Reactant cum solvent water: Generation of transient λ3-hypervalent iodine, its reactivity, mechanism and broad application

Article abstract of DOI:10.1039/c5ra21932a

An outstanding amidation/imidation process is demonstrated under metal-free benign reaction conditions by grafting terminal alkynes with varied amines and reactant cum solvent water. We explored diverse substrate scope in the nonconventional approach for synthesis of several classes of valuable compounds bearing amide linkages such as N-tosyl, N-aminotosyl, N-oxobenzyl, N-alkylated sugar-based secondary and tertiary chiral amides and also exploiting it for synthesis of valuable cyclic imides through simultaneous activation of triple bond and sp²C-H of aldehyde. The in situ-generated powerful reagent PhI(OH)₂ enables selective cleavage and functionalization of terminal C-C triple bonds through simultaneous construction of C-N and C=O bonds. A measurable breakthrough in time-resolved ATR-MIR spectroscopy of the ongoing λ³-hypervalent iodine controlled reaction revealed formation of the unknown intermediates. The ATR-MIR technology is used for identifying infrared (IR) spectra of the individual intermediate/component present in the reaction mixture, which contains several compounds. The structures of the intermediates and their IR spectra were determined by DFT study. This unprecedented combination of experimental results and theoretical prediction provided useful information regarding the reaction insights such as the cleavage of triple bond, amination and amidation in the complex reaction process involving λ³-hypervalent iodine-bearing labile intermediates to the desired amide. The NMR and labelling (²H and ¹⁸O) studies supported the DFT-IR predicted reaction pathway.

Full text of DOI:10.1039/c5ra21932a

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Reactant cum solvent water: generation of
transient l3-hypervalent iodine, its reactivity,
mechanism and broad application†
Cite this: RSC Adv., 2015, 5, 106633
*
Saikat Khamarui, Rituparna Maiti, Ramij R. Mondal and Dilip K. Maiti
An outstanding amidation/imidation process is demonstrated under metal-free benign reaction conditions
by grafting terminal alkynes with varied amines and reactant cum solvent water. We explored diverse
substrate scope in the nonconventional approach for synthesis of several classes of valuable compounds
bearing amide linkages such as N-tosyl, N-aminotosyl, N-oxobenzyl, N-alkylated sugar-based secondary
and tertiary chiral amides and also exploiting it for synthesis of valuable cyclic imides through
simultaneous activation of triple bond and sp2C–H of aldehyde. The in situ-generated powerful reagent
PhI(OH)2 enables selective cleavage and functionalization of terminal C–C triple bonds through
simultaneous construction of C–N and C]O bonds. A measurable breakthrough in time-resolved ATR-
MIR spectroscopy of the ongoing l3-hypervalent iodine controlled reaction revealed formation of the
unknown intermediates. The ATR-MIR technology is used for identifying infrared (IR) spectra of the
individual intermediate/component present in the reaction mixture, which contains several compounds.
The structures of the intermediates and their IR spectra were determined by DFT study. This
unprecedented combination of experimental results and theoretical prediction provided useful
information regarding the reaction insights such as the cleavage of triple bond, amination and amidation
in the complex reaction process involving l3-hypervalent iodine-bearing labile intermediates to the
desired amide. The NMR and labelling (2H and 18O) studies supported the DFT-IR predicted reaction
pathway.
Received 20th October 2015
Accepted 2nd December 2015
DOI: 10.1039/c5ra21932a
www.rsc.org/advances
transformations8 towards easy access to diverse compounds
especially under benign reaction conditions.3–10 PhI(OAc)2 (ref.
9) and PhIO10 are commercially available inexpensive hyper-
Introduction
Water is one of the important ingredients cum reaction media
for essential biochemical processes. In contrast to the tradi-
tionally used toxic, expensive and volatile organic solvents, the
unique physical and chemical properties of water, environ-
mentally benign nature, large abundance, low cost and easy
product isolation have grown interest for exploiting it as
a universal solvent.1 Water can also be used as a reactant cum
solvent, which found scant application. Recently developed
metal catalyzed splitting of water to hydrogen and oxygen is
interesting.2 It is especially challenging to switch a frequently
used anhydrous reaction such as amidation and imidation into
operationally simple aqueous process using oxygen from reac-
tant water. The l3-hypervalent iodines are attractive for their
easy preparation and application,3 compatibility with water as
a reaction medium,4 fast reaction rate,5 efficient Lewis acid-like
valent iodines. PhI(OAc)2 is converted into polymeric PhIO
under alkaline conditions using strong base such as aqueous
NaOH or KOH.9a However, PhI(OAc)2 may be transformed into
highly reactive PhI(OH)2 under the mild basic conditions, and
its novel chemical properties will be exploited in organic
synthesis. The understanding of reaction insights11 is desirable
to improving the knowledge of new hypervalent iodine chem-
istry, enhancing the reactivity, selectivity and yield of the
desired products. The major obstacle for investigating the
reaction process is the low volatile, thermally labile and tran-
sient nature of the hypervalent iodine and its intermediates. It
is attempted to detect simple hypervalent iodine reagents such
as 4-substituted iodosylbenzene and iodosobenzene by mass
spectrometry.12 Expectantly the labile hypervalent iodines
provided several peaks for ions under the instrumental condi-
tions. Thus, it is practically impossible to identify relatively
large and complex hypervalent iodine intermediates-bearing
organic precursor from the reaction mixture because of their
low volatility, less stability, high reactivity and labile nature
under the experimental conditions. It is desirable to exploit the
in situ-generated new l3-hypervalent iodine reagent under
oxidant,6
catalytic
activity7
and
metal
mediated
Department of Chemistry, University of Calcutta, University College of Science, 92, A.
P. C. Road, Kolkata-700009, India. E-mail: dkmchem@caluniv.ac.in; Fax: +91-33-
2351-9755; Tel: +91-33-2350-9937
† Electronic supplementary information (ESI) available: Experimental procedures,
characterization data, NMR spectra, and DFT le. See DOI: 10.1039/c5ra21932a
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benign reaction conditions to improve the substrate scope
towards diverse syntheses of amides and imides, and also to
identify the involved l3-hypervalent iodine – bearing interme-
diates in the novel unorthodox organic transformations. The
modern Mid-IR13,14 experimental technique of the ongoing
reaction and the theoretical Gaussian approach6,10,15–17 can be
attempted together to overcome this difficulty.
The construction of amides is a fundamental reaction and
oen used in our body for keeping it functioning,18c syntheses of
invaluable natural products (antibacterial MSX 47401, I,
Fig. 1),18e medicinal products,18a agrochemicals,18d catalysts18b
and semiconducting materials for organic electronics.18f The
cyclic imides also revealed a wide range of medicinal properties
(II–VI).19 There are increasing interest on direct synthesis of
amides and imides especially due to their presence in most of
the drugs of pharmaceuticals industry. The traditional
syntheses of amides and imides through dehydrative coupling
of carboxylic acids and amines under strongly heating condi-
tions, microwave irradiation and metal-catalyzed stringent
processes have a very limited substrate scope.20 The usefulness
of the compounds leads to development of several interesting
strategies in recent time such as for amides metal catalyzed
processes,21a–c umpolung approach,21d silatropic switch strat-
egy21e and decarboxylative method,21f and imides by palladium
catalyzed carbonylation with carbon monoxide, amines and
haloarenes,22a–d Rh-catalyzed C–H activated imidation of amide
with CO,22e,f and trans-imidation.22g–j Recently we have commu-
nicated23 a new l3-hypervalent iodine chemistry under basic
reaction conditions for synthesis of amides and ketoesters. In
this article we have explored the wide-spread application,
reactivity and mechanistic study of the transient l3-hypervalent
iodine for graing functionalized-terminal alkynes with several
types of amines and water towards synthesis of important
classes of valuable compounds such as N-tosyl, N-aminotosyl, N-
oxobenzyl, N-alkylated sugar-based secondary and tertiary
chiral amides (7, eqn (i), Scheme 1) under benign reaction
conditions. The scope of the strategy is exploited for synthesis
of valuable cyclic imides through simultaneous activation of
triple bond and sp2C–H of aldehyde (8, eqn (ii)). We have also
executed the DFT-transition states, NMR, and labeling experi-
ments of the new amidation strategy to achieve reaction
insights of the unorthodox processes.
Scheme 1 Application of transient l3-hypervalent iodine.
Experimental
Materials and methods
All reagents were purchased from commercial suppliers and
used without further purication, unless otherwise specied.
Commercially supplied ethyl acetate and petroleum ether were
distilled before use. Dichloromethane (CH2Cl2) and acetonitrile
(MeCN) were dried by distillation over P2O5. Petroleum ether
ꢀ
used in our experiments was in the boiling range of 60–80 C.
Column chromatography was performed on silica gel (60–
120 mesh, 0.120–0.250 mm). Analytical thin layer chromatog-
raphy was performed on 0.25 mm extra hard silica gel plates
with UV254 uorescent indicator. Reported melting points are
uncorrected. 1H NMR and 13C NMR spectra were recorded using
1
300 MHz spectrometers (300 MHz for H and 75 MHz for 13C).
Chemical shi is reported in ppm from internal reference tet-
ramethylsilane and coupling constant in Hz. Proton multiplic-
ities are represented as s (singlet), d (doublet), dd (double
doublet), t (triplet), q (quartet), and m (multiplet). Infrared
spectra were recorded on FT-IR spectrometer in thin lm. HR-
MS data were acquired by electron spray ionization technique
on a Q-Tof-micro quadruple mass spectrophotometer. Optical
rotation of the chiral compounds was measured in a polarim-
eter using standard 10 cm quartz cell in sodium-D lamp at
ambient temperature. Optical purity of the choral amides and
imide were determined by chiral HPLC using normal phase
semipreparative chiral column. MIR-ATR spectroscopy of the
inline reaction was executed by React IR 15 instrument using iC
IR 4.3 soware.
General procedure for amidation
Terminal alkyne (1, 1.0 mmol, 102 mg) and iodobenzene diac-
etate (3.0 mmol, 966 mg) were stirred for 30 min and allowed to
react with aqueous sodium bicarbonate solution (2.1 mmol,
176 mg in 2.0 mL of water) under stirring conditions at ambient
temperature. Aer one hour amine (4, 1.5 mmol) was added in
a drop-wise manner. The reaction was monitored by thin layer
chromatography (TLC). The post-reaction mixture was extracted
with EtOAc (2 ꢁ 15 mL), and the combined organic layer was
washed successively with saturated sodium bicarbonate solu-
tion (1 ꢁ 10 mL) and brine (1 ꢁ 10 mL). It was then dried over
anhydrous Na2SO4, ltered and evaporated in a rotary evapo-
rator under reduced pressure at room temperature. Thus, the
Fig. 1 Amide and imide-bearing bioactive natural products.
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reaction with phenylacetylene (1a, 102 mg, 1.0 mmol) and N-
tosylamine (1.5 mmol, 256 mg) afforded N-tosylbenzamide (7a)
aer purication by column chromatography on silica gel (60–
120 mesh) with ethyl acetate-petroleum ether (1 : 24, v/v) as an
eluent in an yield of 65% (179 mg, 0.65 mmol). The synthesized
amide (7a (ref. 24)) and other compounds were characterized by
means of NMR (1H and 13C), FT-IR and mass (HR-MS) spectral
analyses.
Trapping of intermediate VIII
To a suspension of 2-ethynylbenzaldehyde (3, 1.0 mmol,
130 mg) and iodobenzene diacetate (1.0 mmol, 322 mg) in water
(2.0 mL) sodium bicarbonate (2.0 mmol, 168 mg) was added
and allowed to stir for one hour. n-Benzylamine (6c, 1.5 mmol,
160 mg) was added drop-wise under stirring condition at room
temperature. The reaction was monitored by the thin layer
chromatography (TLC). Aer three hours the reaction mixture
was quenched by addition of NH4Cl and subsequently extracted
with EtOAc (30 mL). The organic layer was washed successively
with saturated sodium bicarbonate solution (1 ꢁ 10 mL) and
brine (1 ꢁ 10 mL). It was dried over anhydrous Na2SO4, ltered
and evaporated in a rotary evaporator under reduced pressure at
room temperature. The intermediate 2-benzyl-3-methylene-2,3-
dihydro-isoindol-1-one (VIII) was isolated aer purication by
column chromatography on silica gel (60–120 mesh) using ethyl
acetate-petroleum ether (1 : 24, v/v) as an eluent in an yield of
50% (120 mg, 0.50 mmol). The synthesized compound (VIII)
was characterized by means of NMR (1H and 13C), FT-IR, Mass
(HR-MS) spectral analysis and comparing with the literature
spectroscopic data.25
Labeling experiment with H2O18
On treatment of phenylacetylene (1a) with n-butylamine (6a) in
presence of sodium bicarbonate and iodobenzene diacetate in
H2O18 (eqn (iii), Scheme 2) for 4 h at room temperature the
desired amide was formed with incorporated O18-isotope (9b). It
was conrmed by performing GC-MS analysis of the post reac-
tion mixture which showed appearance of 179 (9a + 2) for 9b
(ESI†). The peak at 177 indicates formation of 9a by reaction
with the in situ generated H2O.16
Labeling experiment with D2O
A mixture of phenyl acetylene (1a, 1 mmol, 102 mg), n-butyl-
amine (6a, 1 mmol, 73 mg) and iodobenzene diacetate (322 mg)
were allowed to stir for 24 h in D2O to obtain 9c. The post-
reaction mixture was extracted with EtOAc (2 ꢁ 15 mL), and
the combined organic layer was washed successively with dilute
HCl, saturated aqueous sodium bicarbonate solution (1 ꢁ
10 mL) and brine (2 ꢁ 10 mL). It was then dried over anhydrous
Na2SO4, ltered and evaporated in a rotary evaporator under
reduced pressure at room temperature. The product
(PhCOCD2OAc) was isolated and characterized (ESI†) by NMR,
FT-IR and mass spectroscopy (m/z 180.0752).
General procedure for synthesis of imides (8)
To a suspension of 2-ethynylbenzaldehyde (3, 1.0 mmol,
130 mg) and iodobenzene diacetate (4.0 mmol, 1.288 g) in water
(2.0 mL) sodium bicarbonate (3.1 mmol, 260 mg) was added
and allowed to stir for one hour. Primary aliphatic amine
(1.5 mmol) was added drop-wise under stirring condition at
room temperature. The reaction required nine to ten hours to
complete, which was conrmed by TLC monitoring. The post
reaction mixture was extracted with EtOAc (2 ꢁ 15 mL) and the
combined organic layer was washed successively with saturated
sodium bicarbonate solution (1 ꢁ 10 mL) and brine (1 ꢁ 10
mL). It was dried over anhydrous Na2SO4, ltered and evapo-
rated to dryness in a rotary evaporator under reduced pressure
at room temperature. Thus, the reaction with 2-ethynyl benz-
aldehyde (1.0 mmol, 130 mg) and benzylamine (1.5 mmol,
160 mg) afforded 2-benzylisoindole-1,3-dione (8a) which was
isolated aer purication by column chromatography on silica
gel (60–120 mesh) using ethyl acetate-petroleum ether (1 : 24, v/
v) as an eluent in an yield of 65% (154 mg, 0.65 mmol). All
synthesized compounds including 8a (ref. 26) were character-
ized by means of NMR (1H and 13C), FT-IR, Mass (HR-MS)
spectral analysis data (ESI†).
Investigation reaction mechanism by NMR study
The particular amidation reaction with similar composition was
performed in D2O or water and 1H-NMR of the reaction
mixtures were recorded (ESI†). The NMR experiments were
performed using CD3CN as a NMR solvent at different time
intervals and the relevant spectra are uploaded in the ESI.†
Results and discussion
Development of alkyne-amine-water coupling reactions
Simultaneous coupling of N-tosylamine (4a) for C–N and water
for C]O bonds was achieved through graing of phenyl acet-
ylene (1a) using NaHCO3 (2.1 mmol) and PhI(OAc)2 (3 mmol) to
afford directly the primary amide (entry 1, Table 1) equivalent N-
tosylbenzamide (7a, entry 1, Table 2). The amidation reaction
was rapid (3 h) and subsequent SiO2-chromatographic separa-
tion of the post reaction mixture provided the desired product
in 65% yield. To optimize the reaction we have employed
Scheme 2 Labelling experiments.
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Table 1 Optimization of the amidation and imidation reactions
Entry
Hypervalent iodinea
Solventb
Basec
Time (h)
7a/8a, Yieldd (%)
1
2
3
4
5
6
7
8
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
PhIO
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
H2O
H2O
H2O
H2O
H2O
H2O
CH2Cl2
MeCN
MeOH
H2O
NaHCO3
NaOH
K2CO3
KOH
NaHCO3
—
NaHCO3
Na2CO3
Na2CO3
NaHCO3
NaHCO3
NaOH
3
4
10
4
24
48
48
48
48
6
7a, 65
7a, 62
7a, 62
7a, 63
7a, 20
7a, nde
7a, nd
7a, nd
7a, nd
8a, 51
8a, 65
8a, 62
8a, 63
8a, 25
9
10
11
12
13
14
f
PhI(OAc)2
H2O
H2O
H2O
H2O
4
5
5
24
f
PhI(OAc)2
f
PhI(OAc)2
KOH
NaHCO3
PhIOf
a
e
3 mmol. b 2 mL. c 2.1 mmol. d Yield of the isolated product aer column chromatography. Not detected. f 4 mmol.
stronger base NaOH, K2CO3 and KOH and a comparable yield tremendous importance in glycoscience as well as medicinal
was obtained in each experiments (entries 2–4, Table 1). The chemistry. Several types of cyclic imides (8a–e, entries 1–5,
reaction was very slow (20 h) and low yielding (20%) on use of Table 3) and its chiral analogue (8f, entry 6) were synthesized
polymeric PhIO (entry 5). As expected the amidation reaction under the reaction conditions.
was completely arrested in absence of base and water (entries 6–
9). To understand the amidation process by the in situ-gener-
ated hypervalent iodine we have installed one aldehyde group at
ortho-position of the aromatic alkyne (3, eqn (ii), Scheme 1).
Interestingly the sp2C–H of aldehyde was also involved in the
amidation process with phenylethylamine (6a), (entry 10, Table
1) to afford directly a valuable cyclic imide 8a (entry 1, Table 3)
through dual amidation. Initially we applied the similar
reagents and reaction conditions (entry 10, Table 1) and the
desired compound was obtained in a moderate yield (51%). The
yield and reaction time were improved (entry 11) on use of little
excess amount of PhI(OAc)2 (4 mmol). Herein also comparable
yield was obtained on switching the reaction using strong bases
(entries 12 and 13) and the yield was drastically reduced on
employing neutral l3-hypervalent iodine PhIO (entry 14) under
the similar reaction conditions.
Labelling experiment
To understand reaction insight of the new unorthodox process
we rst performed labelling experiments of a relatively simple
amidation (eqn (iii), Scheme 2) using phenyl acetylene (1a) and n-
butylamine (6a) to afford n-butyl benzamide (9a, eqn (iii), Scheme
2) in 4 h. On use of H218O as a reaction medium under basic
conditions a high level of incorporation of 18O into the product 9a
was observed (9b, eqn (iv)), which was isolated, characterized and
conrmed by mass spectrometry (ESI†). In absence of NaHCO3
complete cleavage of the C–C triple bond did not occur in D2O
and eventually produced deuterium incorporated end-product 9c
(eqn (v)) aer a long period of time (ꢂ24 h).
NMR study of the ongoing amidation reaction
On the other hand, the 1H NMR studies of the reaction mixture
in D2O and the precipitated out solid material from water
medium also supported the formation of a complex-adduct
(ESI†), with new broad peaks appearing in the aromatic
region (7.39–8.69 ppm) and simultaneous disappearance of the
spC–H (^C–H; d 3.47 ppm) with progress of time (ꢂ1 h).
Subsequent addition of amine (6a) and breaking of the C–C
bond is expected to have produced the desired amide 9a aer
Substrate scope for amidation and imidation reaction
With the developed synthetic strategy in hand (entry 1, Table 1)
we explored the scope of the metal-free unorthodox synthesis
with substituted alkyne (1b, entry 2, Table 2), which smoothly
produced the desired amide 7b in 3 h. Surprisingly the benign
strategy was also equally efficient for synthesis of valuable
amides bearing N-tosyl amino (7c) and benzyloxy (7d) groups
(entries 3 and 4) in 3.0–3.5 h. We successfully installed sugar-
based 2ꢀ-amine towards synthesis chiral amide 7e with inter-
esting structural features (entry 5). We then turned our atten-
tion to prepare and use the sugar-based alkynes (2a,b entries 6–
8) in the benign approach to afford successfully corresponding
sugar-based chiral amides bearing lipophilic hydrocarbon
chain (7f–h) with good yield (68–75%). The amidation reaction
with water was also validated for amidation of highly polar free-
1
1.5 h. We found a peak at 8.42 ppm in the H NMR and 181.3
ppm in the 13C NMR spectrum, which persisted in the 13C-DEPT
NMR experiment (181.3 ppm, Fig. 2) indicating the existence of
a –CHO bearing byproduct such as sodium formate and/or
PhI(OH)–CHO. PhI was isolated from the post reaction
mixture and characterized.
Inline ATR-MIR spectroscopy
amino sugar (5c, entry 9) with alkyne (1d) towards chemo- With this preliminary observation in hand we have evaluated the
selective benzoylation product 7i. Thus this green strategy has reaction insights of the base-tuned new hypervalent chemistry by
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Table 2 Synthesized amides utilizing alkynes, water and analogues
Entry
Alkyne (1–3)
Amine (4–6)
Product (7)
Time (h)
3.0
Yield (%)
1
TsNH2, 4a
7a, 65
2
4a
3.0
7b, 72
3
4
1a
1a
TsNHNH2, 4b
NH2OBn, 4c
3.0
3.5
7c, 60
7d, 60
5
1a
3.5
7e, 68
6
7
nBuNH2, 6a
3.0
3.0
7f, 75
7g, 75
1a
8
9
Me–(CH3)15–NH2, 4b
4.5
3.5
7h, 68
1b
7i, 60
exploiting time-resolved Mid-IR spectroscopy (React-IR) combined (Fig. 5) and 1 h 31 min 14 s.1 h 35 min 14 s (Fig. 6) were captured.
with ATR (attenuated total reectance) technology, which recently The texture and colour of the reaction mixture changed very
found tremendous application.13,14 To the best of our knowledge quickly to form a uorescent gel-like material (panels A to C,
this is the rst application of ATR-MIR spectroscopy for investi- Fig. 3), which (panel C) was ready for coupling with n-butyl amine
gating insights of a l3-hypervalent iodine reaction. The physical (6a), in 1 h (Fig. 3). Upon addition of 6a the amidation reaction
appearance of the reaction mixture over time (panels A–D, Fig. 3), proceeded quickly. Transformation of the gel-like material to an
solvent-deducted 3D-reaction surface monitored by inline ATR- oily product (9a, Scheme 2) was observed that was deposited in the
Mid-IR (Fig. 4) and combined FT-IR spectra of the reaction reaction container as an oil (panel D).
mixture at selected point of time such as at 2 min, 27 s/40 min, 27 s
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Table 3 Synthesized cyclic imides with 2-ethynylbenzaldehyde (3)
Entry
Amine
Product
Time (h)
Yield (%)
1
9.0
8a, 65
2
3
10.0
9.0
8b, 60
8c, 60
nBuNH2, 6a
Fig.
4
Mid-IR-ATR 3D-surface of amidation reaction. PhI(OAc)2,
alkyne (1a) and water (5 mL) were mixed together and stirred for 30
min, added NaHCO3, and progress of the reaction was monitored
through continuously recording FTIR spectra (3D surface) at room
temperature by insertion of an ATR-MIR probe. n-Butyl amine (6a) was
added after 1 h for initiation of the amidation process towards
generation of desired amide 9a.
4
9.0
8d, 70
5
6
9.0
8e, 64
8f, 61
10.0
Fig. 5 FTIR spectra of the intermediates before adding 6a. (i) FTIR
spectrum of precursor phenyl acetylene (1a) is displayed as blue line.
(ii) FTIR spectrum (red line) of the mixture of alkyne (1a) and PhI(OAc)2
in water was recorded at 2 min 27 s (for intermediate I) (iii) FTIR
spectrum (green line) of reaction mixture with NaHCO3 at 40 min 27 s
revealed formation of intermediate II.
Fig. 2 1H and 13C-NMR spectra of the reaction mixture.
probable intermediate I (Fig. 4) were observed in the 3D reac-
tion surface and captured FTIR spectrum showed intense
characteristic peaks at 1384 cmꢃ1 (2 min 27 s, red line, Fig. 5). It
might be due to generation of a charged-complex species.
Characteristic peaks (2141 and 2051 cmꢃ1, blue line) for a C–C
triple bond of phenyl acetylene disappeared in the red line
(Fig. 5), which conrmed cleavage of the triple bond. Surpris-
ingly the 3D-reaction surface of ATR-Mid-IR was drastically
changed on addition of NaHCO3 into the reaction mixture. The
captured FTIR spectrum at 40 min 27 s revealed generation of
three intense peaks 2010, 1563 and 1365 cmꢃ1 (green line) with
the disappearance of intense peak 1384 cmꢃ1 (red line). It
Fig. 3 Outlook of the reaction mixture with progress of amidation.
The PhI(OAc)2-alkyne (1a) complex is expected to have
formed within 2 min in the water medium (panel A, Fig. 3)
through preactivation of the triple bond. FTIR-peaks of the
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understanding of the correlation between the reactant(s), tran-
sition state and the product(s). The energy prole of the ami-
dation reaction is displayed in panel Fig. 7 and the DFT
optimized structures of the intermediates (Int-II to Int-IV) and
the corresponding transition states (TS-II) in Fig. 8. Results of
DFT calculation reveals that transformation of intermediate II
to IV is very fast, which was observed in the ATR-Mid-IR spec-
troscopy. It is expected that PhI(OAc)2 transformed to transient
PhI(OH)2 rapidly under the mild basic conditions. The highly
reactive PhI(OH)2 is susceptible for dehydration process to
build polymeric PhIO compound.6,10 Herein, under the mild
reaction conditions the in situ-generated PhI(OH)2 rapidly
formed an adduct with the electron rich triple bond of phe-
nylacetylene (Int-I) and was considered as the zero energy in the
energy prole diagram in the Fig. 7. The in situ-generated
hypervalent iodine PhI(OH)2 was added to the terminal of C–C
triple bond via TS-1 with addition of another molecule of
PhI(OH)2 and simultaneous transfer of hydroxyl group to
generate a stable Int-II with the energy barriers +1.141 and
+0.082 kcal molꢃ1. Int-II rapidly transformed into intermediate
Int-IV in presence of the n-butylamine (6a). The successive
energy barriers for the two steps towards formation of the
product 9a were very low (+0.03 kcal molꢃ1). Thus DFT studies
strongly supported formation of the desired amide 9a from the
imine intermediate (Int-IV) in a fast process, which passes
through six-member cyclic transition state TS-5.
Fig. 6 FTIR spectra of the intermediates towards amide 9a. (i) The FTIR
spectra of reactant n-butyl amine (6a) and product amide (9a) are
presented in pink and red dotted line respectively. (ii) FTIR spectrum at
1 h 31 min and 14 s (green line) showed generation of intermediate III.
(iii) The FTIR spectra at 1 h 35 min 14 s displayed appearance of the
desired amide 9a.
clearly indicates that NaHCO3 played a crucial role in replacing
the acetate groups from PhI(OAc)2 with HOꢃ towards formation
of a highly reactive new transient hypervalent iodine PhI(OH)2
leading to immediate construction of another intermediate II
(Fig. 2).
On addition of n-butylamine (6a, pink dotted line) two
intense peaks were observed at 1551 and 1421 cmꢃ1 aer 1 h 31
min 14 s (green line, Fig. 6) due to formation of a new inter-
mediate (IV, Fig. 4). Interestingly break down of the interme-
diate IV into the desired amide 9a was very fast because we
could not identify FTIR spectrum for any other intermediate(s).
React-IR monitoring revealed sharp enhancement of the amide
threshold only aer 4 min (blue line, at 1 h 35 min 14 s) in the
3D energy surface with the characteristic FTIR peaks at 1641
and 1544 cmꢃ1, which were also comparable with the standard
peaks of the authentic amide sample (red dotted line). The 3D
energy surface of the MIR spectroscopy showed that consump-
tion of precursor 6a was very fast as its characteristic threshold
at 822 cmꢃ1 (pink dotted line) was sharply reduced due to
formation of the desired product 9a (eqn (iii), Scheme 2).
DFT-MIR spectroscopy
Inline ATR-Mid-IR spectroscopy is the most emerging tech-
nology to probe reaction mechanism. However, mechanistic
study of a reaction using this modern technology is applicable
only if the structures and FTIR spectra of the intermediates of
the ongoing reaction are known in the literature. Thus, the
immerging technology is not so helpful for a reaction going
through unknown intermediates or forming new types of bonds.
Another problem is the assignment of the FTIR frequencies of
the different bonds, functionalities or groups of the unknown
intermediates. For the rst time we resolved it by watching their
animation mode and correlating the corresponding DFT-IR
peaks (panels G–K, Fig. 5 and 6). In our experiments the char-
acteristic vibrational frequencies obtained from ATR-Mid-IR
spectroscopy were comparable with the theoretical IR frequen-
DFT study for transition states and intermediates
In a continuous effort to study DFT calculation,6,10b,16 we cies of the intermediates Int-II and Int-IV (panels L and N). The
attempted DFT investigation of the fast unorthodox amidation structure of the intermediate Int-II established convincingly
process to determine the probable transition state and inter- through assignment of new bonds such as C–I (entry 1, panels
mediates involved in the reaction. To the best of our knowledge P), two different hydroxyl groups (entries 2 and 6), aromatic and
only a limited number of DFT studies were devoted on metal- alkyne double bonds (entries 3–5). Similarly vibrational
free l3-hypervalent iodine mediated organic trans- frequencies such as C–I, C–N, C]N and C]C (entries 7–11)
formations.6,16,17 Herein, all calculations were carried out with from experimental and theoretical values suggested the struc-
the Gaussian 09 package of programs. The stationary points of ture of the intermediate Int-IV (panel N). Thus, we successfully
the structures were optimized in the gaseous phase using the determined the two important intermediates (Int-II and Int-IV,
LSDA method and LANL2DZ and/or 6-31G basis sets. Vibration Fig. 3) formed in the ongoing unorthodox amidation reaction
analyses were performed to check stable geometries of both the and the possible reaction path by introducing a combination of
structures at ground and transition states. All possible transi- theoretical DFT-IR and modern MIR-ATR technology. However,
tion states were calculated using QST3 model. We executed IRC formation of the desired amide (9a, eqn (iii), Scheme 2) is ex-
transition states calculation for every individual steps for better pected to have undergone through the cyclic transition state TS-4
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Fig. 7 Important transition states intermediates expected to be formed as predicated by DFT calculation(Gaussian 09).
involving C–C cleavage of Int-IV (Fig. 7). We could not nd the corresponding transition states (Fig. 7) in DFT studies also
corresponding DFT-IR peaks of the Int-III in the 3D-reaction strongly support this mechanistic path.
surface (Fig. 3) of the Mid-IR spectroscopy. It indicates that
intermediate Int-III is a very unstable species, which immedi-
Validation through substrate-guided imidation
ately transformed into the relatively stable imine intermediate
Int-IV, which subsequently transformed to the desired product
9a. The low energy barriers (ꢂ1 kcal molꢃ1) found for
Formation of the important intermediate II (Fig. 3 and 7)
bearing the in situ-generated active hypervalent iodine PhI(OH)2
was also veried by installation of an aldehyde group at the
Fig. 8 DFT optimized structures of intermediate II and IV, predicated and experimental IR peaks.
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establishing reaction pathway, hypervalent iodine chemistry for
the nonmetallic activation of various bonds, developing inno-
vative chemistry and robust synthetic strategies for valuable
functionalized molecules, which are signicantly important for
chemical science and green industrial processes.
Acknowledgements
We are thankful to DST, India for nancial supports (project no.
SR/S5/GC-04/2012 and SR/S1/OC-05/2012) and senior research
fellowships (SRF) from CSIR (SK) and UGC (RRM), Govt. of
India.
Scheme 3 Possible mechanistic path for imidation process.
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