Light-induced enantiospecific 4π ring closure of axially chiral 2-pyridones: Enthalpic and entropic effects promoted by H-bonding

Article abstract of DOI:10.1021/ja203087a

Nonbiaryl axially chiral 2-pyridones were synthesized and employed for light-induced electrocyclic 4π ring closure leading to bicyclo-β-lactam photoproducts in solution. The enantioselectivity in the photoproducts varied from 22 to 95% depending on the reaction temperature and the ability of the axially chiral chromophore to form intramolecular and/or intermolecular H-bonds with the solvent. On the basis of the differential activation parameters, entropic control of the enantiospecificity was observed for 2-pyridones lacking the ability to form H-bonds. Conversely, enthalpy played a significant role for 2-pyridones having the ability to form H-bonds.

Full text of DOI:10.1021/ja203087a

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Light-Induced Enantiospecific 4π Ring Closure of Axially Chiral
2-Pyridones: Enthalpic and Entropic Effects Promoted by H-Bonding
Elango Kumarasamy, Josepha L. Jesuraj, Joseph N. Omlid, Angel Ugrinov, and Jayaraman Sivaguru*
Department of Chemistry and Biochemistry, North Dakota State University, Fargo, North Dakota 58108, United States
S Supporting Information
b
Scheme 1. Light-Induced 4π Ring Closure of 2-Pyridones
ABSTRACT: Nonbiaryl axially chiral 2-pyridones were
synthesized and employed for light-induced electrocyclic
4π ring closure leading to bicyclo-β-lactam photoproducts
in solution. The enantioselectivity in the photoproducts
varied from 22 to 95% depending on the reaction tempera-
ture and the ability of the axially chiral chromophore to form
intramolecular and/or intermolecular H-bonds with the
solvent. On the basis of the differential activation para-
meters, entropic control of the enantiospecificity was ob-
served for 2-pyridones lacking the ability to form H-bonds.
Conversely, enthalpy played a significant role for 2-pyr-
idones having the ability to form H-bonds.
he role of H-bonds in orchestrating chemical and biological
processes in nature defies imagination. Chemists have cleverly
T
taken advantage of H-bonding to perform asymmetric catalytic
chemical transformations.1 While established methodologies for
asymmetric thermal reactions exist,1 light-induced asymmetric
reactions2 in solution have not met the same level of success as
their thermal counterparts. Various groups over the last three
decades have employed constrained media to achieve stereo-
selectivity with varying degrees of success.3 However, achiev-
ing stereoselectivity during photoreactions in solution has not
been generalized because of the short lifetime of the photo-
excited chromophores, which limits the interaction necessary
to achieve stereoselectivity. In this regard, we have been explor-
ing the use of nonbiaryl axially chiral chromophores4,5 to achieve
stereoselectivity during photoreactions in solution and have
successfully achieved very high enantioselectivity (>90% ee in
the photoproduct) in 6π photocyclization and NorrishꢀYang
reactions.6 In the present work, a novel class of axially chiral
2-pyridones 1, where H-bonding contributes to the axial chirality,
have been synthesized and employed for light-induced electro-
cyclic 4π ring closure leading to bicyclo-β-lactam photoproducts,
namely, 2-(aryl)-2-azabicyclo[2.2.0]hex-5-en-3-ones (2), with
very high enantiomeric excess (ee values) in solution.
Figure 1. X-ray crystal structure, CD spectra, and [α]D values of 1c.
The individual P and M isomers9 of 1aꢀc were easily isolable
by HPLC on a chiral stationary phase and characterized by NMR
spectroscopy, circular dichroism (CD) spectroscopy, optical
rotation, high-resolution mass spectrometry (HRMS), and single-
crystal X-ray diffraction (XRD) (Figure 1 and Scheme 1).10
Analysis of the single-crystal X-ray structure10 of 1a revealed that
the pyridone ring is perpendicular to the N-aryl substituent,
possibly reflecting a minimized steric interaction between the
pyridone ring and the o-tert-butyl substituent.5 Similarly, the
single-crystal X-ray structure of 1c revealed an analogous geo-
metry (Figure 1) in which the pyridone ring is perpendicular to
the N-aryl substituent. In addition, intramolecular H-bonding
between the pyridone amide carbonyl and the 3° hydroxyl
The photoreactivity of 2-pyridones has been studied in depth
in both solution7aꢀc and the solid state.7d Depending on the
concentration, 2-pyridones can either undergo 4π ring closure or
[4+4] photocycloaddition.7b The molecularly chiral 2-pyridones
1aꢀc were synthesized to evaluate the influence of intra- and
intermolecular H-bonding8 on the rotation about the NꢀC(aryl)
chiral axis and to elucidate the transfer of axial chirality to point
chirality through weak interactions during photochemical 4π
ring closure leading to bicyclo-β-lactams 2 (Scheme 1).
Received: April 4, 2011
Published: October 07, 2011
r
2011 American Chemical Society
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Table 1. Half-Lives of Racemization (t1/2‑rac) for 1 and Values of Enantiomeric Excess for 2 in Various Solvents at Different
Temperatures, and the Corresponding Eyring Parametersa
a Racemization values (error (5%) and ee values (average of three trials; (3% error) were determined by HPLC using a chiral stationary phase. b See the
Supporting Information (SI) for values of ΔGqrac and krac. c Not water-soluble. d No observable racemization after 2 months. e Values of t1/2-rac in hours.
f The signs of optical rotation of 1 in MeOH. For 2a, (S,R) and (R,S) represent the (1S,4R) and (1R,4S) configurations, respectively. For 2b and 2c, A and
B refer to the elution order for a given pair of enantiomers. g Similar selectivities were found using Pyrex and 340 nm cutoff filters. h The ee values at 25 °C
in toluene were 82% (2 h), 76% (4 h), 70% (5 h), and 68% (6 h). Even though there was no noticeable racemization of 1a in the dark, slow racemization
of 1a was observed in irradiated samples (see the SI). i Calculated by 1H NMR spectroscopy with Ph3CH as an internal standard at 25 °C for 18 h of
irradiation. For 1c, values are given in parentheses. Mass balance was 83ꢀ98% depending on the solvent. j Noticeable racemization of 2-pyridones 1b
and 1c occurred at 65 °C (see the SI). k For 1c, ΔΔHq and ΔΔSq values were computed at <10% conversion. In MeOH, irradiation times were 5 min
(65 °C), 11 min (45 °C), and 12 min (25 °C) to keep the conversion below 10% (see the SI). l To ascertain low conversions at 25 °C, irradiation times
were 35 min (toluene and MeCN) and 12 min (MeOH). m Below the freezing point of the solvent. n In the case of 1a, positive and negative ΔΔGq
favor the (1R,4S)-2a and (1S,4R)-2a photoproducts, respectively.
SRꢀRS
group with a bond length of 1.702 Å was observed. The distance
between the two oxygen atoms was 2.68 Å for 1c, indicating a
moderate intramolecular H-bond strength11 (Figure 1).
cluster hindering NꢀC(aryl) bond rotation.10,13 This is reflected
in the slow NꢀC(aryl) bond rotation, resulting in higher t1/2‑rac
values for 1b in polar solvents (Table 1). Hence, for 1b,
enantiospecific chiral transfer from polar solvents is expected
to be more efficient than from nonpolar solvents. For 1c, fast
racemization with similar krac values was observed in the solvents
investigated. We believe that the hydrophobic phenyl group
likely hinders the formation of H-bonding solvent clusters in 1c,
which is reflected in its high racemization rates (Table 1).10
Photoirradiation of optically pure atropisomers (P or M) of 1
was performed using a 450 W medium-pressure Hg lamp with a
Pyrex cutoff filter and a cooling jacket under a constant flow of N2
at various temperatures (ꢀ25 to 65 °C) in different solvents
(toluene, MeCN, MeOH, and H2O). The reaction progress and
conversion were followed by 1H NMR and/or UVꢀvis spectro-
scopy.10 The reaction was found to be clean and efficient.10
The conversion was dependent on the temperature, solvent, and
irradiation time.10 For example, 1b at 25 °C with 18 h of
irradiation gave 98% conversion with 91% mass balance in
water and 75% conversion with 92% mass balance in toluene
(Table 1).10 The photoproduct 2 was purified by chromatog-
raphy and characterized by NMR spectroscopy and single-crystal
XRD; it was found to be enantiomeric, as ascertained by optical
rotation values and CD spectroscopy.10 It is well-established14
To ascertain the role of H-bonding in influencing the axial
chirality in 1, the racemization kinetics of 1aꢀc was studied in
different solvents at various temperatures to establish the half-life
(t1/2‑rac), rate constant (krac), and activation free energy (ΔGqrac)
of racemization.10 For a given solvent at a particular temperature,
the racemization rates were ordered as 1c > 1b > 1a (Table 1).10
Inspection of Table 1 reveals that o-tert-butyl-substituted 2-pyr-
idone 1a (which lacks the ability to form an intramolecular
H-bond) racemized slowly in comparison with 2-pyridones 1b
and 1c (which have the ability to form intramolecular H-bonds).
For 1b, polar solvents with the ability to form H-bonds de-
creased the rate of racemization, as reflected in the higher
t1/2‑rac values. For example, at 45 °C, the t1/2‑rac value of 1b was
3.4 h (ΔGqrac = 24.83 kcal molꢀ1, krac = 5.6 ꢁ 10ꢀ5
s
ꢀ1) in
toluene, compared with ∼28 days (ΔGqrac = 28.17 kcal molꢀ1
,
krac = 2.9 ꢁ 10ꢀ7 sꢀ1) in water (Table 1, entry 10). We believe
that the slow racemization of 1b in polar solvents is likely due to
(a) the possibility of resonance-induced H-bonding via the
zwitterionic structure11,12 that might be preferred in polar
solvents (Scheme 1, top-right inset) and (b) additional inter-
molecular H-bonding from polar solvents that form a solvent
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that the NꢀC(aryl) bond with an o-tert-butyl substituent can
rotate freely because of the reduced CꢀNꢀC bond angle in
β-lactams. Single-crystal XRD analysis of 2c revealed an intra-
molecular H-bonding distance of 1.911 Å, a distance of 2.73 Å
between the two oxygen atoms, and a reduced CꢀNꢀC bond
angle in the β-lactam ring.10 Similarly, single-crystal XRD analysis
of 2a revealed a reduced CꢀNꢀC bond angle in the β-lactam ring.10
Table 1 reveals moderate to high enantiomeric excess (ee) in
photoproduct 2. Distinct trends were observed for 1b and 1c
with the ability to form an intramolecular H-bond and o-tert-
butyl-substituted 1a that lacks the ability to form an intramole-
cular H-bond. For 1a, there was no observable temperature effect
irrespective of the solvent employed (Table 1).10 For example,
for 1a in MeOH, an ee value of 86% was observed at both 65
and ꢀ25 °C. There was minimal variation in the ee values upon
changing the solvent from toluene (72%) to methanol (86%).
On the other hand, for 1b and 1c, the ee values were not only
dependent on the solvent but also on the reaction temperature.
For example, for 1b, the ee values at a given temperature were
higher in polar solvents with the ability to form H-bonds (water)
and progressively decreased with decreasing solvent polarity.
The ee values were lower in nonpolar solvents that lacked
the ability to form H-bonds (toluene) than in solvents with
higher polarity. For example, for 1b at 65 °C, the ee values
in H2O, MeOH, MeCN, and toluene were 93, 61, 51, and 22%,
respectively (Table 1). Similar selectivities were observed with
both Pyrex and 340 nm cutoff filters.10 As 4π ring closure of
2-pyridones is reversible depending on the irradiation wave-
length,7 control studies were carried out by irradiating photo-
product 2a using both a Pyrex cutoff filter and a >340 nm cutoff
filter.10 As expected, no photoreversion from 2 to 1 was observed,
as 2 does not have absorbance beyond 280 nm.10 The stereo-
chemical course of the photoreaction was deciphered by single-
crystal XRD,10 which showed that (P)-1a gave (1S,4R)-2a and
(M)-1a gave the optical antipode, (1R,4S)-2a, indicating a well-
behaved system. Mechanistically, the 4π dis-“in” rotation was
likely hindered by the developing steric interactions, while the 4π
dis-“out” rotation was favored, resulting in the observed enan-
tioenriched photoproduct (Scheme 1). Our results raise critical
questions pertaining to the temperature and solvent dependence
of the ee values during photochemical 4π ring for closure of 1:
What is the role of intra- and intermolecular H-bonding? What is
the role of entropic factors and/or enthalpic factors? To address
these questions, the differential activation parameters (ΔΔHq and
ΔΔSq) were computed using Eyring plots (eqs 1ꢀ3). Because of
the fast racemization of 1c at elevated temperatures (65 °C), we
computed ΔΔHq and ΔΔSq at low conversions (5ꢀ10%) to
ascertain their true magnitudes. The ee value given by the ln(kSR/
kRS) term is related to ΔΔGq, which depends on both ΔΔHq and
ΔΔSq. The magnitudes and signs of ΔΔHq and ΔΔSq help
explain the effect of solvent and temperature on ee values in 2.
Figure 2. Eyring plot for the photoreactivity of (left) 1a and (right) 1b.
investigated (Figure 2 left). Because of the near-zero/minimal
contribution from ΔΔHq, the ln(kSR/kRS) term (eq 2) hence the
ee values (eq 1) are unaffected by changes in temperature. Thus,
for (P)-1a (Table 1, entries 6 and 7) the positive ΔΔSqSRꢀRS value
gives kSR > kRS, resulting in (1S,4R)-2a. For (M)-1a, the negative
ΔΔSqSRꢀRS value gives kSR < kRS, leading to the optical antipode
(1R,4S)-2a, as observed. Based on the differential activation
parameters, we believe that the 4π photocyclization in o-tert-
butyl-substituted pyridone 1a is entropically controlled. This
speculation is based on the observed free NꢀC(aryl) bond
rotation in the photoproduct 2a compared with the restricted
NꢀC(aryl) bond rotation in 2-pyridone 1a.10 This free Nꢀ
C(aryl) bond rotation possibly manifests itself in the transi-
tion state as entropic control of enantiospecificity, reflecting a
higher contribution from ΔΔSq and minimal contribution from
ΔΔHq. For 1b, the relative contributions from ΔΔHq and ΔΔSq
depend on the solvent. As the solvent polarity decreases (from
water to toluene), the contribution from ΔΔHq increases (Table 1,
entries 14 and 15). There is a substantial contribution from
ΔΔHq in toluene. This higher contribution from ΔΔHq is
reflected in the larger slope values in the Eyring plots (Figure 2
right). The higher values of ΔΔHq reflect the transition state
being influenced by the intramolecular H-bond during the
photochemical transformation in toluene (where only an intra-
molecular H-bond is expected). Apart from the magnitudes of
ΔΔHq and ΔΔSq in 1b, it is important to note the sign of ΔΔHq
and ΔΔSq for a given solvent. In MeOH, MeCN, and toluene,
ΔΔHq and ΔΔSq have the same sign, while in water, ΔΔHq and
ΔΔSq have opposite signs. The ee value, which is given by the
ln(kSR/kRS) term (eq 1), is thus determined by the relative
contributions from ΔΔHq and ΔΔSq (eq 2). Additionally, the
ln(kSR/kRS) term is influenced by temperature through ΔΔHq/
RT term in eq 2. For 1b, the ΔΔHq values are comparable to the
ΔΔSq values in toluene, MeOH, and MeCN. As both ΔΔHq and
ΔΔSq have the same sign in MeOH, MeCN, and toluene,
when the temperature increases, the relative contribution from
the ΔΔHq/RT term decreases, changing the magnitude of the
ln(kSR/kRS) term (eq 2). This is reflected in the temperature
dependence of the ee values. The change in the magnitude of
the ln(kSR/kRS) term (and thus the ee values) is pronounced in
toluene, as there is significant contribution from ΔΔHq. Con-
versely, in water, the contribution from ΔΔHq is minimal,
with a higher contribution from ΔΔSq. As ΔΔHq and ΔΔSq
carry opposite signs, irrespective of their relative contributions,
the magnitude of ln(kSR/kRS) increases, albeit moderately, with
Â
Ã
lnðkSR=kRSÞ ¼ ln ð100 þ %eeÞ=ð100 ꢀ %eeÞ
ð1Þ
ð2Þ
ð3Þ
lnðkSR=kRSÞ ¼ ΔΔSqSRꢀRS=R ꢀ ΔΔHSqRꢀRS=RT
ΔΔGqSRꢀRS ¼ ΔΔHSqRꢀRS ꢀ TΔΔSSqRꢀRS
Table 1 reveals that for 1a, ΔΔSq is dominant with a near-
zero/minimal contribution from ΔΔHq. This is reflected in the
Eyring plots, which have near-zero slopes in all the solvents
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decreasing temperature because of the minimal contribution
from the ΔΔHq/RT term (eq 2). Thus, in water, as ΔΔHq
and ΔΔSq carry opposite signs for a given axially chiral 1b
(P or M), the same enantiomer is enhanced with minimal change
in the ee value at different temperatures.
Our current investigation has provided an opportunity to
manipulate enantiospecific photochemical transformations of
axially chiral chromophores through H-bonding. The dynamic
aspects that arise as a result of H-bonding offer new avenues to
control and comprehend fundamental mechanistic features dur-
ing light-induced transfer of molecular chirality.
For 1c, a trend similar to that for 1b was observed in toluene,
MeOH and MeCN (Table 1, entries 17ꢀ19) . Because of the
fast racemization of 1c at elevated temperatures, ΔΔHq and
ΔΔSq values were computed at low conversions (5ꢀ10%) to
gauge their influence in the initial stages of the reaction. Similar
to 1b, the ΔΔHq values for 1c are comparable to the ΔΔSq
values for a given reaction temperature in toluene, MeOH, and
MeCN. As both ΔΔHq and ΔΔSq have the same sign in MeOH,
MeCN, and toluene, when the temperature is increased, the rela-
tive contribution from the ΔΔHq/RT term decreases, changing
the magnitude of the ln(kSR/kRS) term (eq 2), which is reflected in
the temperature dependence of the ee values (similar to 1b).
The enthalpyꢀentropy compensation plot10 gave a straight
line passing through the origin, indicating that the same mechan-
ism is operating irrespective of the solvent employed.15 To
comprehend the dichotomy between the solvent and tempera-
ture dependences for 1a versus 1b and 1c, it is critical to
appreciate the influence of the solvent molecules surrounding
the substrates and their influence on both ΔΔHq and ΔΔSq. For
1a, few solvent molecules around the amide group will likely
be enough to freeze the CꢀN bond rotation irrespective of the
temperature. Hence, the ee values are not affected drastically by
changes in the temperature or solvent. Conversely, for 1b and
1c, a cluster of intermolecular H-bonds with the solvent in
addition to the intramolecular H-bond facilitated by the amide
carbonyl and the 3° hydroxyl groups likely contributes to both
the differential activation enthalpy and entropy.10 Temperature
plays a crucial role in determining the strength and magnitude
of the H-bonds. This dependence is reflected in the solvent and
temperature effect on the ee values for 1b and 1c.
’ ASSOCIATED CONTENT
S
Supporting Information. Experimental procedures, sin-
b
gle-crystal XRD data (CIF), characterization data, and analysis
conditions. This material is available free of charge via the
Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
sivaguru.jayaraman@ndsu.edu
’ ACKNOWLEDGMENT
The authors thank the NSF for financial support (CAREER
CHE-0748525) and generous funding through NSF-CRIF
(CHE-0946990) for the purchase of departmental XRD instru-
mentation. Anoklase Ayitou, Barry Pemberton, and Ramya
Raghunathan are thanked for help with manuscript preparation.
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