and we turned our attention to
the thermal generation of 23.
Gratifyingly, radical 23 can be generated by flash vacuum
pyrolysis (FVP) of 1 at 700 °C with subsequent trapping of
the products in solid argon at 10 K (Figure 3a). The
second equally prominent product formed under these
conditions is radical 26, obtained from 23 by
rearrangement via TS3 (Figure 3) in the gas phase. The
computed spectrum of 23 reproduces the experimental
spectrum obtained after FVP experiments well. The most
intense band due to the C=O stretch was observed at 1635
cm–1, which is in good agreement with the unscaled
computed value (1788 cm–1). With the aid of the
computations, the additional intense IR bands of medium
intensity at 1433, 1396, 1300, 1079, 1034, and 984 cm–1
could be assigned to the radical 23 (Table S2). In addition,
the strongest absorption at 1748 cm–1 is attributed to the
C=O stretching vibration in 26, which is in agreement with
its computed IR spectrum (1871 cm–1, Figure 3c).
Moreover, UV irradiation (λ = 366 nm) of the matrix
containing 23 results in the complete disappearance of all
its bands and the simultaneously appearance of a new set
of bands in the region between 2350–2250 cm–1 indicating
complete destruction of the five-membered ring.
Figure 3. IR spectra showing the products of the FVP of 1 in
argon with subsequent trapping in an argon matrix at 10 K:
(a) Spectrum obtained after FVP at 700 °C; (b) Spectrum of 23
computed at M06-2X/6-311++G(2d,2p); (c) Spectrum of 26
computed at M06-2X/6-311++G(2d,2p).
radical and its alkylated analogues have been known to
exist in thermodynamic equilibrium with their ring-
opened isomers.30
Many theoretical investigations
concerning the σ versus π character of the succinimidyl
radical have been reported.30,31 According to recent G3B3
computations, the succinimidyl radical prefers a σ rather
than a π ground state, in which the nitrogen lone pair of
electrons is localized in a π molecular orbital.27
We aimed at generating and spectroscopically identifying
the N-centered radical 23, derived from 1, under
photochemical and thermal conditions. For this goal, we
matrix isolated 23 via high-vacuum flash pyrolysis of 1 in
argon at 10 K. The infrared spectrum of 1 isolated in a
solid argon matrix at 10 K is presented in Figure 1; the
agreement between experimental and computed spectrum
is very good. The matrix containing 1 was irradiated with
monochromatic UV light tuned to specific wavelengths.
Irradiation of the matrix (λ > 366 nm) induced no changes.
However, irradiation at λ = 366 nm resulted in a decrease
of all IR absorptions assigned to 1 and in the formation of
new bands at around 2350–2250 cm–1 that were
attributed to the decomposition products 27 and 28
(Figure 1b).
1.5
6000
4000
2000
0
0.12
0.08
0.04
0.00
290
393
1.0
0.5
0
0
100
300
500
700
900
Excitation Energy / nm
374
(b)
(a)
250
300
350
400
Wavelength / nm
450
500
550
Figure 4. (a) UV/Vis spectrum of 1 in an argon matrix at 10 K.
(b) UV/Vis spectrum obtained after FVP at 700 °C, indicative
of radical 23. Inset: TD-M06-2X/6-311+G(2d,2p) computed
UV/Vis spectrum of 23.
Formation of such isocyanate products could not be ruled
out by comparison with literature data and computed
spectra.32 Therefore, a detailed computational analysis
was undertaken to shed some light onto the mechanism of
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range of 4500−400 cm−1 and a resolution of 0.7 cm−1 and
UV/Vis spectra were recorded with JASCO V-670
1
2
3
4
5
6
7
8
Figure 4 shows the matrix isolated UV/Vis absorption
spectrum of 23 recorded in the 250–800 nm range. The
spectrum reveals a strong absorption band located at λmax
a
spectrophotometer. For the combination of high-vacuum
flash pyrolysis with matrix isolation, we employed a small,
home-built, water-cooled oven, which was directly
connected to the vacuum shroud of the cryostat. The
pyrolysis zone consisted of an empty quartz tube with an
inner diameter of 8 mm, which was resistively heated over
a length of 50 mm by a coaxial wire. The temperature was
monitored with a NiCr−Ni thermocouple. 1-iodo-3,5,5-
trimethylhydantoin (1-ITMH, 1) were evaporated (60 °C)
from a storage bulb into the quartz pyrolysis tube. At a
distance of approximately 50 mm, all pyrolysis products
were co-condensed with a large excess of argon (typically
60−120 mbar from a 2000 mL storage bulb) on the surface
of the matrix window at 11 K Several experiments with
pyrolysis temperatures ranging from 600 to 960 °C were
performed in order to determine the optimal pyrolysis
conditions. A high-pressure mercury lamp (HBO 200,
Osram) with a monochromator (Bausch & Lomb) was used
for irradiation.
=
374 nm.
The absorption band of 23 observed
experimentally is in good agreement with the computed
(TD-M06-2X/6-311++G(2d,2p) value at λmax = 393 nm (f =
0.0234). Upon photolysis using 312 nm light, the broad
absorption at 373 nm disappeared.
According to UM06-2X/6-311++G(2d,2p) computations,
9
2
radical 23 displays a Cs point group with a A” electronic
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ground state. This formally corresponds to the odd
electron being localized in the nitrogen
p orbital
perpendicular to the plane, i.e., in conjugation with the π-
system. However, a hypothetical isodesmic reaction of the
1-IMTH radical with ammonia at 298.15 K (below) gives a
thermoneutral reaction enthalpy (∆H298) at (U)M06-2X/6-
311++G(2d,2p) of only 0.1 kcal mol–1. The stabilization of
23 apparently derives through hyperconjugative
interactions of the unpaired spin with adjacent C–C bonds,
which compensates the potentially destabilizing effect of
the adjacent carbonyl group.
In summary, we established a novel facile and efficient
method for the synthesis of iodoalkanes via direct C–H
bond iodination with the new iodoamide 1. While other
N–I amides proved inefficient in this process, this
iodination fills the “missing link” in C–H halogenations
utilizing N–Hal compounds. A substantial advantage of
this approach is the facile preparation of the new
iodination reagent, its solubility in non-polar solvents, and
its thermal stability. Our mechanistic studies led to the
Computations. All geometries were optimized and
characterized as minima or transition structures by means
of analytical harmonic vibrational frequency computations
at the M06-2X/6-311++G(2d,2p) level of theory (for more
details, refer to the supporting information).34-37 All
computations were performed with the Gaussian09
program.38
Preparation of N-Iodoamides:18
1-Iodo-3,5,5-trimethylhydantoin (1-ITMH, 1): A mixture of
3,5,5-trimethylhydantoin (1.0 g, 7 mmol), PhI(OAc)2 (1.36
g, 4.22 mmol), I2 (1.17 g, 4.57 mmol), and cyclohexane (20
mL) was stirred at rt for 40 h, then cooled to 0 °C and
stirring continued for an additional hour. The precipitated
solid was filtered, washed on the filter with cold
cyclohexane and dried in vacuo to give 1.64 g (88%) of
crystalline 1-ITMH; mp 198-9 °C (dec); 1H NMR (CDCl3, 400
MHz) δ 3.07 (s, 3H, CH3), 1.24 (s, 6H, 2 CH3) ppm; 13C NMR
(CDCl3, 100 MHz) δ 175.1, 156.1, 65.5, 26.4, 24.6 ppm;
HRMS (ESI-TOF) m/z: (M+H)+ calcd for C6H10N2O2I
268.9787, found 268.9773.
3-Iodo-1,5,5-trimethylhydantoin (3-ITMH, 4): A mixture of
1,5,5-trimethylhydantoin (1.0 g, 7.0 mmol), PhI(OAc)2 (1.4
g, 4.2 mmol), I2 (1.2 g, 4.6 mmol) and MeCN (10 mL) was
stirred at rt for 5 h and then concentrated in vacuo. CCl4
(10 mL) was added to the residue and the obtained
mixture was stirred for 15 min at rt and 1 h at 0 to 5 °C.
The precipitated solid was filtered, washed on the filter
with cold CCl4 and dried in vacuo to give 1.84 g (98%) of
crystalline 3-ITMH; mp 213-4 °C (dec); 1H NMR (CDCl3, 400
MHz) δ 2.95 (s, 3H), 1.39 (s, 6H) ppm; 13C NMR (CDCl3, 100
MHz) δ 178.6, 154.4, 64.2, 26.0, 22.9 ppm; HRMS (ESI-TOF)
m/z: (M+H)+ calcd for C6H10N2O2I 268.9787, found
268.9795.
isolation
and
first
IR-
and
UV-spectroscopic
characterization of the elusive N-radical derived from 1,
which represents the key species of this process.
EXPERIMENTAL SECTION
General Information
Reagents: All reagents and solvents were purchased from
Sigma-Aldrich a part of Merck, Alfa Aesar and Acros
Organics unless specified otherwise and used without
further purification.
Techniques: All reactions were performed under nitrogen
atmosphere. Yields of isolated product refer to products
with more than 95% purity by 1H NMR. Flash column
chromatography was performed employing 63-200 μm
silica gel 60 according to standard techniques.33
Analytical methods: GC analyses were performed on
Shimadzu GC-2010 gas chromatograph with flame
ionization detector (FID) using a 30 m × 0.25 mm Quadrex
capillary column with methyl 5% phenyl silicone
stationary phase, 0.25 μm film thickness. For TLC analysis,
Merck precoated TLC plates (silica gel 60 F-254 on glass
plates, 0.25 mm) were used. NMR spectra were recorded
on a Bruker AV-400 (1H/13C/19F at 400/100/376 MHz).
1
For H and 13C NMR residual solvent peak was used as an
N-Iodophthalimide (7): A mixture of phthalimide (1.00 g,
6.8 mmol), PhI(OAc)2 (1.31 g, 4.1 mmol), I2 (1.12 g, 4.4
mmol), and MeCN (25 mL) was stirred for 6 h, at rt and
concentrated in vacuo. CCl4 (25 mL) was added to the
residue and the obtained mixture was stirred for 15 min at
rt and 1 h at 0 to 5 °C. The precipitated solid was filtered,
washed on the filter with cold CCl4 and dried in vacuo to
internal standard. For 19F NMR spectra the signal of C6F6 (δ
-164.9 ppm) was used as an internal standard.
Matrix Apparatus Design. For the matrix isolation
studies, we used an APD Cryogenics HC-2 cryostat with a
closed-cycle refrigerator system, equipped with an inner
CsI window for IR measurements. Spectra were recorded
with a Bruker IFS 55 FT-IR spectrometer with a spectral
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The Journal of Organic Chemistry
give 1.80 g (97%) of N-iodophthalimide as off-white
reaction mixture was analyzed by GC. The experimental
results are presented in Table 2.
The general procedure for synthesis of benzyl
benzoate derivatives (ArCH2OBz):
1
1
2
3
powder. H NMR (DMSO-d6, 100 MHz) δ 7.82-7.72 (m, 4H)
ppm; 13C NMR (DMSO-d6, 100 MHz) δ 170.7, 133.8, 132.8,
122.8 ppm.
4
5
6
7
8
9
N-Iodo-4-nitrophthalimide (8):
A
mixture of 4-
A mixture of methylarene ArCH3 (7 mL), benzene (28 mL)
and 1-ITMH (0.7 g, 2.61 mmol) was stirred and heated at
120 °C, under 3 W white LED lamp irradiation. After 3 h
the reaction was cooled to the room temperature and
tetrabutylammonium benzoate [NBu4]OBz (0.95 g, 2.61
nitrophthalimide (0.40 g, 2.08 mmol), PhI(OAc)2 (0.40 g,
1.25 mmol), I2 (0.34 g, 1.35 mmol) and MeCN (10 mL) was
stirred (4 h) at rt and concentrated in vacuo. CCl4 (10 mL)
was added to the residue and the obtained mixture was
stirred for 15 min at rt and 1 h at 0 to 5 °C. The
precipitated solid was filtered off, washed on the filter with
cold CCl4 and dried in vacuo to give 0.63 g (100%) of N-
iodo-4-nitrophthalimide. 1H NMR (CD3CN, 400 MHz) δ 8.51
(d, J = 8.8 Hz, 1H), 8.47 (s, 1H) 7.97 (d, J = 8.6 Hz, 1H) ppm;
13C NMR (CD3CN, 100 MHz) δ 169.3, 168.9, 152.3, 138.4,
135.1, 130.0, 125.3, 119.0 ppm; HRMS (APCI-QTOF) m/z:
(M+H2O)+ calcd for C8H5IN2O5 335.9243, found 335.92.40.
Preparation of 3,5,5-trimethylhydantoin:
A mixture of 5,5-dimethylhydantoin (12.8 g, 100 mmol),
MeI (21.3 g, 150 mmol), K2CO3 (20.7 g, 150 mmol) and
acetone (200 mL) was stirred for 16 h, at rt and
concentrated in vacuo. An aqueous solution of the residue
was extracted with CH2Cl2 (3 × 50 mL). Combine organic
extracts were washed with water (50 mL), dried over
Na2SO4, filtered and concentrated in vacuo to give 11.8 g
mmol) was added. After 0.5
h the mixture was
concentrated under reduced pressure and desired
compound was purified by silica gel chromatography
(eluent: gradient CH2Cl2/hexane). The experimental
results are presented in Table 2.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Benzyl benzoate (16b):40 1H NMR (CDCl3, 400 MHz) δ 8.07
(m, 2H), 7.56 (m, 1H), 7.49-7.32 (m, 7H), 5.37 (s, 2H); 13C
NMR CDCl3, 100 MHz) δ 166.4, 136.1, 133.0, 130.2, 129.7,
128.6, 128.4, 128.3, 128.2, 66.7 ppm.
2-Methylbenzyl benzoate (17b):41 1H NMR (CDCl3, 400
MHz) δ 8.07 (m, 2H), 7.56 (m, 1H), 7.43 (m, 3H), 7.2-7.3
(m, 4H), 5.38 (s, 2H), 2.42 (s, 3H); 13C NMR CDCl3, 100
MHz) δ 166.1, 136.9, 133.9, 132.9, 130.3, 130.1, 129.5,
129.1, 128.4, 128.3, 125.9, 65.0, 18.8 ppm.
3-Methylbenzyl benzoate (18b):41 1H NMR (CDCl3, 400
MHz) δ 8.1 (m, 2H), 7.56 (m, 1H), 7.44 (m, 2H), 7.28 (m,
3H), 7.17 (m, 1H), 5.34 (s, 2H), 2.38 (s, 3H); 13C NMR CDCl3,
100 MHz) δ 166.2, 138.1, 135.9, 132.9, 130.1, 129.6, 128.9,
128.4, 128.3, 125.2, 66.6, 21.3 ppm.
1
(83%) of 3,5,5-trimethylhydantoin. H NMR δ (CDCl3, 400
MHz) 6.49 (br s, 1H), 3.00 (s, 3H, CH3), 1.43 (s, 6H, 2 CH3)
ppm. 13C NMR δ (CDCl3, 100 MHz) 177.6, 157.0, 59.0, 25.1,
24.7 ppm.
4-Methylbenzyl benzoate (19b):41 1H NMR δ (CDCl3, 400
MHz) 8.24 (m, 2H), 7.63 (m, 1H), 7.55-7.47 (m, 4H), 7.32
(m, 2H), 5.48 (s, 2H), 2.49 (s, 3H); 13C NMR CDCl3, 100
MHz) δ 166.2, 137.8, 133.0, 132.8, 130.2, 129.6, 129.1,
128.23, 128.20, 66.5, 21.1 ppm.
The general procedure for iodination of alkanes:
1-Iodo-3,5,5-trimethylhydantoin (1-ITMH) (0.125g, 0.466
mmol) and 5 mL of alkane were stirred at 120 °C under 3
W white LED lamp irradiation. Than the reaction mixture
was washed with 1 M aq Na2SO3, dried over Na2SO4 and
filtered. The solvent was removed by distillation, and the
residue was purified by chromatography on silica gel
(eluent: pentane). The experimental results are presented
in Table1.
3,5-Dimethylbenzyl benzoate (20b):42 1H NMR (CDCl3, 400
MHz) δ 8.1 (m, 2H), 7.56 (m, 1H), 7.43 (m, 2H), 7.1 (s, 2H),
6.98 (s, 1H), 5.3 (s, 2H), 2.4 (s, 6H); 13C NMR (CDCl3, 100
MHz) δ 166.4, 138.2, 135.9, 133.0, 129.9, 129.7, 128.3,
126.1, 66.8, 21.3 ppm.
Iodocyclohexane (2a)9: 1H NMR (CDCl3, 400 MHz) δ 4.35
(m, 1H), 2.13 (m, 2H), 1.93-1.99 (m, 2H), 1.60-1.70 (m, 3H),
1.30-1.40 (m, 3H) ppm; 13C NMR CDCl3, 100 MHz) δ 39.7,
32.8, 27.4, 25.3 ppm; HRMS (APCI-QTOF) m/z: (M)+ calcd
for C6H11I 209.9906, found 209.9900.
4-Fluorobenzyl benzoate (21b):41 1H NMR (CDCl3, 400
MHz) δ 8.06 (m, 2H), 7.57 (m, 1H), 7.44 (m, 4H), 7.07 (m,
2H), 5.32 (s, 2H); 13C NMR CDCl3, 100 MHz) δ 166.2, 162.6
(d, J = 246.8 Hz), 133.1, 131.9 (d, J = 3.3 Hz), 130.2 (d, J =
8.4 Hz), 130.0, 129.6, 128.4, 115.4 (d, J = 21.7 Hz), 65.9; 19
F
Iodocycloheptane (10a):9 1H NMR (CDCl3, 400 MHz) δ 4.48
(m, 1H), 2.24-2.30 (m, 2H), 2.10-2.20 (m, 2H), 1.52-1.64
(m, 6H), 1.38-1.50 (m, 2H) ppm; 13C NMR CDCl3, 100 MHz)
δ 41.9, 36.0, 27.3, 27.0 ppm; HRMS (ESI-TOF) m/z: (M-H)-
calcd for C7H12I 222.9984, found 222.9982.
(CDCl3, 376 MHz) δ –116.6 ppm.
4-Chlorobenzyl benzoate (22b):41 1H NMR (CDCl3, 400
MHz) δ 8.05 (m, 2H), 7.58 (m, 1H), 7.47 (m, 2H), 7.43-7.35
(m, 4H), 5.32 (s, 2H); 13C NMR (CDCl3, 100 MHz) δ 166.3,
134.6, 134.1, 133.2, 129.9, 129.7, 129.6, 128.8, 128.4, 65.8
ppm.
Iodocyclooctane (11a):39 1H NMR (CDCl3, 400 MHz) δ 4.57
(m, 1H), 2.20-2.23 (m, 4H), 1.40-1.70 (m, 10H) ppm; 13C
NMR CDCl3, 100 MHz) δ 38.2, 37.9, 27.5, 26.7, 25.2 ppm;
HRMS (ESI-TOF) m/z: (M+H)+ 239.0267, C8H16I calc. mass
239.0297.
Preparation of GC standards:
Preparation of alkyl iodides from alcohols was
performed via a known procedure:39
2-Iodohexane (13c)9 was prepared from 2-hexanol with
64% yield. 1H NMR (CDCl3, 400 MHz) δ 4.15 (m, 1H), 1.88
(d, J = 6.9 Hz, 3H), 1.76-1.85 (m, 1H), 1.54-1.62 (m, 1H),
1.23-1.46 (m, 4H), 0.88 (t, J = 7.1 Hz, 3H) ppm; 13C NMR
(CDCl3, 100 MHz) δ 42.7, 31.9, 30.5, 29.0, 21.9, 14.0 ppm.
3-Iodohexane (13b)9 was prepared from 3-hexanol with
67% yield. 1H NMR (CDCl3, 400 MHz) δ 4.06 (m, 1H), 1.70-
1.90 (m, 3H), 1.47-1.66 (m, 2H), 1.30-1.43 (m, 1H), 0.98 (t,
J = 7.2 Hz, 3H), 0.89 (t, J = 7.3 Hz, 3H) ppm; 13C NMR
(CDCl3, 100 MHz) δ 42.4, 42.0, 33.8, 22.8, 14.2, 13.3 ppm.
1,2-Dichloro-1-iodoethane (14a): 1H NMR (CDCl3, 400
MHz) δ 5.71 (dd, J = 8.3, 4.8 Hz, 1H), 4.16 (dd, J = 12.0, 4.8
Hz, 1H), 4.03 (dd, J = 12.0, 8.3 Hz, 1H) ppm; 13C NMR CDCl3,
100 MHz) δ 53.0, 25.7 ppm; HRMS (ESI-TOF) m/z: (M)+
calcd for C2H3Cl2I 223.8650, found 223.8650.
The general procedure for iodination of methylarenes:
A mixture of methylarene ArCH3 (1 mL), benzene (4 mL)
and 1-ITMH (0.10 g, 0.73 mmol) was stirred at 120 °C
under 3 W white LED lamp irradiation during 3 h. The
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1-Chloro-2-iodobutane (15c) was prepared from 1- mmol), DMF (one drop) and CH2Cl2 (5 mL). The obtained
chlorobutan-2-ol with 37% yield. 1H NMR (CDCl3, 400
MHz) δ 4.15-4.24 (m, 1H), 4.03 (dd, J = 11.1, 4.5 Hz, 1H),
3.80 (dd, J = 11.1, 10.3 Hz, 1H), 1.95-2.10 (m, 1H), 1.70-
1.84 (m, 1H), 1.04 (t, J = 7.2 Hz, 3H) ppm; 13C NMR (CDCl3,
100 MHz) δ 49.5, 35.4, 29.7, 13.3 ppm; HRMS (ESI-TOF)
m/z: (M-H)- calcd for C4H7ICl 216.9281, found 216.9269.
1-Chloro-3-iodobutane (15b) was prepared from 4-
chlorobutan-2-ol with 61% yield. 1H NMR (CDCl3, 400
MHz) δ 4.30-4.40 (m, 1H), 3.55-3.75 (m, 2H), 2.20-2.30 (m,
1H), 1.90-2.00 (m, 2H), 1.97 (d, J = 6.9 Hz, 3H) ppm; 13C
NMR (CDCl3, 100 MHz) δ 44.9, 44.8, 28.8, 25.3 ppm.
mixture was stirred overnight at rt, and then treated with
saturated aqueous solution of NH4Cl. The organic fraction
was dried with Na2SO4 and concentrated in vacuo. NaBH4
(0.43 g, 11.4 mmol) was added by small portions to a
stirred solution of the residue in MeOH (5 mL) at 0 °C and
the mixture was stirred (1 h) at rt. Water was added to the
stirred mixture and the product was extracted with Et2O.
The combined organic extracts were dried over Na2SO4,
filtered and concentrated in vacuo. The residue was
purified by chromatography on silica gel (eluent: gradient
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
CH2Cl2/pentane) to give 0.45
chlorobutan-2-ol.
g (73% yield) of 4-
Preparation of alkyl iodides from carboxylic acids was
performed by known procedure:22
4-chlorobutan-2-ol46 1H NMR (CDCl3, 400 MHz) δ 4.05 (m,
1-Chloro-1-iodobutane (15d) was prepared from 2-
1H), 3.67 (m, 2H), 1.88 (m, 2H), 1.24 (d, J = 6.2 Hz, 3H); 13
NMR (CDCl3, 100 MHz) δ 64.8, 41.8, 41.3, 23.3 ppm.
Preparation of 1-chlorobutan-2-ol:
C
1
chloropentanoic acid with 60% yield. H NMR (CDCl3, 400
MHz) δ 5.77 (t, J = 6.3 Hz, 1H), 2.67 (m, 2H), 1.56 (m, 2H),
0.96 (t, J = 7.4 Hz, 3H) ppm; 13C NMR (CDCl3, 100 MHz) δ
48.6, 30.4, 22.2, 12.7 ppm; HRMS (ESI-TOF) m/z: (M-H)-
calcd for C4H7ICl 216.9281, found 216.9269.
The reaction was performed via a known procedure47
from 1,2-epoxybutane giving 20% of corresponding 1-
chlorobutan-2-ol.
A
mixture of 2-exo- (63%) and 2-endo- (37%)
1-chlorobutan-2-ol48 1H NMR (CDCl3, 400 MHz) δ 3.68 (m,
1H), 3.58 (dd, J = 11.1, 3.5 Hz, 1H), 3.44 (dd, J = 11.1, 6.8
Hz, 1H), 2.73 (s, 1H), 1.53 (m, 2H), 0.93 (t, J = 7.5 Hz, 3H)
ppm; 13C NMR (CDCl3, 100 MHz) δ 72.75, 49.9, 27.2, 9.9
ppm.
iodonorbornanes (12a, 12b) was prepared from 2-endo-
norbornanecarboxylic acid with 30% yield. 2-exo-
iodonorbornane:43 1H NMR (CDCl3, 400 MHz) (diagnostic
signal) δ 3.97 ppm. 13C NMR (CDCl3, 100 MHz) δ 48.1, 45.3,
38.1,
36.44,
30.5,
28.9,
28.5
ppm.
2-endo-
iodonorbornane:43 1H NMR (CDCl3, 400 MHz) (diagnostic
signal) δ 4.20 ppm. 13C NMR (CDCl3, 100 MHz) δ 44.9, 43.4,
37.0, 36.37, 32.6, 29.7, 28.6 ppm.
ASSOCIATED CONTENT
The Supporting Information is available free of charge on the
ACS Publications website at DOI:
Supporting information includes spectra of new
compounds (1H NMR, 13C NMR and 19FNMR), tabulated
geometric structure data and electronic energies and
reaction optimization conditions for p-xylene.
Preparation of benzyl iodides from benzyl chlorides or
bromides was performed by known procedure:44
2-Methylbenzyl iodide (17a)7 was prepared from 2-
methylbenzyl chloride with 81% yield. 1H NMR (CDCl3,
400 MHz) δ 7.29 (m, 1H), 7.21-7.11 (m, 3H), 4.45 (s, 2H),
2.34 (s, 3H) ppm; 13C NMR (CDCl3, 100 MHz) δ 136.9,
136.6, 130.9, 129.4, 128.4, 126.5, 19.0, 5.3 ppm.
AUTHOR INFORMATION
Corresponding Author
* E-mail: chmark@tx.technion.ac.il
* E-mail: prs@uni-giessen.de
3-Methylbenzyl iodide (18a)7 was prepared from 3-
methylbenzyl bromide with 76% yield. 1H NMR (CDCl3,
400 MHz) δ 7.19-7.17 (m, 3H), 7.05 (m, 1H), 4.43 (s, 2H),
2.33 (s, 2H) ppm; 13C NMR (CDCl3, 100 MHz) δ 139.2,
138.5, 129.5, 128.79, 128.78, 125.9, 21.4, 6.1 ppm.
4-Methylbenzyl iodide (19a)7 was prepared from 4-
methylbenzyl chloride with 80% yield. 1H NMR (CDCl3,
400 MHz) δ 7.16 (d, J = 8.0 Hz, 2H), 7.00 (d, J = 7.9 Hz, 2H),
4.34 (s, 2H), 2.2 (s, 3H) ppm; 13C NMR (CDCl3, 100 MHz) δ
137.8, 136.4, 129.6, 128.7, 21.3, 6.3 ppm.
ACKNOWLEDGMENT
This research was supported by a grant from the German–
Israeli Project Cooperation (DIP 597/19-1) between M.G. and
P.R.S.
REFERENCES
4-Chlorobenzyl iodide (22a)7 was prepared from 4-
chlorobenzyl chloride acid with 85% yield. 1H NMR (CDCl3,
400 MHz) δ 7.22 (d, J = 8.5 Hz, 2H), 7.18 (d, J = 8.5 Hz, 2H),
4.33 (s, 2H) ppm; 13C NMR (CDCl3, 100 MHz) δ 138.0,
133.7, 130.2, 129.1, 4.3 ppm.
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4-Fluorobenzyl iodide (21a)45 was prepared from 4-
fluorobenzyl chloride with 92% yield. 1H NMR (CDCl3, 400
MHz) δ 7.35 (dd, J = 8.6, 5.3 Hz, 2H), 6.98 (dd, J = 8.6, 8.6
Hz, 2H), 4.44 (s, 2H) ppm; 13C NMR (CDCl3, 100 MHz) δ
162.2 (d, J = 248 Hz), 135.3 (d, J = 3 Hz), 130.6 (d, J = 8 Hz),
115.9 (d, J = 22 Hz), 4.7 ppm; 19F NMR (CDCl3, 376 MHz) δ -
116.7 ppm; HRMS (APSI-QTOF) m/z: (M+K)- calcd for
C7H5FKI 273.9057, found 273.9039.
Preparation of 4-chlorobutan-2-ol:
SOCl2 (0.43 mL, 6.0 mmol) was added dropwise to a
stirred mixture of 4-hydroxybutan-2-one (0.50 g, 5.7
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Chem. Commun. 1997, 1501.
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Eur. J. 2001, 7, 4996.
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