Copper-Catalyzed Transfer Hydrodeuteration of Aryl Alkenes with Quantitative Isotopomer Purity Analysis by Molecular Rotational Resonance Spectroscopy

Article abstract of DOI:10.1021/jacs.1c00884

A copper-catalyzed alkene transfer hydrodeuteration reaction that selectively incorporates one hydrogen and one deuterium atom across an aryl alkene is described. The transfer hydrodeuteration protocol is selective across a variety of internal and terminal alkenes and is also demonstrated on an alkene-containing complex natural product analog. Beyond using 1H, 2H, and 13C NMR analysis to measure reaction selectivity, six transfer hydrodeuteration products were analyzed by molecular rotational resonance (MRR) spectroscopy. The application of MRR spectroscopy to the analysis of isotopic impurities in deuteration chemistry is further explored through a measurement methodology that is compatible with high-throughput sample analysis. In the first step, the MRR spectroscopy signatures of all isotopic variants accessible in the reaction chemistry are analyzed using a broadband chirped-pulse Fourier transform microwave spectrometer. With the signatures in hand, measurement scripts are created to quantitatively analyze the sample composition using a commercial cavity enhanced MRR spectrometer. The sample consumption is below 10 mg with analysis times on the order of 10 min using this instrument - both representing order-of-magnitude reduction compared to broadband MRR spectroscopy. To date, these measurements represent the most precise spectroscopic determination of selectivity in a transfer hydrodeuteration reaction and confirm that product regioselectivity ratios of >140:1 are achievable under this mild protocol.

Full text of DOI:10.1021/jacs.1c00884

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Article
Copper-Catalyzed Transfer Hydrodeuteration of Aryl Alkenes with
Quantitative Isotopomer Purity Analysis by Molecular Rotational
Resonance Spectroscopy
Zoua Pa Vang,∥ Albert Reyes,∥ Reilly E. Sonstrom, Martin S. Holdren, Samantha E. Sloane,
Isabella Y. Alansari, Justin L. Neill, Brooks H. Pate, and Joseph R. Clark*
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ABSTRACT: A copper-catalyzed alkene transfer hydrodeuteration
reaction that selectively incorporates one hydrogen and one deuterium
atom across an aryl alkene is described. The transfer hydrodeuteration
protocol is selective across a variety of internal and terminal alkenes
and is also demonstrated on an alkene-containing complex natural
1
2
product analog. Beyond using H, H, and 13C NMR analysis to
measure reaction selectivity, six transfer hydrodeuteration products
were analyzed by molecular rotational resonance (MRR) spectroscopy.
The application of MRR spectroscopy to the analysis of isotopic
impurities in deuteration chemistry is further explored through a
measurement methodology that is compatible with high-throughput
sample analysis. In the first step, the MRR spectroscopy signatures of
all isotopic variants accessible in the reaction chemistry are analyzed using a broadband chirped-pulse Fourier transform microwave
spectrometer. With the signatures in hand, measurement scripts are created to quantitatively analyze the sample composition using a
commercial cavity enhanced MRR spectrometer. The sample consumption is below 10 mg with analysis times on the order of 10
min using this instrumentboth representing order-of-magnitude reduction compared to broadband MRR spectroscopy. To date,
these measurements represent the most precise spectroscopic determination of selectivity in a transfer hydrodeuteration reaction and
confirm that product regioselectivity ratios of >140:1 are achievable under this mild protocol.
efficiently incorporate deuterium into small molecules, but
significant challenges exist to control the quantity and precise
placement of deuterium in a given molecule.27,28 Specific to
making small molecules with one deuterium atom installed at a
benzylic carbon, a general technique to access small molecules
with a benzylic C(sp2)−D bond was recently reported.29
However, to make a small molecule with exactly one benzylic
C(sp3)−D bond, chemists typically use reactions involving
stoichiometric organometallic intermediates.30
The similar physical properties of deuterium relative to
hydrogen further complicate unselective deuteration reactions.
Isotopic mixtures are not only inseparable using common
purification techniques, but common spectroscopic techniques
used to characterize organic compounds are insufficient at
measuring the precise location and quantity of deuterium in
1. INTRODUCTION
Reactions that incorporate deuterium into molecular scaffolds
are of topical relevance to scientists across several disciplines.
Among many applications, deuterated small molecules are used
as standards for high-resolution mass spectrometry1−3 and can
serve as probes to study reaction mechanisms,4,5 perform
kinetic isotope effect experiments,6,7 determine the stereo-
chemical course of microbiological or enzymatic reactions, and
elucidate biosynthetic pathways.8−17 Importantly, deuterated
small molecules are also deployed to alter absorption,
distribution, metabolism, and excretion (ADME) properties
of drug molecules.18,19 Consequently, designing deuterated
bioisosteres to modify the metabolic “soft spots” of small
molecule drugs holds much potential for the development of
safer therapeutics.20−24
Transition metal catalyzed reactions are commonly used to
selectively install oxygen, nitrogen, or carbon functionality into
small molecules.25,26 Mild protocols and modular catalytic
frameworks are often exploited in these reactions to optimize
both reactivity and selectivity. However, highly selective
transition metal catalyzed methods for deuterium incorpo-
ration remain underdeveloped. For example, transition metal
catalyzed hydrogen isotope exchange (HIE) reactions
Received: January 23, 2021
Published: May 17, 2021
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isotopic product mixtures. This can have major implications in
drug discovery, and guidance to address deuterated active
pharmaceutical ingredients (APIs) is being developed for these
spectroscopic and synthetic challenges.31 Ultimately, synthetic
access to deuterated compounds free of isotopic impurities and
analytical methods to identify all isotopic species in a product
mixture will be crucial for developing novel deuterated APIs.
Catalytic transfer hydrogenations represent powerful and
mild methods for the reduction of alkene functionality.32−35
We believe that mechanistically similar catalytic transfer
hydrodeuteration reactions hold much promise for making
selectively deuterated small molecules. Until recently, selective
catalytic hydrodeuteration reactions were rare and usually
employed as mechanistic probes for alkyne semireduc-
tions.36−38 A major challenge in catalytic transfer hydro-
deuteration is discriminating between hydrogen (H) and
deuterium (D) for selective incorporation into alkene
functionality.39,40 Catalytic alkene transfer hydrodeuteration
reactions are now possible on a variety of alkenes.41−45
Transition metal catalyzed transfer hydrodeuteration typically
occurs in a regioselective manner for unactivated terminal
alkenes, but selectivity is generally lower for terminal aryl
alkene substrates (Scheme 1a).41−43 Alternatively, using a
boron catalyst, highly selective installation of deuterium into
activated 1,1-diarylalkenes is possible, but with a limited alkene
scope (Scheme 1b).44,45
reaction optimization. In the presence of catalytic Cu(OAc)2,
dimethoxymethylsilane (DMMS was chosen for the optimiza-
tion studies because it can be easily removed under vacuum
during product purification), and EtOD, we found that
bidentate bisphosphine ligands such as DPPE, DPPF, rac-
BINAP, and DPPBz were not efficient at supporting the
desired transformation (Table 1, entries 1−4). Switching to
a
Table 1. Reaction Optimization
entry
Cu(OAc)2
ligand
D-source
1 (%)
2(%)
b
1
2
3
4
5
6
7
8
9
2 mol %
2 mol %
2 mol %
2 mol %
2 mol %
2 mol %
2 mol %
1 mol %
1 mol %
L1
L2
L3
L4
L5
L5
L5
L5
L5
EtOD
EtOD
EtOD
EtOD
EtOD
MeOD
D2O
69
70
89
47
−
−
−
−
85
69
21
85
90
b
b
b
c
−
c
c
8
c
c
59
−
−
c
IPA-d8
EtOD
c
a
Reactions conducted using 0.2 mmol of substrate. Cu(OAc)2 was
b
used as a 0.2 M solution in THF. Yield was determined by 1H NMR
analysis of the crude reaction mixture, using mesitylene as an internal
standard. Denotes isolated product yield.
c
Scheme 1. Transfer Hydrodeuteration of Alkenes
the more sterically crowded DTB-DPPBz ligand dramatically
affected reactivity, and deuterated aryl alkane 2 was isolated in
85% yield (entry 5). Importantly, evaluation of the product by
2
1H, H, and 13C NMR revealed that one deuterium atom was
incorporated exclusively at the benzylic position (>20:1
regioselective ratio). Varying the deuterium source revealed
that using CH3OD led to a slight decrease in yield (entry 6),
while D2O only led to partial conversion to product 2 (entry
7). Employing 2-propanol-d8 permitted the catalyst loading to
be lowered and was similarly efficient as EtOD (entry 8).
Ultimately, returning to the reaction conditions from entry 5
and decreasing the catalyst loading to 1 mol % was found to be
optimal (entry 9).
With the optimal reaction conditions in hand, we evaluated
the substrate scope of the reaction (Scheme 2). Electron-rich
monosubstituted alkenyl arenes containing oxygen function-
ality performed well in the reaction, and excellent yields of the
desired deuterated products were obtained (Scheme 2a, 4a−
4d, 73−97% yield). Alternatively, an alkenyl arene substituted
with an electron-withdrawing nitro group also underwent
transfer hydrodeuteration to provide the deuterated aryl
alkane, albeit in moderate yield (4e, 47% yield). Nitrogen
substitution is permitted on the alkenyl arene substrate (4f−
4g, 57−97% yield). Importantly, we demonstrated that
polymethylhydrosiloxane could be used instead of DMMS in
the synthesis of 4g. We also found that (4-vinylphenyl)boronic
acid pinacol ester can undergo Cu-catalyzed transfer hydro-
deuteration (4h, 67% yield).
2. REACTION OPTIMIZATION AND SCOPE
Based on insight gleaned from our recently published Cu-
catalyzed regioselective aryl alkyne transfer hydrodeuteration
studies, we hypothesized that a highly regioselective aryl alkene
transfer hydrodeuteration may be possible (Scheme 1c).46 Cu-
catalyzed aryl alkene hydroamination reactions are also
regioselective, and we envisioned the transfer hydrodeuteration
occurring with excellent regioselectivity because of the
thermodynamic favorability of the benzylic copper intermedi-
ate depicted in Scheme 1c.47−51 Under transfer hydro-
deuteration conditions, we reasoned that the H-donor and
D-donor would operate at distinct points during the reaction
and therefore allow for precise insertion of each atom at the
desired location within the aryl alkene.
Accordingly, tert-butyldimethylsilyl-protected (TBS) cin-
namyl alcohol trans-1 was chosen as the aryl alkene for
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analog was deuterated in good yield (4q, 73% yield). Lastly, we
evaluated the transfer hydrodeuteration reaction selectivity for
a 1,1-disubstituted aryl alkene (Scheme 2d). The reaction of 3r
was only moderately selective with deuterium incorporation
favoring the benzylic position (4:1 benzylic:methyl selectivity).
We attribute the moderate selectivity to the demanding steric
environment of this 1,1-disubstituted alkene inhibiting the Cu-
catalyst from approaching the benzylic site.
Scheme 2. Aryl Alkene Transfer Hydrodeuteration
Substrate Scope
The alkenyl arene transfer hydrodeuteration scope was
extended, and the resulting isotopic products were analyzed
using molecular rotational resonance (MRR) spectroscopy
(Scheme 3; see below for analysis details). In addition to a
Scheme 3. Substrate Scope Analyzed by Molecular
Rotational Resonance
a
The major products were 6a−f, the product distribution was
determined by MRR, and the ratio represents the ratio of all products
in the product mixture (6a−f:7a−f:8a−f) after purification.
b
Compound not detected (nd) by 2H NMR or MRR. See Supporting
c
Information (SI) for detection limits. 2 mol % Cu(OAc)2 and 2.2
mol % DTB-DPPBz were used. Transfer hydrodeuteration product
d
a
b
2 mol % Cu(OAc)2 and 2.2 mol % DTB-DPPBz used. IPA-d8 (3
was purified then subjected to TBS deprotection.
c
equiv) used instead of EtOD. Reaction conducted at 5 °C.
d
Polymethylhydrosiloxane (3 equiv) used instead of HSiMe(OMe)2.
e
3 mol % Cu(OAc)2, 3.3 mol % DTB-DPPBz, and HSiMe(OMe)2 (4
equiv) used at 60 °C.
vinyl biphenyl substrate, polyaromatic compounds such as 2-
vinylnaphthalene and 2-methoxy-6-vinylnaphthalene were
readily converted to their corresponding deuterated products
(6a−c, 83−91% yield). Heterocycle-containing aryl alkenes
and an internal alkene were also evaluated under the transfer
hydrodeuteration protocol (6d−6f, 76−86% yield). In all six
examples, the major products (6a−f) were formed in high
yield in a highly regioselective manner. In addition to
providing higher sensitivity measurements for isotopic product
analysis, using MRR to analyze the reaction products depicted
in Scheme 3 further validates our claims that this reaction is
highly regioselective. It removes any ambiguity when analyzing
isotopic product mixtures consisting of isotopologues and
isotopomers that share deuterium substitution at the same
atom, such that several isotopic species contribute to the same
1H/2H resonance in an NMR spectrum. It also precisely
quantifies each regioisomer, even when the d0-species is
present in the product mixture.
Due to their prevalence in bioactive molecules, nitrogen-
and oxygen-containing heterocycles were examined under the
transfer hydrodeuteration protocol.52,53 We found that quino-
line, indole, and azaindole substituted alkenes perform well in
the transfer hydrodeuteration reaction (4i−4k, 54−73% yield).
Alternatively, an alkenyl arene substituted with a morpholine
ring is efficiently converted to the deuterated aryl alkane
product (4l, 80% yield). Internal alkene substrates are also
viable candidates for transfer hydrodeuteration. Cinnamyl
alcohol derivatives were evaluated when the alcohol was
protected with a TBS, benzyl (Bn), or pivaloyl (Piv) group
(Scheme 2b). All three derivatives were deuterated in high
yield (2, 4m−4n, 77−90% yield). Notably, product 2 was
synthesized from the cis-alkene starting material, whereas in
Table 1 it was synthesized from the trans-alkene starting
material. Substitution on the arene is also possible for internal
alkene substrates. A bromine substituted alkenyl arene and
pyridine substituted alkenyl arene underwent transfer hydro-
deuteration in high yield (4o−4p, 77−83% yield). Notably, no
dehalogenation product was observed in the synthesis of 4o.
We also explored the capacity for the Cu-catalyzed transfer
hydrodeuteration to proceed in a complex small molecule
setting (Scheme 2c). Accordingly, a vinyl substituted estrone
To demonstrate the versatility of the reaction, we
hypothesized that flipping the regioselectivity of the reaction
would be possible by simply replacing the Si−H and EtOD
with Si−D and EtOH. This was examined with vinyl biphenyl
substrate 5a (Scheme 4a) and resulted in an 80% yield of
desired product 7a. An increase of the “underdeuterated”
transfer hydrogenation side product 8a was observed in this
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impurity analysis. In MRR spectroscopy, the rotational
spectrum arises through electric-dipole transitions between
the quantized rotational kinetic energy levels of the molecule.54
In the rigid rotor approximation, the energy levels can be
calculated from the three rotational constants (A, B, C) derived
from the moments-of-inertia for rotation about the three
principal rotational axes (IA, IB, IC)
Scheme 4. Reaction Studies
−1
A = (ℏ2/2)IA
(1)
where the moment-of-inertia is calculated from the nuclear
masses and the shortest distance of each nucleus to the
rotation axis.
I =
m r2
∑
A
i Ai
(2)
i
The intensities for the rotational transitions are governed by
the electric dipole moment, and the molecule must be polar to
have a rotational spectrum.
MRR spectroscopy provides measurement solutions for
several of the challenges that have been highlighted for the
analysis of deuterated molecules.31 The important feature of
rotational spectroscopy in this application is that each isotopic
variant has its own unique spectral signature. In particular,
isotopomers have distinct MRR spectra and can be separately
analyzed within a complex mixture.55 By comparison, mass
spectrometry can only analyze the isotopologue composition.
NMR spectroscopy also has limitations and cannot perform
the composition analysis when isoptologues and isotopomers
in the mixture share deuterium substitution at the same atom
such that several isotopic species contribute to the same
1H/2H resonance. MRR spectroscopy has two additional
advantages in this application. First, MRR spectroscopy has
exceptionally high spectral resolution so that spectral overlap is
not an issue even for complex mixtures. Second, the rotational
spectrum for any isotopic variant can be predicted to high
accuracy using the equilibrium geometry obtained from
quantum chemistry so that high-confidence identification of
isotopic species is possible without the need for reference
samples.55−57
For the products depicted in Scheme 3, the rotational
spectrum was measured using a broadband chirped-pulse
Fourier transform microwave (CP-FTMW) spectrometer
operating in the 2−8 GHz frequency range.58−60 The
broadband spectral coverage makes it possible to capture
enough of the rotational spectrum to obtain a highly
characteristic spectral pattern for each isotopic variant of the
analyte present in the sample. The adiabatic expansion of a
dilute mixture of the analyte in neon (0.1% mixture) into the
spectrometer vacuum chamber produces a cold gas with a
rotational temperature of about 1 K. The cooling of the gas
increases the measurement sensitivity through reduction of the
partition function. The reduced Doppler broadening of the
pulsed jet expansion produces a high-resolution spectrum (line
width of about 70 kHz fwhm). This feature is crucial in
isotopologue/isotopomer analysis because it is not possible to
separate the different species by chromatography to simplify
the analysis.61 CP-FTMW instruments have a large linear
dynamic range so that quantitative analysis can be performed
using the spectral transition intensities even for trace
impurities.58
reaction likely because of the reduced deuterium content in the
Si−D reagent.
To probe the chemoselectivity of the reaction, we performed
the transfer hydrodeuteration on a substrate containing both a
1,2-disubstituted styrenyl alkene and 1,1,2-trisubstituted alkene
(Scheme 4b, substrate 9). We were pleased to find the reaction
was not only highly selective for incorporation of deuterium at
the benzylic site of 10 but also chemoselective, as no reduction
of the 1,1,2-trisubstituted alkene was observed. Another
chemoselectivity probe was carried out using substrate 11. In
this case, the chemoselective reaction of an unactivated
terminal alkene was evaluated in the presence of a more
sterically hindered internal alkene. Furthermore, substrate 11
evaluated the potential for an unactivated alkene to undergo
regioselective Cu-catalyzed transfer hydrodeuteration using the
DTB-DPPBz ligand. Isolation of deuterated product 12
revealed that the reaction was highly selective for copper
inserting into the less sterically hindered terminal position of
the terminal alkene, as no reduction of the trisubstituted alkene
was observed. Ongoing studies in our research group are
underway to explore the scope of the Cu-catalyzed alkene
transfer hydrodeuteration for unactivated alkenes. Lastly, we
probed whether the selectivity of the Cu−H insertion into the
alkene occurred with syn- or anti-addition using 1,2,2-
trisubstituted alkene 13. We isolated product ( )-14 in 77%
yield (>20:1 dr) which suggests that syn-addition of the Cu−H
across the alkene is operative (Scheme 4c). Furthermore, this
example also indicates that trisubstituted alkenes are viable
substrates for regioselective transfer hydrodeuteration.
3. SPECTROSCOPIC ANALYSIS OF PRODUCTS
Quantitative Sample Analysis by Molecular Rota-
tional Resonance Spectroscopy − A New Tool for
Deuteration Chemistry. The isotopic composition of the
reaction products depicted in Scheme 3 was analyzed by
molecular rotational resonance (MRR) spectroscopy. The
measurements provide high resolution and specificity for the
analysis of isotopic species and represent the first quantitative
assessment of the MRR spectroscopy technique for deuterated
In the Cu-catalyzed transfer hydrodeuteration reaction, a
possible impurity is the “misdeuterated” reaction product that
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Figure 1. The isotopologue and isotopomer analysis of two of the reaction products is illustrated. Part (a) shows the analysis of the 5-
ethylbenzofuran-d1 sample (6d, 7d, 8d). The first three panels show a 6 MHz window of the rotational spectrum centered on the predicted
transition frequency for the strongest transition in the spectrum (also marked by the vertical red line). The conformers of the d1-methyl isotopomer
give different spectra and the deuteration position for each transition is denoted by the purple colored atom in the structure above the spectral
region. A transition assigned to each isotopomer rotational spectrum is observed and marked by the red dot. The fourth panel is centered on the
observed frequency of the underdeuterated isotopologue. The fifth panel shows the rotational transition for one of the two conformers of the
desired isotopomer of 5-ethylbenzofuran-d1 (note the change in the intensity axis scale). Part (b) shows the same analysis using the strongest
rotational transition of 2-ethylnaphthalene-d1 (7b). In this case, no transitions in the prediction window for the misdeuterated isotopomer can be
assigned to rotational spectra. The lack of detection of any rotational transitions is used to derive the upper limit to misdeuterated 2-
ethylnaphthalene-d1 reported in the SI.
results from deuterium inserting at the homobenzylic position
and hydrogen at the benzylic position (minor product 7 in
Scheme 3). The reaction is also expected to produce
“underdeuterated” reaction product where there is no
deuterium incorporation (minor product 8 in Scheme 3).
This reaction product is expected from the hydrogen
impurities in the alcohol-OD or trace H2O in the alkenyl
arene substrate, silane, and alcohol-OD. An overview of the
MRR analysis for two of the reaction products is shown in
Figure 1. The top panel of images shows narrow regions of the
measured spectrum where the strongest transition in the
rotational spectrum of different isotopic variants of 5-
ethylbenzofuran (6d, 7d, 8d) are expected. The dominant
isotopic species in the sample is the desired reaction product
6d as indicated by the strong observed transition in the
rotational spectrum assigned to this isotopomer. The
attribution of the observed spectrum to the specific isotopomer
is based on the agreement between experimental and
theoretical rotational constants. For the transfer hydro-
deuteration of 5-vinylbenzofuran, the underdeuterated im-
purity 8d is also observed.
In the case of the misdeuterated reaction product 7d, three
equal intensity rotational spectra are expected from the
conformational isomers of this isotopomer. The first three
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Figure 2. Portrayed above is the predicted and experimental analysis of the 2-ethylnaphthalene product mixture from the cocktail reaction and the
method for analyzing the reaction product mixture when a near 1:1 mixture of H and D-reagents is used in the Cu-catalyzed transfer
hydrogenation/deuteration reaction. Panels A and B show the basic MRR analysis process for a commercial sample of 2-ethylnaphthalene-d0. The
simulation of the spectrum from quantum chemistry (blue) is used to guide an experimental fit of the rotational constants (Panel B, red) of the
spectrum. The results from this initial fit are used to make scaled predictions for the rotational constants for other isotopic species. The predicted
transitions for the six conformers of the d2-benzylic-methyl isotopomer are shown in Panel C. The transition marked with a red asterisk is
unassigned. All strong transitions are assigned to four chemical species (d0, d1-benzylic, d1-methyl, d2-benzylic-methyl), and no further species could
be identified in the residuals of the reaction product mixture spectrum shown in Panel D (blue, with the intensity multiplied by a factor of 10).
spectral regions shown in Figure 1a are 6 MHz frequency
bandwidth windows centered on the predicted transition
frequency obtained using the quantum chemistry equilibrium
geometry calculated using the B3LYP density functional theory
with Grimme’s D3 dispersion correction including Becke−
Johnson damping and the 6-311++G(d,p) basis set model
chemistry in Gaussian16.62 The transitions marked by the red
dot are assigned to the rotational spectra of the three
conformers of the d1-methyl isotopomer. The conformational
geometry associated with the spectral transition is indicated by
the purple atom in the molecular structure shown above the
section of the spectrum. The 2H NMR spectrum of the
ethylbenzofuran sample is shown in the Supporting Informa-
tion (SI), and the resonance for the methyl group is barely
detectable. The MRR measurement has about an order-of-
deuteration of 2-vinylnaphthalene (6b, 7b, 8b), where no
misdeuteration reaction product is identified at the measure-
ment sensitivity using the broadband MRR instrument.
After the initial analyses of the six reaction products depicted
in Scheme 3 (these results are tabulated in the SI), a modified
MRR analysis approach was developed to address some
weaknesses in the application of MRR to the development of
synthetic methodologies for selective deuteration chemistry.
One issue with the CP-FTMW analysis is the possibility that
the spectral signature of an isotopic impurity is missed because
the quantum chemistry predictions of the rotational spectrum
make it difficult to identify the spectrum when it is near the
detection limit. The sample consumption for the analysis is
also a potential limitation. The broadband MRR analysis
initially performed for the products depicted in Scheme 3
consumed 60−100 mg to reach a detection limit of about 1%
on the expected isotopic impurities. Finally, the measurement
2
magnitude higher sensitivity than the H NMR measurement.
Figure 1b illustrates the analysis of the transfer hydro-
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Table 2. Isotopic Composition of the 2-Ethylnaphthalene Mixture Giving the Total Intensity for Eight Transitions of Each
Conformer for the Four Chemically Distinct Isotopic Variants Observed in the Spectrum
d0
d1-benzylic
57.0 μV
d1-methyl
38.0 μV
d2-benzylic-methyl
D19 D22
D19 D23
D19 D24
D20 D22
D20 D23
D20 D24
a
280 μV
D19
D20
D22
D23
D24
8.17 μV
8.72 μV
7.82 μV
9.25 μV
9.38 μV
10.6 μV
53.9 μV
9.6
55.4 μV
36.3 μV
41.9 μV
Total
%
280 μV
49.8
112.4 μV
20.0
116.2 μV
20.7
d1-methyl conformers:
d2-benzylic-methyl conformers:
Mean: 38.7 μV
Mean: 8.99 μV
σ = 2.84 μV
σ = 0.98 μV
a
The isotope labels, like D19, refer to the atom labeling from the quantum chemistry geometry optimization as shown in the Supporting
Information.
time is approximately 3 h. Shorter measurement times are
needed to facilitate screening of reaction conditions to
optimize the deuteration selectivity.
A and B show the spectrum for a commercial sample of
ethylnaphthalene-d0 for simplicity (this species is also the
dominant species in the cocktail reaction mixture). Panel A
shows the MRR spectrum in a small frequency range of the full
2−8 GHz measured spectrum. The rotational spectrum
prediction from the equilibrium geometry and dipole moments
obtained from the quantum chemistry geometry optimization
is shown in blue and is a close match to the observed pattern.
Panel B shows an expanded frequency region for two of the
transitions in ethylnaphthalene-d0. The assignment listed above
The new measurement approach combines broadband MRR
spectroscopy to obtain the spectral signatures of all possible
isotopic species accessible from the transfer hydrodeuteration
chemistry, with high-throughput sample analysis performed on
an IsoMRR instrument.63 The IsoMRR instrument uses the
tunable cavity-enhanced FTMW design introduced by Balle
and Flygare.64 The instrument employs coaxial injection of the
sample through a solenoid valve mounted in the resonator
mirror as introduced by Grabow, Stahl, and Dreizler to
increase the measurement sensitivity.65 The compact instru-
ment design is based off the mini-FTMW instrument design
from NIST.66 The IsoMRR spectrometer has approximately an
order-of-magnitude greater sensitivity than the broadband
spectrometer for equal sample consumption. The instrument is
also capable of performing high-throughput sample screen-
ing.67 The trade-off of using a cavity-enhanced FTMW
spectrometer is that the cavity resonator limits the measure-
ment bandwidth to about 1 MHz. Due to the small bandwidth
window, efficient use of the instrument relies on the availability
of the transition frequencies of each isotopic species to be
studied and these are supplied from the broadband analysis.
The sample analyzed by broadband MRR is prepared by
performing the reaction with a 1:1 mixture of H and D
reagents so that a “cocktail” of all possible reaction products is
produced (eq 3). Once this sample is analyzed, the spectral
signatures are used to set up a high-speed measurement script
using a cavity-enhanced Fourier transform microwave
(FTMW) spectrometer. This measurement methodology was
tested on the isolated products from the Cu-catalyzed
“cocktail” reactions performed with 5a, 5b, and 5d shown in
(eq 3) below:
each transition uses the usual notation in rotational spectros-
54
copy that labels the energy levels JKaKc
.
The blue spectrum
simulation is from quantum chemistry. The red simulation uses
the experimental fit rotational constants which are given in the
Supporting Information.
The spectral signatures of each deuterated 2-ethylnaph-
thalene species can be predicted to high accuracy using the
theoretical equilibrium geometry and scale factors obtained
from the theoretical and fit constants of ethylnaphthalene-d0.
This process is described in the Supporting Information and is
a common analysis tool in rotational spectroscopy where it is
used to identify 13C (and other) isotopomers in natural
abundance in structure determination.68 The accuracy of this
analysis is illustrated in Panel C where the predicted transitions
of the 616 − 515 rotational transitions of the six conformers of
the d2-benzylic-methyl isotopomer are compared to the
measured spectrum. The Supporting Information gives the
comparison between the scaled rotational constant predictions
and the experimental fit rotational constants for the 11 isotopic
species identified in the spectrum. Agreement is on the order
of 0.01%. Panel D shows the J = 6 − J = 5 spectral region of
the reaction product mixture and the residual spectrum (blue)
after all isotopic species (including the rotational spectra for
the 12 singly substituted 13C isotopomers of the dominant
ethylnaphthalene-d0 species) are cut from the spectrum. The
only isotopomers identified in the spectrum are d0, d1-benzylic,
d1-methyl, and d2-benzylic-methyl, and this is consistent with
the proposed reaction products.
The broadband spectrum can be used to perform
quantitative analysis of the reaction product mixture. To
average fluctuations from the frequency-dependent electric
field of the chirped excitation pulse, the total intensity of a set
of rotational transitions is used. The analysis needs to include
the spectral intensity from all conformers of a given
isotopomer. The result using eight transitions in the 2-
ethylnaphthalene spectrum is shown in Table 2. Analysis of the
The analysis of the reaction mixture using the broadband
CP-FTMW spectrometer is illustrated in Figure 2 for the Cu-
catalyzed “cocktail” reaction of 2-vinylnaphthalene 5b. Panels
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Table 3. Comparison Between Calculated NMR Integration Using MRR Sample Composition and Measured NMR Integration
Ethylbenzofuran
Ethylnaphthalene
Ethylbiphenyl
MRR
Ethylbiphenyl (D-enhanced)
a
NMR Resonance
MRR
NMR
MRR
NMR
NMR
MRR
NMR
1
Methyl H
2.72(1)
1.45(2)
0.28(1)
0.55(2)
2.69
1.43
0.31
0.57
2.70(2)
1.70(2)
0.30(2)
0.30(2)
2.71
1.71
0.29
0.28
2.69(2)
1.66(2)
0.31(2)
0.34(2)
1.0%
2.73
1.69
0.27
0.30
2.46(2)
1.31(2)
0.54(2)
0.69(2)
2.46
1.29
0.52
0.71
1
Benzylic H
2
Methyl H
2
Benzylic H
Mean Absolute Percent Difference (1H Only):
Mean Absolute Percent Difference (All):
4.0%
a
The MRR integrations give the 1σ uncertainty derived from the composition uncertainty.
Table 4. Comparison of Sample Composition Analysis by Broadband and Cavity-Enhanced MRR Spectroscopy
a
b
Ethylbenzofuran
d0
d1-benzylic
d1-methyl
d2-methyl-benzylic
Ethylnaphthalene
Run 1
Run 2
Run 3
IsoMRR
CP-FTMW
|Difference|
29.4%
33.7%
13.4%
23.5%
Run 1
30.3%
31.9%
14.3%
23.5%
Run 2
30.0%
31.8%
15.1%
23.1%
Run 3
29.9(0.45)
32.6(1.1)
14.3(0.85)
23.4(0.23)
34(2.4)
38(2.1)
4.1%
5.4%
2.9%
6.6%
|Difference|
11.4(0.8)
16.8(0.9)
CP-FTMW
a
b
IsoMRR
d0
55.2%
14.9%
21.0%
9.0%
54.3%
15.1%
21.5%
9.2%
54.2%
14.8%
21.4%
9.6%
54.6(0.55)
14.9(0.15)
21.3(0.26)
9.3(0.31)
50(2.7)
20(1.6)
21(1.4)
9.6(0.6)
4.6%
5.1%
0.3%
d1-benzylic
d1-methyl
d2-methyl-benzylic
Ethylbiphenyl
0.3%
a
b
Run 1
Run 2
IsoMRR
CP-FTMW
|Difference|
d0
49.7%
18.7%
20.8%
10.8%
51.7%
18.0%
20.3%
9.9%
50.7(1.4)
18.4(0.49)
20.6(0.35)
10.4(0.64)
46(2.7)
23(1.7)
21(1.4)
10.6(0.7)
4.9%
4.7%
0.4%
d1-benzylic
d1-methyl
d2-methyl-benzylic
0.2%
a
b
The IsoMRR results are the mean value of the replicate measurements with a 1σ sample standard deviation reported in parentheses. The
measurement uncertainty reported for the CP-FTMW broadband measurements is a 1σ standard deviation determined by assuming that there is a
10% relative uncertainty in the intensity measurement ((σI/I) = 0.1) for each rotationally distinct species in the sample mixture.
results for the 5-ethylbenzofuran and ethylbiphenyl product
mixtures are included in the Supporting Information.
and 2H NMR spectra of the reaction mixture. It is important to
note that NMR spectroscopy cannot analyze the composition
of this reaction mixture. The resonances used in the NMR
analysis are assigned to the benzylic and methyl protons.
However, the reaction mixture contains three isotopic species
(d1-benzylic, d1-methyl, and d2-benzylic-methyl) that contrib-
ute to the two resonances making it impossible to analyze the
sample composition by NMR. This simple example illustrates
the limitations of NMR spectroscopy for reaction product
analysis in deuteration chemistry. MRR can perform the
analysis because all isotopic variants have a unique spectral
signature.
The accuracy of the MRR composition is assessed by
calculating the expected NMR integration for the sample using
the MRR results reported in Table 2 (2-ethylnaphthalene) and
the Supporting Information (5-ethylbenzofuran and ethyl-
biphenyl). For example, the integration of the methyl proton
resonance using the fractional composition of the sample is
There are two important spectroscopy details in the analysis.
First, the analysis assumes that the dipole moment is the same
for all isotopic variants so that the total spectral intensity is
directly proportional to the isotopic composition. The dipole
moment differs for the different species through two effects.
Deuterium substitution reorients the principal axis system for
molecular rotation and changes the components of the dipole
moment vector in this axis system. This effect can be calculated
from the equilibrium geometry and is negligible in the samples
analyzed in this work. For example, the value of μa2the
square of the component of the electric dipole moment along
the a-principal axis which governs the intensities of the
transitions used in the analysisvaries by just 0.1% for the 12
rotationally distinct structures analyzed for ethylnaphthalene.
The dipole moment also changes magnitude upon deuteration
from changes in the zero-point motion of the C−H bond.
These effects have been measured, and the bond dipole
changes are on the order of 0.01 D which is small compared to
the dipole moments of the molecules in this study (>0.4 D).69
The second spectroscopy issue that can affect the quantitative
analysis is the presence of nuclear quadrupole hyperfine
splitting in the spectrum from the deuterium nucleus (I = 1).
The quantitative analysis uses only a-type rotational transitions
where the hyperfine structure is small compared to the line
width and can, therefore, be neglected.
1H Methyl = (fd0 )*3 + (fd1‐benzylic )*3 + (fd1‐methyl )*2
+ (fd2‐benzylic‐methyl )*2
(4)
The quantitative comparison between MRR and NMR
resonance integrations is presented in Table 3 for four reaction
mixtures that were analyzed in this work (this includes a
second ethylbiphenyl (D-enhanced)mixture where the ratio of
H/D reagents was 1:2 to increase the contribution from the
deuterated species). The mean absolute percent difference
The accuracy of the sample composition analysis by
broadband MRR spectroscopy has been validated by
1
1
comparison to integration of specific resonances in the H
between the results is 1% for the H integration.
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The reaction product mixtures prepared using a 1:1 ratio of
H/D reagents were subsequently analyzed using the IsoMRR
instrument. A measurement script was designed to permit
detection of the four chemically distinct isotopic species at the
1% level for each of the three analytes. These scripts are
described in the Supporting Information. The measurement
script does not need to make measurements for all conformers
of a given isotopomer. As shown in Table 2, equal amounts of
the conformers are observed in the spectrum (within a 10%
intensity uncertainty) so that the measurement can use just
one and then apply the statistical factor to get the total sample
composition for the isotopomer. The sample composition from
the IsoMRR measurements is compared to the CP-FTMW
analysis in Table 4.
The composition analysis from the two MRR instruments
are in good agreement with a percentage variation of about 5%.
However, the 5% accuracy has little practical importance in
applications of high-throughput screening where the measure-
ment precision (better than 1%) is needed to determine which
samples have higher purity. The lower accuracy of the IsoMRR
measurements results from the instrument design which uses a
cavity-resonator with high quality factor (Q) to enhance the
measurement sensitivity. There has been no attempt to correct
for frequency-dependent variation in the cavity Q in these
measurements (although transitions in a narrow frequency
range are used to minimize variations in the cavity Q). In
practice, the IsoMRR measurements can achieve both high
precision and accuracy by calibrating the instrument response
using a reference sample that has been analyzed by broadband
rotational spectroscopy where the quantitative accuracy is
demonstrated in Table 3.
The more important feature of the IsoMRR measurements is
the repeatability in back-to-back analysis runs which is about
1%. This measurement precision shows that the technique
would be able to reliably detect changes in the sample
composition for high-throughput screening of reaction
conditions. The IsoMRR measurement for 2-ethylnaphthalene
and 5-ethylbenzofuran uses 2.5 mg of sample (for ethyl-
biphenyl where the spectrum is weaker, the sample
consumption is 5 mg). The measurement time is approx-
imately 10 min (20 min for ethylbiphenyl). Both performance
metrics are order-of-magnitude improvements over sample
analysis by broadband MRR using the CP-FTMW spectrom-
eter.
The IsoMRR instrument was also used to analyze the
reaction products depicted in Scheme 3. These measurements
detected the presence of the d1-methyl isotopomer in
ethylnaphthalene that was not observable in the broadband
analysis (Figure 1b): (94.8% d1-benzylic (6b), 4.4% d0 (8b),
0.8% d1-methyl (7b), <0.6% d2 (nd)). For ethylbenzofuran, the
IsoMRR analysis agrees with the broadband analysis within the
performance comparison limits of Table 4: (95.1% d1-benzylic
(6d), 1.7% d0 (8d), 3.2% d1-methyl (7d), <0.7% d2 (nd)). For
ethylbiphenyl, only the underdeuterated isotopic impurity was
detected: (98.4% d1-benzylic (6a), 1.6% d0 (8a), <0.7% d1-
methyl (7a) (nd), <1.3% d2 (nd)). In addition, three separate
preparations of ethylbiphenyl using the optimized chemistry
were analyzed. The only two species detected were the desired
d1-benzylic and the underdeuterated d0 isotopologue. The
amount of d0 (8a) impurity in the three samples was 1.6%,
2.3%, and 1.8%.
4. CONCLUSIONS
In summary, a highly regioselective alkene transfer hydro-
deuteration for the synthesis of deuterated small molecules
where deuterium is incorporated at the benzylic position is
reported. The Cu-catalyzed reaction is able to incorporate both
an H and a D across an alkene with high levels of precision.
This mild protocol can be carried out across a broad range of
aryl alkene substrates, including those containing heterocycles
and reduceable functionality. A detailed characterization of six
reaction product mixtures was performed using molecular
rotational resonance spectroscopy. MRR provides a general
method to perform isotopomer composition analysis of
deuteration reactions. The following advantages of MRR
spectroscopy for characterization of isotopic products were
outlined during the characterization of six isotopic product
mixtures from the alkene transfer hydrodeuteration reaction.
(1) Isotopomers have distinct MRR spectra that can be
predicted to high accuracy from the theoretical equilibrium
geometry from quantum chemistry. This feature makes it
possible to identify the isotopomers with high confidence
without the need for reference samples. (2) Instruments for
MRR provide high spectral resolution so that isotopologue and
isotopomer mixtures can be quantitatively analyzed without
issues arising from signal overlap. (3) High-throughput analysis
is possible using cavity-enhanced FTMW spectrometers
making it possible to screen a wide range of reaction
conditions for isotopic reactions. These capabilities were
especially important for analyzing the reaction products from
the reported Cu-catalyzed alkene transfer hydrodeuteration
reaction. Reaction mixtures may contain three isotopic species
(d1-benzylic, d1-methyl, and d2-benzylic-methyl), and these
contribute to two NMR resonances. This scenario made it
challenging to analyze the sample composition by NMR. In
addition to the enhanced sensitivity of MRR, the identification
of the d1-methyl isotopomer 7b (the minor regioisomer from
the transfer hydrodeuteration of 2-ethylnaphthalene) was
possible. This species was not detected by NMR. Ultimately,
using MRR spectroscopy to analyze the isotopic products
formed from the reported highly regioselective Cu-catalyzed
alkene transfer hydrodeuteration reaction led to the highest
regioselectivities ever reported for this reaction. We anticipate
that the advances reported for the selective hydrodeuteration
chemistry and MRR spectroscopy will facilitate new reaction
discovery in selective deuteration chemistry and expand the
utility of deuterium-labeled organic compounds in applications
that require the molecule has high deuterium content at
precisely the desired site.
ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/jacs.1c00884.
General information, procedures for transfer hydro-
deuteration and synthesis of starting materials along with
2
1H NMR, H NMR, 11B NMR and 13C NMR spectra,
and HRMS and IR data of all newly characterized
products. Molecular rotational resonance spectroscopy
data for compounds in Scheme 3 is also included. (PDF)
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(4) Meek, S. J.; Pitman, C. L.; Miller, A. J. M. Deducing Reaction
Mechanism: A Guide for Students, Researchers, and Instructors. J.
Chem. Educ. 2016, 93, 275−286.
(5) Anslyn, E. V.; Dougherty, D. A. Modern physical organic
chemistry; University Science Books: 2006; pp 424−441.
(6) Simmons, E. M.; Hartwig, J. F. On the Interpretation of
Deuterium Kinetic Isotope Effects in C-H Bond Functionalizations by
Transition-Metal Complexes. Angew. Chem., Int. Ed. 2012, 51, 3066−
3072.
AUTHOR INFORMATION
■
Corresponding Author
Joseph R. Clark − Department of Chemistry, Marquette
University, Milwaukee, Wisconsin 53233-1881, United
States; orcid.org/0000-0002-3081-5732;
Email: joseph.r.clark@marquette.edu
Authors
(7) Giagou, T.; Meyer, M. P. Kinetic Isotope Effects in Asymmetric
Reactions. Chem. - Eur. J. 2010, 16, 10616−10628.
Zoua Pa Vang − Department of Chemistry, Marquette
University, Milwaukee, Wisconsin 53233-1881, United States
Albert Reyes − Department of Chemistry, Marquette
University, Milwaukee, Wisconsin 53233-1881, United States
Reilly E. Sonstrom − Department of Chemistry, University of
Virginia, Charlottesville, Virginia 22904-4319, United
States; orcid.org/0000-0003-0497-6660
Martin S. Holdren − Department of Chemistry, University of
Virginia, Charlottesville, Virginia 22904-4319, United States
Samantha E. Sloane − Department of Chemistry, Marquette
University, Milwaukee, Wisconsin 53233-1881, United States
Isabella Y. Alansari − Department of Chemistry, Marquette
University, Milwaukee, Wisconsin 53233-1881, United States
Justin L. Neill − BrightSpec, Inc., Charlottesville, Virginia
22903, United States; orcid.org/0000-0003-0964-3275
Brooks H. Pate − Department of Chemistry, University of
Virginia, Charlottesville, Virginia 22904-4319, United States
(8) Atzrodt, J.; Derdau, V.; Kerr, W. J.; Reid, M. Deuterium- and
Tritium-Labelled Compounds: Applications in the Life Sciences.
Angew. Chem., Int. Ed. 2018, 57, 1758−1784.
(9) Jarling, R.; Sadeghi, M.; Drozdowska, M.; Lahme, S.; Buckel, W.;
Rabus, R.; Widdel, F.; Golding, B. T.; Wilkes, H. Stereochemical
Investigations Reveal the Mechanism of the Bacterial Activation of n-
Alkanes without Oxygen. Angew. Chem., Int. Ed. 2012, 51, 1334−
1338.
(10) Klinman, J. P. A new model for the origin of kinetic hydrogen
isotope effects. J. Phys. Org. Chem. 2010, 23, 606−612.
(11) Schwab, J. M. Stereochemistry of an enzymic Baeyer-Villiger
reaction. Application of deuterium NMR. J. Am. Chem. Soc. 1981, 103,
1876−1878.
(12) Battersby, A. R.; Gutman, A. L.; Fookes, C. J. R.; Gunther, H.;
̈
Simon, H. Stereochemistry of formation of methyl and ethyl groups in
bacteriochlorophyll a. J. Chem. Soc., Chem. Commun. 1981, 645−647.
(13) Leinberger, R.; Rétey, A.; Hull, W. E.; Simon, H. Steric Course
of the NIH Shift in the Enzymic Formation of Homogentisic Acid.
Eur. J. Biochem. 1981, 117, 311−318.
Complete contact information is available at:
https://pubs.acs.org/10.1021/jacs.1c00884
(14) Luthy, J.; Rétey, J.; Arigoni, D. Asymmetric Methyl Groups:
̈
Preparation and Detection of Chiral Methyl Groups. Nature 1969,
221, 1213−1215.
Author Contributions
∥Z.P.V. and A.R. contributed equally.
(15) White, R. E.; Miller, J. P.; Favreau, L. V.; Bhattacharyya, A.
Stereochemical dynamics of aliphatic hydroxylation by cytochrome P-
450. J. Am. Chem. Soc. 1986, 108, 6024−6031.
Funding
Financial support for this work was provided by Marquette
University. MRR analysis of the isotopic impurities was
performed with support from the National Science Foundation
Chemical Measurement and Imaging Program under grant
NSF-1904686.
(16) Shapiro, S.; Piper, J. U.; Caspi, E. Steric course of hydroxylation
at primary carbon atoms. Biosynthesis of 1-octanol from (1R)- and
(1S)-[1−3H,2H,1H; 1−14C]octane by rat liver microsomes. J. Am.
Chem. Soc. 1982, 104, 2301−2305.
(17) Nelson, S. D.; Trager, W. F. The Use of Deuterium Isotope
Effects to Probe the active site properties, Mechanism of Cytochrom
P450-Catalyzed Reactions, and Mechanisms of Metabolically
Dependent Toxicity. Drug Metab. Dispos. 2003, 31, 1481−1497.
(18) Pirali, T.; Serafini, M.; Cargnin, S.; Genazzani, A. A.
Applications of Deuterium in Medicinal Chemistry. J. Med. Chem.
2019, 62, 5276−5297.
Notes
The authors declare the following competing financial
interest(s): Brooks H. Pate has founders equity in BrightSpec
which commercializes applications of rotational spectroscopy
in chemical analysis. Reilly Sonstrom and Justin Neill also have
equity in BrightSpec.
(19) Gant, T. G. Using Deuterium in Drug Discovery: Leaving the
Label in the Drug. J. Med. Chem. 2014, 57, 3595−3611.
(20) Meanwell, N. A. Synopsis of Some Recent Tactical Application
of Bioisosteres in Drug Design. J. Med. Chem. 2011, 54, 2529−2591.
(21) Stepan, A. F.; Mascitti, V.; Beaumont, K.; Kalgutkar, A. S.
Metabolism-guided drug design. MedChemComm 2013, 4, 631−652.
(22) Belleau, B.; Burba, J.; Pindell, M.; Reiffenstein, J. Effect of
Deuterium Substitution in Sympathomimetic Amines on Adrenergic
Responses. Science 1961, 133, 102−104.
ACKNOWLEDGMENTS
■
A.R. is grateful for a 2020 Eugene Kroeff summer research
fellowship and 2020 Ronald E. McNair summer research
fellowship. I.A. is grateful for a 2020 James Moyer summer
research fellowship.
REFERENCES
(23) Harbeson, S. L.; Tung, R. D. Deuterium Medicinal Chemistry:
A New Approach to Drug Discovery and Development. Medchem
News 2014, 24, 8−22.
■
(1) Atzrodt, J.; Derdau, V. Pd- and Pt-catalyzed H/D exchange
methods and their application for internal MS standard preparation
from a Sanofi-Aventis perspective. J. Labelled Compd. Radiopharm.
2010, 53, 674−685.
(24) Schmidt, C. First deuterated drug approved. Nat. Biotechnol.
2017, 35, 493−494.
(25) Ludwig, J. R.; Schindler, C. S. Catalyst: Sustainable Catalysis.
Chem. 2017, 2, 313−316.
(2) Qin, M.; Qiao, H.-q.; Yuan, Y.-j.; Shao, Q. A quantitative LC-
MS/MS method for simultaneous determination of deuvortioxetine,
vortioxetine and their carboxylic acid metabolite in rat plasma, and its
application to a toxicokinetic study. Anal. Methods 2018, 10, 1023−
1031.
(3) Iglesias, J.; Sleno, L.; Volmer, D. A. Isotopic Labeling of
Metabolites in Drug Discovery Applications. Curr. Drug Metab. 2012,
13, 1213−1225.
(26) Zhou, Q.-L. Transition-Metal Catalysis and Organocatalysis:
Where Can Progress Be Expected? Angew. Chem., Int. Ed. 2016, 55,
5352−5353.
(27) Atzrodt, J.; Derdau, V.; Fey, T.; Zimmermann, J. The
Renaissance of H/D Exchange. Angew. Chem., Int. Ed. 2007, 46,
7744−7765.
7716
https://doi.org/10.1021/jacs.1c00884
J. Am. Chem. Soc. 2021, 143, 7707−7718

Journal of the American Chemical Society
pubs.acs.org/JACS
Article
(28) Atzrodt, J.; Derdau, V.; Kerr, W. J.; Reid, M. C−H
Functionalisation for Hydrogen Isotope Exchange. Angew. Chem.,
Int. Ed. 2018, 57, 3022−3047.
Polymethylhydrosiloxane and Hydroxylamines. Angew. Chem., Int.
Ed. 2013, 52, 10830−10834.
̌
(50) Sorádová, Z.; Sebesta, R. Enantioselective Cu-Catalyzed
(29) Puleo, T. R.; Strong, A. J.; Bandar, J. S. Catalytic α-Selective
Deuteration of Styrene Derivatives. J. Am. Chem. Soc. 2019, 141,
1467−1472.
Functionalizations of Unactivated Alkenes. ChemCatChem 2016, 8,
2581−2588.
(51) Mohr, J.; Oestreich, M. Balancing C = C Functionalization and
C = O Reduction in Cu-H Catalysis. Angew. Chem., Int. Ed. 2016, 55,
12148−12149.
(52) Vitaku, E.; Smith, D. T.; Njardarson, J. T. Analysis of the
Structural Diversity, Substitution Patterns, and Frequency of Nitrogen
Heterocycles among U.S. FDA Approved Pharmaceuticals. J. Med.
Chem. 2014, 57, 10257−10274.
(53) Taylor, R. D.; MacCoss, M.; Lawson, A. D. G. Rings in Drugs. J.
Med. Chem. 2014, 57, 5845−5859.
(54) W. Gordy, R. L. C. Microwave Molecular Spectra, 3rd ed.;
Knovel, 1984; Chapter VII, pp 227−296.
(55) Smith, J. A.; Wilson, K. B.; Sonstrom, R. E.; Kelleher, P. J.;
Welch, K. D.; Pert, E. K.; Westendorff, K. S.; Dickie, D. A.; Wang, X.;
Pate, B. H.; Harman, W. D. Preparation of cyclohexene isotopologues
and stereoisotopomers from benzene. Nature 2020, 581, 288−293.
(56) Grimme, S.; Steinmetz, M. Effects of London dispersion
correction in density functional theory on the structures of organic
molecules in the gas phase. Phys. Chem. Chem. Phys. 2013, 15, 16031−
16042.
(57) Lee, K. L. K.; McCarthy, M. Bayesian Analysis of Theoretical
Rotational Constants from Low-Cost Electronic Structure Methods. J.
Phys. Chem. A 2020, 124, 898−910.
(58) Brown, G. G.; Dian, B. C.; Douglass, K. O.; Geyer, S. M.;
Shipman, S. T.; Pate, B. H. A broadband Fourier transform microwave
spectrometer based on chirped pulse excitation. Rev. Sci. Instrum.
2008, 79, No. 053103.
(59) Neill, J. L.; Shipman, S. T.; Alvarez-Valtierra, L.; Lesarri, A.;
Kisiel, Z.; Pate, B. H. Rotational spectroscopy of iodobenzene and
iodobenzene−neon with a direct digital 2−8 GHz chirped-pulse
Fourier transform microwave spectrometer. J. Mol. Spectrosc. 2011,
269, 21−29.
(60) Pérez, C.; Lobsiger, S.; Seifert, N. A.; Zaleski, D. P.; Temelso,
B.; Shields, G. C.; Kisiel, Z.; Pate, B. H. Broadband Fourier transform
rotational spectroscopy for structure determination: The water
heptamer. Chem. Phys. Lett. 2013, 571, 1−15.
(61) Armstrong, D. W.; Talebi, M.; Thakur, N.; Wahab, M. F.;
Mikhonin, A. V.; Muckle, M. T.; Neill, J. L. A Gas Chromatography-
Molecular Rotational Resonance Spectroscopy Based System of
Singular Specificity. Angew. Chem., Int. Ed. 2020, 59, 192−196.
(62) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.;
Robb, M. A.; Cheeseman, J. R.; Scalmani, G.; Barone, V.; Petersson,
G. A.; Nakatsuji, H.; Li, X.; Caricato, M.; Marenich, A. V.; Bloino, J.;
Janesko, B. G.; Gomperts, R.; Mennucci, B.; Hratchian, H. P.; Ortiz, J.
V.; Izmaylov, A. F.; Sonneberg, J. L.; Williams-Young, D.; Ding, F.;
Lipparini, F.; Egidi, F.; Goings, J.; Peng, B.; Petrone, A.; Henderson,
T.; Ranasinghe, D.; Zakrzewski, V. G.; Gao, J.; Rega, N.; Zheng, G.;
Liang, W.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.;
Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H.; Vreven, T.;
Throssell, K.; Montgomery, J. A., Jr.; Peralta, J. E.; Ogliaro, F.;
Bearpark, M. J.; Heyd, J. J.; Brothers, E. N.; Kudin, K. N.; Staroverov,
V. N.; Keith, T. A.; Kobayashi, R.; Normand, J.; Raghavachari, K.;
Rendell, A. P.; Burat, J. C.; Iyengar, S. S.; Tomasi, J.; Cossi, M.;
Millam, J. M.; Klene, M.; Adamo, C.; Cammi, R.; Ochterski, J. W.;
Martin, R. L.; Morokuma, K.; Farkas, O.; Foresman, J. B.; Fox, D. J.
Gaussian 16, rev. C.01; Gaussian Inc.: Wallingford, CT, 2016.
(63) The IsoMRR instrument is available from BrightSpec Inc.
(64) Balle, T. J.; Flygare, W. H. Fabry−Perot cavity pulsed Fourier
transform microwave spectrometer with a pulsed nozzle particle
source. Rev. Sci. Instrum. 1981, 52, 33−45.
(30) Karlsson, S.; Hallberg, A.; Gronowitz, S. Hydrozirconation of
(E)-3-methoxy-1-phenyl-1-propene and (E)-3-phenyl-2-propenol. J.
Organomet. Chem. 1991, 403, 133−144.
(31) Czeskis, B.; Elmore, C. S.; Haight, A.; Hesk, D.; Maxwell, B. D.;
Miller, S. A.; Raglione, T.; Schildknegt, K.; Traverse, J. F.; Wang, P.
Deuterated Active Pharmaceutical Ingredients: A Science-Based
Proposal for Synthesis, Analysis, and Control. Part 1: Framing the
Problem. J. Labelled Compd. Radiopharm. 2019, 62, 690−694.
(32) Wang, D.; Astruc, D. The Golden Age of Transfer
Hydrogenation. Chem. Rev. 2015, 115, 6621−6686.
(33) Korytiaková, E.; Thiel, N. O.; Pape, F.; Teichert, J. F.
Copper(i)-Catalysed Transfer Hydrogenations with Ammonia Bor-
ane. Chem. Commun. 2017, 53, 732−735.
(34) Chatterjee, I.; Oestreich, M. Brønsted Acid-Catalyzed Transfer
Hydrogenation of Imines and Alkenes Using Cyclohexa-1,4-dienes as
Dihydrogen Surrogates. Org. Lett. 2016, 18, 2463−2466.
(35) Lau, S.; Gasperini, D.; Webster, R. L., Amine-Boranes as
Transfer Hydrogenation and Hydrogenation Reagents: A Mechanistic
Perspective. Angew. Chem., Int. Ed. 2021, DOI: 10.1002/
anie.202010835.
(36) Semba, K.; Fujihara, T.; Xu, T.; Terao, J.; Tsuji, Y. Copper-
Catalyzed Highly Selective Semihydrogenation of Non-Polar Carbon-
Carbon Multiple Bonds using a Silane and an Alcohol. Adv. Synth.
Catal. 2012, 354, 1542−1550.
(37) Whittaker, A. M.; Lalic, G. Monophasic Catalytic System for
the Selective Semireduction of Alkynes. Org. Lett. 2013, 15, 1112−
1115.
(38) Kaicharla, T.; Zimmermann, B. M.; Oestreich, M.; Teichert, J.
F. Using Alcohols as Simple H2-Equivalents for Copper-Catalysed
Transfer Semihydrogenations of Alkynes. Chem. Commun. 2019, 55,
13410−13413.
(39) Okuhara, T.; Tanaka, K.-I. Orientation in the Addition of HD
to Butadiene on MoS2. J. Chem. Soc., Chem. Commun. 1976, 199−200.
(40) Okuhara, T.; Kondo, T.; Tanaka, K. Oriented Adsorption of
Hydrogen Deuteride on Zinc Oxide and Addition to Butadiene. J.
Phys. Chem. 1977, 81, 808−809.
(41) Espinal-Viguri, M.; Neale, S. E.; Coles, N. T.; Macgregor, S. A.;
Webster, R. L. Room Temperature Iron-Catalyzed Transfer Hydro-
genation and Regioselective Deuteration of Carbon−Carbon Double
Bonds. J. Am. Chem. Soc. 2019, 141, 572−582.
(42) Wang, Y.; Cao, X.; Zhao, L.; Pi, C.; Ji, J.; Cui, X.; Wu, Y.
Generalized Chemoselective Transfer Hydrogenation/Hydrodeutera-
tion. Adv. Synth. Catal. 2020, 362, 4119−4129.
(43) Linford-Wood, T. G.; Coles, N. T.; Webster, R. L. Room
temperature iron catalyzed transfer hydrogenation using n-butanol
and poly(methylhydrosiloxane). Green Chem. 2021, 23, 2703−2709.
(44) Walker, J. C. L.; Oestreich, M. Regioselective Transfer
Hydrodeuteration of Alkenes with a Hydrogen Deuteride Surrogate
Using B(C6F5)3 Catalysis. Org. Lett. 2018, 20, 6411−6414.
(45) Li, L.; Hilt, G. Regiodivergent DH or HD Addition to Alkenes:
Deuterohydrogenation versus Hydrodeuterogenation. Org. Lett. 2020,
22, 1628−1632.
(46) Sloane, S. E.; Reyes, A.; Vang, Z. P.; Li, L.; Behlow, K. T.;
Clark, J. R. Copper-Catalyzed Formal Transfer Hydrogenation/
Deuteration of Aryl Alkynes. Org. Lett. 2020, 22, 9139−9144.
(47) Liu, R. Y.; Buchwald, S. L. CuH-Catalyzed Olefin
Functionalization: From Hydroamination to Carbonyl Addition.
Acc. Chem. Res. 2020, 53, 1229−1243.
(48) Zhu, S.; Niljianskul, N.; Buchwald, S. L. Enantio- and
Regioselective CuH-Catalyzed Hydroamination of Alkenes. J. Am.
Chem. Soc. 2013, 135, 15746−15749.
(49) Miki, Y.; Hirano, K.; Satoh, T.; Miura, M. Copper-Catalyzed
Intermolecular Regioselective Hydroamination of Styrenes with
(65) Grabow, J.; Stahl, W.; Dreizler, H. A multioctave coaxially
oriented beam-resonator arrangement Fourier-transform microwave
spectrometer. Rev. Sci. Instrum. 1996, 67, 4072−4084.
(66) Suenram, R. D.; Grabow, J. U.; Zuban, A.; Leonov, I. A
portable, pulsed-molecular-beam, Fourier-transform microwave spec-
7717
https://doi.org/10.1021/jacs.1c00884
J. Am. Chem. Soc. 2021, 143, 7707−7718

Journal of the American Chemical Society
pubs.acs.org/JACS
Article
trometer designed for chemical analysis. Rev. Sci. Instrum. 1999, 70,
2127−2135.
(67) Neill, J. L.; Mikhonin, A. V.; Chen, T.; Sonstrom, R. E.; Pate, B.
H. Rapid Quantitation of Isomeric and Dehalogenated Impurities in
Pharmaceutical Raw Materials Using MRR Spectroscopy. J. Pharm.
Biomed. Anal. 2020, 189, 113474.
(68) Gordy, R. L. C. W. Microwave Molecular Spectra, 3rd ed.;
Knovel, 1984; Chapter XIII, pp 647−724.
(69) Fliege, E.; Dreizler, H. Investigation of the Stark Shift of the
Benzene-d1 l01 - 000 Rotational Transition by Microwave Fourier
Transform Spectroscopy. Z. Naturforsch., A: Phys. Sci. 1987, 42a, 72−
78.
7718
https://doi.org/10.1021/jacs.1c00884
J. Am. Chem. Soc. 2021, 143, 7707−7718