Discovery of a Photoinduced Dark Catalytic Cycle Using in Situ LED-NMR Spectroscopy

Article abstract of DOI:10.1021/jacs.8b08596

We report the use of LED-NMR spectroscopy to study the reaction mechanism of a newly discovered photoinduced iron-catalyzed cycloisomerization of alkynols to cyclic enol ethers. By understanding on/off ligand binding to the catalyst, we were able to appro

Full text of DOI:10.1021/jacs.8b08596

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Article
Discovery of a Photoinduced Dark Catalytic
Cycle using in situ LED-NMR Spectroscopy
Dan Lehnherr, Yining Ji, Andrew J. Neel, Ryan D. Cohen,
Andrew P. J. Brunskill, Junyu Yang, and Mikhail Reibarkh
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.8b08596 • Publication Date (Web): 24 Sep 2018
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Journal of the American Chemical Society
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Discovery of a Photoinduced Dark Catalytic Cycle using in situ LED-
NMR Spectroscopy
Dan Lehnherr,‡* Yining Ji,‡* Andrew J. Neel, Ryan D. Cohen, Andrew P. J. Brunskill, Junyu Yang,
Mikhail Reibarkh
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Process Research & Development, Merck & Co., Inc., Rahway, New Jersey, 07065, United States
Supporting Information Placeholder
yields (<70%) and/or require high catalyst loadings (10 to 25
ABSTRACT: We report the use of LEDꢀNMR spectroscopy to
study the reaction mechanism of a newly discovered photoinꢀ
mol%).13 For these reasons, we sought an inexpensive and susꢀ
tainable alternative, ideally based on an Earthꢀabundant first row
transition metal such as iron. In particular, we were drawn to sevꢀ
eral reports employing metal carbonyl complexes supported by
cyclopentadienone ligands,14 namely, LFe(CO)3 (L = tetraphenylꢀ
cyclopentadienone) (cat•CO). Although cycloisomerization reacꢀ
tivity is precedented with these complexes,15 specifically with
allenes to provide a net endoꢀcyclization, alkynꢀol cycloisomeriꢀ
zation is unexplored, including successfully achieving the 5ꢀexoꢀ
cyclization mode.
duced ironꢀcatalyzed cycloisomerization of alkynꢀols to cyclic
enol ethers. By understanding on/off ligand binding to the cataꢀ
lyst, we were able to appropriately design reaction conditions to
balance catalyst activity and stability. The utility of LEDꢀNMR
was demonstrated to be a powerful tool in elucidating reaction
mechanisms of photochemical reactions. Temporal NMR spectroꢀ
scopic data under visible light illumination: (1) revealed the preꢀ
catalyst activation mechanism, (2) proved that photon flux proꢀ
vides a unique external control of the equilibrium distribution
between the preꢀcatalyst and active catalyst, and ultimately the
rate of reaction, (3) provided information about the reaction drivꢀ
ing forces and the turnover limiting step, and (4) enabled both
realꢀtime structural and kinetic insights into elusive species (e.g.
dissolved gases).
Scheme 1. Cycloisomerization of alkyn-ols to either the 5-
exo or 6-endo product and related side-reactions.
Introduction
The feedback loop between developing new reaction methodolꢀ
ogies and studying their mechanisms enables chemists to make
critical observations which ultimately lead to a hypothesisꢀdriven
reaction optimization process. Facilitating this process, innovaꢀ
tions in analytical tools and techniques can shed light into previꢀ
ously poorly understood “black box” processes. This article deꢀ
scribes such an example of this process in which the leveraging of
a newly reported tool and a related technique, namely LEDꢀNMR1
and NMRꢀactinometry,2 was used to study in detail the mechaꢀ
nism of a newly discovered photochemical reaction, ultimately
guiding us towards rationally improved reaction conditions and
scope exploration. We believe that these analytical tools and techꢀ
niques will undoubtedly be transformative for the field of photoꢀ
chemistry, which has secured a pillar in modern synthetic methꢀ
odology for constructing organic molecules.3
A potential challenge in using these carbonyl complexes stems
from the requirement for CO decomplexation to open a coordinaꢀ
tion site for substrate binding. In the aforementioned alleneꢀ
alcohol cycloisomerization examples,15 CO dissociation was efꢀ
fected using an oxidant in the presence of a base and often reꢀ
quired elevated temperatures. Classically, this elementary step has
been effected by an external oxidant such as trimethylamineꢀNꢀ
oxide, generating CO2 and trimethylamine as byproducts.15,16
However, the Lewis basic tertiary amine can potentially inhibit
catalysis via coordination to the complex’s resulting vacant site.17
Brønsted acids have also been employed to decomplex the amine
from the metal via protonation,18 but their presence may catalyze
undesired pathways.19,20 It is also unclear if Me3NO can influence
the redox state of Fe(0) in the preꢀcatalyst, and thereby turn on
undesired catalysis. Alternatively, light has been used to dissociꢀ
ate carbonyl ligands from metal complexes.21 In the present case,
we hypothesized that in addition to providing a substrate binding
site, CO dissociation would generate a bifunctional catalyst conꢀ
taining both Lewis acidic and Lewis basic moieties (Scheme 2).
We envisioned substrate binding via a metalꢀπꢀacid interaction,
and thus activating the alkyne towards nucleophilic attack. Addiꢀ
tionally, the cyclopentadienone ligand could act as a Lewisꢀbasic
As part of our efforts to develop a supply route to an active
pharmaceutical ingredient (API), we became interested in develꢀ
oping a catalytic cycloisomerization of alkynꢀols (Scheme 1) to
produce exocyclic enol ethers. While numerous cycloisomerizaꢀ
tion methodologies have been reported, including those for synꢀ
thesizing enol ethers from alkynꢀol substrates, challenges remain,
including controlling the mode of cyclization (i.e. 5ꢀexo vs 6ꢀendo
cyclization) as well as preventing alkene isomerization or oliꢀ
gomerization processes.4,5a Additionally, many existing methodꢀ
ologies rely on expensive or precious metals such as Rh,5 Ru,6 Ir,7
Au,8 Ag,9 Pt,10 Pd,11 or La,12 and often provide only moderate
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Page 2 of 11
site to deprotonate the alcohol, thus increasing its nucleophilicity
Table 2. Exploration of photochemical conditions for the cy-
cloisomerization of alkyn-ol 1a with cat•CO (1 mol%).
1
2
3
towards attack of the alkyne. This synergistic effect would result
in a photogenerated Lewis pair bifunctional catalyst capable of
twoꢀpoint activation of alkynꢀol substrates toward cycloisomerizaꢀ
tion to generate cyclic enol ethers.
entry λ [nm] modification solvent
2a : 3a : 4a conversion
N2 sparge
1
450
d8-toluene 100 : NA : NA
45%
(1st 1 h)
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5
6
2
3
450
450
closed vial d8-toluene 100 : NA : NA
closed vial CD2Cl2 99 : 0.05 : 0.8
100%
100%
Scheme 2. Photogeneration of Lewis Pair Catalyst for Bi-
functional Catalysis.
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Intrigued by the detrimental effect caused by the removal of the
seeminglyꢀinhibitory CO ligand, we decided to carry out a deꢀ
tailed mechanistic study of this reaction with an eye towards deꢀ
veloping improved reaction conditions and scope exploration.
Three main challenges were encountered when attempting to
study this reaction by standard analytical tools such as HPLC,
ReactIR, etc.: (1) decomposition of product 2a when exposed to
chromatography precluded ex situ methods such as HPLC analyꢀ
sis, (2) the absence of a pristine standard of product 2a rendered it
challenging to obtain an accurate response factor for ReactIR, (3)
quantitative detection of volatile CO by ex situ methods was chalꢀ
lenging. In light of these challenges, we recognized that LEDꢀ
based NMR illumination devices introduced by Gschwind and coꢀ
workers1 could serve us as simple and powerful tools to obtain
dataꢀrich kinetic and structural insights into this reaction. In conꢀ
trast to other established analytical tools, in situ NMR monitoring
has a multitude of advantages:22 (1) it provides quantitative data
that does not require standards or calibration curves, (2) being a
nonꢀdestructive method, it provides structural information of both
stable and unstable compounds, (3) it enables in situ time course
measurements from a single sample, minimizing sample manipuꢀ
lation errors, (4) it typically requires modest sample amounts due
to the high sensitivity of modern NMR spectrometers, and (5) it
provides the ability to observe multiple nuclei independently (1H,
13C, 19F, 31P, etc.) to provide complementary structural inforꢀ
mation. In addition, the coupling of NMR with in situ LED illuꢀ
mination provides capabilities that are essential for determining
kinetics and gaining insight into the mechanisms of photochemiꢀ
cal transformations. Specifically, this combination affords the
ability to observe intermediates or transient species, as well as the
aggregation state or molecular size of the components in the reacꢀ
tion mixture potentially only present under illumination condiꢀ
tions. In this work we demonstrate the utility of LEDꢀNMR as a
powerful tool in elucidating reaction mechanisms of photochemiꢀ
cal reactions.
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2. Results and Discussion
2.1 Reaction Optimization
We initially selected substrate 1a and cat•CO for evaluation. As
discussed above, metal carbonyls can be activated in one of three
methods: (1) heat, (2) oxidant (e.g. Me3NO), or (3) light. We exꢀ
plored known methods15 of activating these types of catalysts,
specifically using combinations of temperatures and oxidants in
the absence or presence of a base (Table 1). Varying ratios of
kinetic product 2a, thermodynamic product 3a, and dimer 4a were
observed. While room temperature conditions did afford cycloiꢀ
somerizationꢀderived products, the conversion was poor. Increasꢀ
ing the reaction temperature to 70 oC provided improved levels of
conversion, although the selectivity for 2a was diminished, as
alkene isomerization (3a) and oligomerization (4a) became preꢀ
dominant.
Table 1. Exploration of thermal conditions for the cycloi-
somerization of alkyn-ol 1a with cat•CO (1 mol%) in
CD2Cl2.
2.2 Kinetics and Actinometry
A proposed catalytic cycle is shown in Scheme 3. Preꢀcatalyst
cat•CO absorbs a photon, resulting in the photomediated loss of
CO to generate active catalyst LFe(CO)2 (cat) which complexes
to substrate 1a. This catalystꢀsubstrate complex (cat•1a) may
facilitate the cyclization step via ligandꢀenabled deprotonation of
the alcohol and concomitant attack onto the pendant alkyne to
generate 5-exo-int. This vinylꢀiron intermediate then undergoes
protoꢀdemetallation to release product 2a and regenerate the acꢀ
tive catalyst LFe(CO)2 (cat).
entry
temp.
RT
RT
RT
RT
oxidant
base
–
K2CO3
K2CO3 99 : 0.05 : 0.8
–
-
2a : 3a : 4a
96 : 1.4 : 2.8
90 : 1.7 : 8.0
conversion
25%
1
2
3
4
5
6
7
8
Me3NO
–
Me3NO
–
Me3NO
–
7%
24%
5%
100%
31%
0 : 0 : 100
3.5 : 32 : 65
91 : 3.9 : 4.7
70 °C
70 °C
70 °C
70 °C
K2CO3
Me3NO
–
K2CO3 96 : 4.0 : 0.15
0 : 0 : 100
14%
To validate our proposed catalytic cycle, we initiated a mechaꢀ
nistic investigation using LEDꢀNMR spectroscopy, including our
recently developed NMR actinometry method.2 Monitoring by in
situ LEDꢀNMR, photoꢀirradiation of substrate 1a in the presence
of catalyst cat•CO in CD2Cl2 afforded quantitative conversion to
2a (Figure 1). Notably, the use of in situ NMR was crucial for
obtaining both structural and quantitative data, as offline methods
such as HPLC were not suitable due to the instability of 2a toward
isomerization to 3a. The observation that all NMR signals, includꢀ
ing those associated with the catalyst, remained sharp throughout
the reaction time course is consistent with the catalyst and all
associated species remaining diamagnetic (e.g. Fe(0)), likely preꢀ
–
8%
We next turned our attention to photochemical methods of CO
dissociation (Table 2). We initially sparged the solution with N2
for the first hour to purge CO and thus render the catalyst activaꢀ
tion process irreversible. Although this resulted in highly selective
formation of 2a, it resulted in incomplete conversion (45%, entry
1). Interestingly, full conversion to the desired product 2a was
achieved when using a closed system (entry 2), with negligible
isomerization of the alkene to 3a. To ensure this was not a solvent
dependent effect, we repeated the reaction in CD2Cl2 and obꢀ
served comparable results (entry 3).
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Journal of the American Chemical Society
cluding the existence of paramagnetic iron species (e.g. Fe3+).
This is in contrast to other metal carbonyls which can generate
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3
4
paramagnetic species upon photoirradiation (e.g. Mn2(CO)10 and
Re2(CO)10 can generate •Mn(CO)5 and •Re(CO)5).23,24,25
Scheme 3. Proposed reaction mechanism.
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Figure 2. UVꢀvis absorption spectra of catalyst cat•CO in CH2Cl2
before and after 450 nm irradiation. Vertical dashed lines indicate
wavelengths associate with isosbestic points.
In order to perform relevant kinetic measurements, we next
needed to locate the linear absorption regime. By avoiding the
photonꢀlimited regime, the catalyst concentration was low enough
relative to the photon flux to ensure the reaction rate was not limꢀ
ited by a lack of photons reaching the photocatalyst. By measurꢀ
ing the initial rate of product formation as a function of catalyst
loading (Figure 3), we determined the linear absorption regime (0
< [cat•CO]T < 4.50 mM). In order to ensure we were characterizꢀ
ing the intrinsic kinetics, reaction mixtures containing 2.25 mM of
preꢀcatalyst cat•CO were used for further kinetic studies.
The reaction progress kinetics (RPK)26 obtained by LEDꢀNMR
in Figure 1 revealed an induction period that is postulated to be
associated with the photomediated loss of a CO from the 18ꢀ
electron preꢀcatalyst cat•CO, LFe(CO)3, to generate the active 16ꢀ
electron catalyst (cat), LFe(CO)2. The photomediated activation
of cat•CO leaves a vacant coordination site on the active catalyst,
enabling cat to bind substrate 1a to both reach an 18ꢀelectron
complex as well as activate the substrate for catalysis. UVꢀvis
absorption of dichloromethane solutions of cat•CO before and
after irradiation at 450 nm using a PennOC m1 photoreactor27,28
illustrated an overall redꢀshift in a low energy absorption band
concomitant with increased molar absorptivity in the 440 nm reꢀ
gion (Figure 2), providing further evidence of catalyst activation
via photomediated loss of a CO.29
Figure 3. Dependence of initial rate of product formation (measꢀ
ured after the induction period) as a function of catalyst loading.
Kinetic data collected using [1a]o = 0.6 M in CH2Cl2 with varying
amounts of preꢀcatalyst [cat•CO]T (0.375, 0.75, 1.5, 3.0 and 6.0
mol%) under 440 nm irradiation using LEDꢀNMR.
The dependence of initial rates on catalyst concentration shown
in Figure 3 can be fit to equation 1.2,30,31 The term εapp (apparent
molar absorptivity) arises due to dissociation of cat•CO into cat
and CO, with both cat•CO and cat contributing to the absorption
at 440 nm. The apparent molar absorptivity of 505 M–1•cm–1 was
obtained from the fit, and then compared to the value of 345 M–
1•cm–1 measured for cat•CO alone. The larger εapp value is conꢀ
sistent with higher molar absorptivity of the active catalyst (cat)
compared to the preꢀcatalyst cat•CO.
Figure 1. Temporal concentration profiles of 1a and 2a monitored
1
by H NMR spectroscopy recorded under 440 nm illumination
using [1a]o = 0.60 M and [cat•CO]T = 0.018 M in CD2Cl2 (preꢀ
treated with solid K2CO3).
ꢁ
ꢄ
ꢀ ꢂꢃ
ꢁ
ꢄ
ꢆ ꢇꢈϕꢉ1 ꢊ 10ꢋꢌ ꢏ ꢐꢃꢑ•ꢒꢓ ꢔ
(1)
ꢍꢎꢎ
ꢀꢅ
Utilizing our recently developed chemical actinometer, 2,4ꢀ
dinitrobenzaldehyde, the light intensity of our 440 nm LED
source was determined to be 5.72×10–5 einstein•L–1•s–1 (see Supꢀ
porting Information for details). Having determined both the light
intensity and the zeroth order kinetic constant (ko = 1.75×10–4
M•s–1) calculated from the fitting of the data in Figure 3 (see Supꢀ
porting Information for details), the quantum yield was calculated
to be 3.06 ± 0.09 based on equation 2, indicating that three moleꢀ
cules of product were formed for every photon absorbed by the
catalyst (vide infra).
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ꢕꢈ ꢆ ꢇꢈϕ
(2)
for nearly 4 h, and then illuminated once again until the reaction
reached full conversion at T = 7 h. Clearly, the data show high
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From the kinetics in the photonꢀsaturated regime ([cat•CO]T =
0 – 4.50 mM) in Figure 3, a clear positive order in catalyst was
revealed. RPK analysis of reaction mixtures with 0.30 M and 0.60
M of substrate 1a are shown in Figure 4. The overlay of the rate
of product formation indicates that the reaction is zeroth order in
substrate 1a. To gain insight into the catalyst stability, an xꢀ
adjusted plot26 (Figure 5) from reactions carried out in the presꢀ
ence of 2.25 mM of cat•CO with either 0.30 M or 0.60 M of 1a
show deviation eventually arises at later time points. This sugꢀ
gests either weak product inhibition or mild catalyst deactivation
upon extended periods of photoirradiation.
reproducibility under identical conditions in the first 30 min, but
as soon as irradiation was ceased (data set shown in red), the rate
of product formation significantly decreased relative to that obꢀ
served for the reaction under constant irradiation at 440 nm (data
in blue). However, product formation did not stop immediately in
the absence of irradiation, suggesting the existence of a lightꢀ
independent (‘dark’) pathway. Importantly, when irradiation was
resumed at 4.17 h (data in red), the reaction went through a 2nd
induction period (see Supporting Information for details) and
proceeded at an accelerated rate relative to dark conditions, effecꢀ
tively reacting at rates comparable to those under illumination
conditions (consistent with negligible catalyst deactivation), and
eventually reached full conversion.
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Figure 4. Graphical RPK data for reaction carried out in the LEDꢀ
NMR setup using either [1a]o = 0.30 or 0.60 M with [cat•CO]T =
2.25 mM in CD2Cl2 irradiated at 440 nm. RPK illustrating zeroth
order in substrate when overlaying product formation.
Figure 6. Hammett plot illustrating the relationship between relaꢀ
tive rates of product formation as a function of σpara values (slope
(
ρ
) = +0.76, R2 = 0.96).
Toward gaining insight into the dynamics of the CO ligand as a
result of switching between light and dark regimes, we repeated
the latter experiment described above but using preꢀcatalyst
cat•13CO which contained 13C enriched CO ligands. We recorded
13C NMR spectra to monitor the temporal evolution of the reacꢀ
tion mixture, particularly related to the kinetics of the decomplexꢀ
ation of the CO ligand.33 We were able to observe both the Feꢀ
bound34 (δC = 208.8 ppm) and unbound (δC = 184.2 ppm) 13CO in
solution upon irradiation (Figure 7, middle). This experiment
enabled us to probe the reversibility of the complexation of CO to
the iron complexes in solution. When the light was turned off, the
concentration of the free 13CO in solution decreased, with conꢀ
comitant reꢀcomplexation to the LFe(CO)2 to generate the preꢀ
catalyst LFe(CO)3. In contrast, if the reaction mixture is illumiꢀ
nated until full conversion, a steady state is reached between both
Feꢀbound and free CO after ca. 30–40 minutes (Figure 7, bottom).
While direct observation of CO being released and reꢀligated deꢀ
pending on illumination state supported our mechanistic hypotheꢀ
sis for the preꢀcatalyst losing a CO ligand to generate the active
catalyst (cat), it also illustrated that once the active catalyst was
formed, the catalytic cycle could proceed in the absence of light
until catalyst deactivation via CO reassociation occurred. The
latter scenario is in good agreement with the obtained quantum
yield of 3.06 ± 0.09, suggesting that one photon converts
LFe(CO)3 to LFe(CO)2 to undergo three catalytic turnovers on
Figure 5. Graphical RPK data for reaction carried out in the LEDꢀ
NMR setup using either [1a]o = 0.30 or 0.60 M with [cat•CO]T =
2.25 mM in CD2Cl2 irradiated at 440 nm. Xꢀadjusted RPK data
for consumption of starting material 1a illustrating partial catalyst
deactivation.
In order to discern between cyclization and protoꢀdemetalation
as the turnover limiting step, a Hammett plot32 was constructed by
measuring the initial rate of 5ꢀexoꢀcyclization for a series of elecꢀ
tronically varied 2ꢀethynylbenzylalcohols (1b–1g) (Figure 6). A
clear correlation between the initial rate of product formation and
the σpara parameter (R2 = 0.96) was observed. The positive slope
(ρ = +0.76) indicates that there is a buildꢀup of negative charge on
the alkynyl carbon, which is consistent with the turnover limiting
step being the concomitant deprotonation and nucleophilic attack
by oxygen on the alkyne. This is in clear contrast to a scenario
where protodemetalation would have provided a negative slope
due to decreasing negative charge on the vinyl carbon.
In order to determine the role of light in catalysis, we exposed
two identical reaction mixtures to two different temporal illuminaꢀ
tion conditions in the LEDꢀNMR setup. In the first experiment,
the reaction mixture was illuminated for the full time course (blue
data points in Figure 7, top), whereas in the second (data points in
red), the mixture was illuminated for the first 30 min, kept dark
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average before being deactivated by a molecule of CO in solution
1a observed in Table 2 when CO is removed from the reaction
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and returning to the inactive preꢀcatalyst. An alternative mechaꢀ
nistic scenario was initially considered, namely, photoexcitation
of the catalystꢀsubstrate complex (cat•1a) to facilitate the proton
transfer and cyclization (see Supporting Information for details).
The fact that the reaction proceeds in the absence of light rules out
this scenario from being the exclusive pathway. Additionally,
since energy transfer cannot proceed via a chain process,35 it is
also ruled out as the dominant pathway under photoirradiation
conditions based on the quantum yield.
mixture by sparging with N2 is consistent with the catalytic deacꢀ
tivation hypothesis presented above. This observation clearly
demonstrates the need for CO to be present to stabilize the cataꢀ
lyst which can be achieved either by (a) minimizing the headspace
volume relative to the solution volume, or (b) performing the
reaction under a partial pressure of CO if headspace is present in
the reaction vessel. At first glance, the requirement for CO seems
counterintuitive since it appears in the denominator of the rate law
shown in equation 3 (see Supporting Information for details).
However, a constant supply of photons provides for a constant
regeneration of the active catalyst from the cat•CO via photomeꢀ
diated CO loss.
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ꢁ
ꢄ
ꢁ
ꢄꢁ ꢄ
ꢛꢜꢝꢞꢟꢠꢟꢡ ꢢꢃ ꢚꢣꢅ
ꢤ
ꢀ ꢖꢗꢘꢀꢙꢚꢅ
ꢆ ꢟ ꢟ
(3)
ꢁ
ꢡ
ꢄ ꢁ ꢄ
ꢢꢃ ꢥ ꢦꢧ ꢥ ꢟꢠ
ꢀꢅ
ꢠ
The bifunctional nature of the catalyst with its Lewis basic (keꢀ
tone) and Lewis acidic (coordinatively unsaturated Fe) sites poꢀ
tentially renders it prone to dimerization, analogous to sterically
unencumbered frustrated Lewis pair (FLP) catalysts.36 We wonꢀ
dered if such a dimerization process could occur under the reacꢀ
tion conditions (Scheme 4), resulting in an inactive, offꢀcycle
species (cat•cat).37 Once again, LEDꢀNMR afforded a unique
ability to answer this question via in situ photoꢀDOSY experiꢀ
ments. While high concentration samples of cat•CO (22.5 mM) in
CD2Cl2 and a headspace present (ca. 20% v/v headspace to soluꢀ
tion) did indeed result in the observation of a species with a slowꢀ
er diffusion coefficient, consistent with a dimer such as cat•cat,
these signals were not observed under typical reaction conditions,
precluding the relevance of this postulated dimer to the overall
mechanism (see Supporting Information for details).
Scheme 4. Potential dimerization of active catalyst.
2.3 DFT Calculations
Next, DFT calculations were performed to gain further insight
into aspects of the reaction and solidify our mechanistic hypotheꢀ
sis. Single point energies presented in Figure 8 were obtained
using B3LYPꢀD3(BJ)/6ꢀ311+G(2d,2p) based on geometries optiꢀ
mized using the B3LYPꢀD3(BJ) functional and a mixed basis set
approach in which 6ꢀ31G(d,p) was utilized for C,H,O and the
effective core potential LANL2DZ was used for Fe. The loss of
CO from the preꢀcatalyst LFe(CO)3 to the active catalyst
LFe(CO)2 was computed to be +28.0 kcal/mol in Gibbs free enerꢀ
gy at 298.15 K. This energy cost is easily paid through the excitaꢀ
tion of the preꢀcatalyst to enable the photomediated loss of CO.
The binding of substrate can occur in two ways: (1) hydroxyl
bound (cat•1a(Oꢀbound)) or (2) alkyne bound (cat•1a(Cꢀbound)), the
latter disfavored but required for product formation. Consistent
with our experimental data, the DFT results also indicate that the
cyclization step is turnover limiting, as it displays a higher barrier
than the protodemetalation step (20.3 vs 14.9 kcal/mol, respecꢀ
tively).
Figure 7. Experiment carried out under 440 nm illumination usꢀ
ing [1a]o = 0.30 M and [cat•CO]T = 2.25 mM in CD2Cl2. (Top)
Temporal concentration profiles of 1a and 2a monitored by H
1
NMR spectroscopy. Data in blue is irradiated at 440 nm for the
entire duration of the reaction; data in red is irradiated from T = 0
h to T = 0.5 h, followed by darkness (grey region on plot) until T
= 4.17 h at which point 440 nm irradiation is resumed. (Middle
and bottom) Temporal equivalents of Feꢀbound and dissolved
(free) 13CO as determined by 13C NMR under conditions for either
light/dark (middle) or constant light illumination (bottom).
Interestingly, if one graphs the sum of the Feꢀbound 13CO and
free 13CO in solution in Figure 7 (bottom) as a function of reacꢀ
tion time, the total only slowly decreases, demonstrating that there
is minimal CO loss from the solution. In part, this is due to loss of
CO to the headspace and ultimately slow leakage from the reacꢀ
tion vessel (i.e. our NMR tube). We hypothesized this CO loss
could account for the mild catalyst deactivation observed in Figꢀ
ure 5 if the active catalyst (cat) is prone to losing a second CO
ligand to form an inactive catalyst. The incomplete conversion of
DFT calculations also enable insight into the structural changes
of the tetraphenylcyclopentadienone ligand throughout the cataꢀ
lytic cycle. While DFT calculated structures of cat•CO, cat, and
(cat•1a(Cꢀbound)) clearly support the presence of ketone character in
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the tetraphenylcyclopentadienone (C=O distance of 1.22, 1.25,
unlikely that product inhibition is also operating to cause the deꢀ
1
2
3
4
5
6
7
8
and 1.23 Å, respectively), lengthening of the ketone begins to
occur in the turnover limiting transition state TS1 (C=O distance
= 1.26 Å) resulting in loss of double bound character (1.34 Å)
with the formation of 5ꢀexoꢀintermediate (5-exo-int) as a result of
complete protonation and generation of a C–OH moiety on the
ligand. This analysis highlights the importance of the bifunctional
nature of the catalyst, as the ligandꢀembedded ketone and Fe cenꢀ
ter serve as Lewis basic and Lewis acidic sites respectively to
enable cycloisomerization. The binding between Fe and the tetraꢀ
phenylcyclopentadienone ligand also changes throughout the
catalytic cycle. η4ꢀBinding to the tetraphenylcyclopentadienone
ligand by Fe is calculated for all 18ꢀelectron structures,38 with
ligand nonꢀplanarity resulting from the carbonyl pointing away
from the Fe relative to the plane generated by the diene moiety.
On the other hand, the formal 16ꢀelectron cat structure is predictꢀ
ed to result in planarization of the ligand to enable the Fe to bind
η5 to the cyclopentadienone moiety (see Supporting Information
for details). Collectively, both the DFT and the experimental data
support the mechanism proposed in Scheme 3.39
viation observed between the same experiments shown in Figure
5. Returning to the remainder of the substrate scope, substrates
bearing sterically hindered hydroxyl groups such as 1m showed
excellent performance, generating bicyclic product 2m in 97%
yield. Due to poor solubility of substrate 1n in toluene, the reacꢀ
tivity of this acyclic substrate was explored in dichloromethane
and provided 91% of the Bocꢀamino functionalized product using
3 mol% of preꢀcatalyst cat•CO. Secondary benzylic alcohol 1o
provided 2o in 68% yield with 3 mol% of catalyst owing to inꢀ
complete conversion. Substrate 1p, containing a ketal protecting
group, smoothly underwent cycloisomerization without unmaskꢀ
ing the ketone functionality, highlighting the mild reaction condiꢀ
tions. Benzylic alcohols featuring tethered alkene substitution of
varying tether length in entries 17─18 (1q and 1r) highlight not
only the alkyne over alkene selectivity, but also the tolerance of
alkene functionality in the cycloisomerization. The ability to carry
out the cycloisomerization with low catalyst loadings42 coupled
with the ubiquitous use of enol ethers in organic synthesis renders
this method attractive for the direct use of the products in subseꢀ
quent derivatizations without purification due to the presence of
minimal impurities in the enol ether products.43,44 Others heteroaꢀ
toms such as nitrogen can be utilized to obtain the net hydroamiꢀ
nation product as exemplified by conversion of 1s into 2s in 93%
yield. More traditional methods to these products rely on Au45 or
Pd46 catalytic systems in combination with elevated reactions
temperatures, in contrast to the mild catalytic conditions presented
herein.
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2.4 Reaction Scope
The scope of the reaction40 was briefly explored using a greener
solvent (toluene),41 at high substrate concentration (1 M) using 1
mol% of preꢀcatalyst cat•CO under illumination at 450 nm in the
PennOC m1 photoreactor. Based on our mechanistic understandꢀ
ing, all the reactions were performed in closed vials to minimize
the loss of CO. Model substrate 1a could be converted to 2a in
98% yield with no observable formation of thermodynamically
preferred regioisomeric product 3a or dimer 4a.20 Arylacetylene
derivatives 1b─1f were suitable substrates (entries 2–6), providꢀ
ing clean formation of the 5ꢀexoꢀcylization product in nearly
quantitative yield, with methoxy analogue 1g slightly lower (71
%, entry 7). Generation of spirocyclic analogues of 2e (2h and 2i,
entries 8─9) occurred smoothly in 90% and 88% yield, respecꢀ
tively. Interestingly, inclusion of only a single benzylic methyl
group (1j, entry 10) resulted in considerably diminished reactivity
(45% yield after 8 h), with starting material accounting for the
mass balance. Full conversion of 1j could be achieved by increasꢀ
ing the catalyst loading to 3 mol% (91% yield of 2j in 8 h). Howꢀ
ever, 1k, which lacks substitution α to the nucleophilic hydroxyl
group, was completely unreactive. We postulate that this result is
due to unproductive offꢀcycle binding of the alcohol to the cataꢀ
lyst as a result of steric accessibility proximal to the hydroxyl
group (Figure 8). This result led us to wonder if the ThorpꢀIngold
effect was critical for the success of the cycloisomerization and
turned our attention to 1l which is devoid of one of the two methyl
groups found in model substrate 1a. Cycloisomerization of 1l with
1 mol% indeed provided product 2l in 55% yield, with the starting
material constituting the remainder of the mass balance. While
increasing the catalyst loading to 3 mol% can effect full converꢀ
sion and 94% yield of 2l, we wondered if reducing the reaction
headspace volume relative to total reaction vessel volume could
enhance catalytic activity. Indeed, when the headspace volume
was reduced from ca. 80% v/v to <5% v/v, an increased yield was
observed (55% yield vs 98% yield at 1 mol% catalyst loading).
We postulate this enhanced catalytic activity is due to the minimiꢀ
zation of catalyst deactivation via reversible dimer cat•cat forꢀ
mation (Scheme 4) and/or irreversible overꢀdecarbonylation of cat
(i.e. cat•CO losing more than one CO). Towards probing this
effect further, we carried out the cycloisomerization of 1j using 1
mol% of cat•CO with different percent fill volume (Figure 9). A
clear increase in yield is observed by reducing the headspace volꢀ
ume relative to the reaction fill volume, consistent with decreased
irreversible catalyst deactivation when headspace is minimized.
Having proved that catalyst deactivation is a viable pathway, it is
Figure 9. Illustration of how the percent fill volume affects the
cycloisomerization yield of 1a in d8ꢀtoluene using 1 mol% of
cat•CO. Note: percent fill volume = 100%•(volume of soluꢀ
tion)/(volume of solution + volume of headspace).
3. Conclusions
In conclusion, we report the use of LEDꢀNMR to gain mechaꢀ
nistic insights into a newlyꢀdiscovered photoinduced Feꢀcatalyzed
5ꢀexoꢀcyclization of alkynꢀols. In the present work, LEDꢀNMR
has been applied: (1) to understand the preꢀcatalyst activation and
to prove that the equilibrium between preꢀcatalyst and active cataꢀ
lyst is controlled by the externally adjustable photon flux, a conꢀ
cept that has remained underꢀexplored, despite its potentially
broad reaching impact,47 (2) to obtain real time reaction kinetics
to reveal the reaction driving forces and the turnover limiting step,
(3) to capture transient intermediates or phenomena such as moꢀ
lecular aggregation that occurs exclusively under illumination
conditions, (4) to easily discern the existence of a dark reaction
pathway after an initial photoactivation of the catalyst, (5) to
measure the quantum yield of the reaction and the apparent cataꢀ
lyst absorptivity by using our recently developed NMR actinomeꢀ
try methodology,2 and most importantly, (6) to understand that
catalyst stability could be achieved through its reꢀassociation to
free CO in solution. Based on this final insight, we recognized
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Figure 8. DFT calculated Gibbs Free energies (B3LYPꢀD3(BJ)/6ꢀ311+G(2d,2p) // B3LYPꢀD3(BJ)/6ꢀ31G(d,p) for C,H,O and LANL2DZ
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for Fe) for the proposed reaction mechanism.
Chart 1. Substrate Scope for Cycloisomerization of Alkyn-ols.
[a] Reactions were run at 1 M in substrate in d8ꢀtoluene using 1 mol% of catalyst 3a, unless noted otherwise, under 450 nm irradiaꢀ
tion for 8 h using the PennOC m1 photoreactor; yields determined by 1H NMR using 1,2ꢀdichlorethane as an internal standard. [b]
Reaction run in abensence of headspace. [c] Alternate solvent was used due to poor solubility of the substrate in d8ꢀtoluene, entry
14 was run in CD2Cl2; entry 16 was performed in 1:1 CD2Cl2 /d8ꢀtoluene (0.5 M in substrate). [d] Run at 0.2 M in substrate.
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son. 2013, 232, 39–44. (b) Feldmeier, C.; Bartling, H.; Magerl, K.;
that a closed system with minimal headspaces should be emꢀ
ployed for optimal results.
Gschwind, R. M. LED‐Illuminated NMR Studies of Flavin‐Catalyzed
Photooxidations Reveal Solvent Control of the Electron‐Transfer Mechaꢀ
nism. Angew. Chem. Int. Ed. 2015, 54, 1347. (c) Renzi, P.; Hioe, J.;
Gschwind, R. M. Decrypting Transition States by Light: Photoisomerizaꢀ
tion as a Mechanistic Tool in Brønsted Acid Catalysis. J. Am. Chem. Soc.
2017, 139, 6752–6760. (d) Seegerer, A.; Nitschke, P.; Gschwind, R. M.
Combined In Situ IlluminationꢀNMRꢀUV/Vis Spectroscopy: A New
Mechanistic Tool in Photochemistry. Angew. Chem. Int. Ed. 2018, 57,
7493–7497.
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The use of the LEDꢀNMR tool to study photochemical reacꢀ
tions provides several advantages over alternative, ex situ methods
(e.g. aliquot analysis with HPLC or GC) in which the nature of
reaction intermediates or products may be altered during the analꢀ
ysis. Furthermore, offline analysis renders characterization of
induction periods or chain processes challenging, particularly
when temporal differences between sampling and analysis may
lead to significant errors in the determination of reaction rate. The
observance of photoꢀgenerated transient intermediates and the
measurement of the kinetics of simultaneous light and dark cycles
further highlight the informationꢀrich nature of the technique. We
demonstrated the utility of LEDꢀNMR to provide full structural
characterization and quantification of unknown intermediates,
products and byproducts without isolation, and to determine quanꢀ
tum yield in order to obtain detailed mechanistic understanding of
photocatalytic reactions. We expect that the approach presented
herein will result in widespread adoption by the photocatalysis
community, facilitating increased mechanistic understanding and
thereby advancing the field.
(2) Ji, Y.; DiRocco, D. A.; Hong, C. M.; Wismer, M. K.; Reibarkh, M.
Facile Quantum Yield Determination via NMR Actinometry. Org. Lett.
2018, 20, 2156–2159.
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ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website.
(5) (a) Elgafi, S.; Field, L. D.; Messerle, B. A.; Cyclisation of acetylenꢀ
ic carboxylic acids and acetylenic alcohols to oxygenꢀcontaining heteroꢀ
cycles using cationic rhodium(I) complexes. J. Organomet. Chem. 2000,
607, 97–104. (b) Trost, B. M.; Rhee, Y. H. A Rh(I)ꢀCatalyzed Cycloisomꢀ
erization of Homoꢀ and Bisꢀhomopropargylic Alcohols. J. Am. Chem. Soc.
2003, 125, 7482–7483.
All experimental procedures, complete characterization (NMR,
MS, UVꢀvis absorption, kinetic data) for all new compounds and
xyz coordinates of DFT computed structurers (PDF)
Crystallographic information file for 3a (CIF)
(6) (a) Trost, B. M.; Rudd, M. T.; Costa, M. G.; Lee, P. I.; Pomerantz,
A. E. Regioselectivity Control in a RutheniumꢀCatalyzed Cycloisomerizaꢀ
tion of Diyneꢀols. Org. Lett. 2004, 6, 4235–4238. (b) Trost, B. M.; Rhee,
Y. H. A Ru Catalyzed Divergence:ꢁ Oxidative Cyclization vs Cycloisomꢀ
erization of Bisꢀhomopropargylic Alcohols. J. Am. Chem. Soc. 2002, 124,
2528–2533. (c) Kucukbay, H.; Cetinkaya, B.; Guesmi, S.; Dixneuf, P. H.
New (Carbene)ruthenium−Arene Complexes:ꢁ Preparation and Uses in
Catalytic Synthesis of Furans. Organometallics, 1996, 15, 2434–2439. (d)
Liu, P. N.; Wen, T. B.; Ju, K. D.; Sung, H. H.ꢀY.; Williams, I. D.; Jia, G.
Mechanism Investigations of the Endo Cycloisomerization of Alkynols
through Isolation and Characterization of Ruthenium Complexes from the
Reactions of Alkynes with a Ruthenium Complex. Organometallics 2011,
30, 2571–2580.
AUTHOR INFORMATION
Corresponding Author
dan.lehnherr@merck.com
yining.jichen@merck.com
ORCID
Dan Lehnherr: 0000ꢀ0001ꢀ8392ꢀ1208
Yining Ji: 0000ꢀ0002ꢀ9650ꢀ6844
Andrew Neel: 0000ꢀ0003ꢀ2872ꢀ5292
Ryan D. Cohen: 0000ꢀ0002ꢀ3112ꢀ6410
Andrew P. J. Brunskill: 0000ꢀ0002ꢀ7655ꢀ1445
Junyu Yang: 0000ꢀ0002ꢀ6275ꢀ513X
Mikhail Reibarkh: 0000ꢀ0002ꢀ6589ꢀ707X
(7) (a) Genin, E.; Antoniotti, S.; Michelet, V.; Genêt, J. P. An IrI‐
Catalyzed exo‐Selective Tandem Cycloisomerization/Hydroalkoxylation
of Bis‐Homopropargylic Alcohols at Room Temperature. Angew. Chem.
Int. Ed. 2005, 44, 4949–4953. (b) Nakagawa, H.; Okimoto, Y.; Sakaguchi,
S.; Ishii, Y. Synthesis of enol and vinyl esters catalyzed by an iridium
complex. Tetrahedron Lett. 2003, 44, 103–106. (c) Masui, D.; Kochi, T.;
Tang, Z.; Ishii, Y.; Mizobe, Y.; Hidai, M. J. Synthesis and structures of
heterobimetallic Ir2M (M=Pd, Pt) sulfido clusters and their catalytic activiꢀ
ty for regioselective addition of alcohols to internal 1ꢀarylꢀ1ꢀalkynes. J.
Organomet. Chem. 2001, 620, 69–79. (d) Li, X. W.; Chianese, A. R.;
Vogel, T.; Crabtree, R. H. Intramolecular Alkyne Hydroalkoxylation and
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5440. (e) Fjermestad, T.; Ho, J. H. H.; Macgregor, S. A.; Messerle, B. A.;
Tuna, D. Computational Study of the Mechanism of Cyclic Acetal Forꢀ
mation via the Iridium(I)ꢀCatalyzed Double Hydroalkoxylation of 4ꢀ
Pentynꢀ1ꢀol with Methanol. Organometallics 2011, 30, 618–626. (f)
Benedetti, E.; Simonneau, A.; Hours, A.; Amouri, H.; Penoni, A.;
Palmisano, G.; Malacria, M.; Goddard, J.ꢀP., Fensterbanka, L. (Pentameꢀ
thylcyclopentadienyl)Iridium Dichloride Dimer {[IrCp*Cl2]2}: A Novel
Efficient Catalyst for the Cycloisomerizations of Homopropargylic Diols
and N‐Tethered Enynes. Adv. Synth. Catal. 2011, 353, 1908 – 1912.
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alkynes into ketones or acetals with a gold(III) catalyst. J. Org. Chem.
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P. Highly Efficient Access to Strained Bicyclic Ketals via GoldꢀCatalyzed
Cycloisomerization of Bisꢀhomopropargylic Diols. J. Am. Chem. Soc.
Author Contributions
‡These authors contributed equally.
Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENT
The authors would like to acknowledge Daniel DiRocco, Louisꢀ
Charles Campeau, Rebecca Ruck, Artis Klapars, Kevin Campos
(all at Merck & Co., Inc.) and Prof. Eric Jacobsen (Harvard) for
useful feedback. We thank Tamas Benkovics and John McIntosh
(Merck & Co., Inc.) for their contribution to this project and Yuꢀ
hong Lam for helpful discussions.
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(31) The terms of equation 1 and 2 are defined as follows: I0 (incident
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(32) A primary KIE was not measured. Due to the high acidity of the
terminal alkyne, selective deuteration of the primary alcohol in 1a using
MeOD was unsuccessful.
(33) Independent measurements of T1 relaxation of 13CO gas dissolved
in CD2Cl2 and of cat•CO preꢀcatalyst revealed corresponding T1 times of
2.6 s and 1.5 s, respectively. Quantitative 13C NMR experiments were
designed using this information; see Supporting Information for details.
(34) The Feꢀbound CO signal corresponds to a timeꢀaveraged signal for
cat•CO and cat due to a fast exchange on the NMR timescale.
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(44) Derivatization of these 5ꢀexoꢀcyclization products can be achieved
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substrate. In a scenario in which an iron hydride were generated, it would
be expected to be the resting state of the catalytic cycle, however, we were
unable to observe such a species by 1H NMR (see Supporting Information
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