Enantiopure [Cs+/Xe?Cryptophane]?FeII 4L4 Hierarchical Superstructures

Article abstract of DOI:10.1021/jacs.9b02866

Hierarchically nested hosts offer new opportunities to control the guest binding of the inner host, functionalize the cavity of the outer host, and investigate communication between different layers. Here we report a selfassembled triazatruxene-based FeII

Full text of DOI:10.1021/jacs.9b02866

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Article
Enantiopure [Cs+/Xe#Cryptophane]#FeII4L4 Hierarchical Superstructures
Dawei Zhang, Tanya K Ronson, Jake L. Greenfield, Thierry Brotin, Patrick
Berthault, Estelle Leonce, Junlong Zhu, Lin Xu, and Jonathan R. Nitschke
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 29 Apr 2019
Downloaded from http://pubs.acs.org on April 29, 2019
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Enantiopure [Cs+/Xe⊂Cryptophane]⊂FeII L
4 4
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Hierarchical Superstructures
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Dawei Zhang,† Tanya K. Ronson,† Jake L. Greenfield,† Thierry Brotin,‡ Patrick Berthault,§
Estelle Léonce,§ Junlong Zhu,# Lin Xu,†,# and Jonathan R. Nitschke*,†
†Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK.
‡Lyon 1 University, Ecole Normale Supérieure de Lyon, CNRS UMR 5182, Laboratoire de chimie, 69364
Lyon, France.
§NIMBE, CEA, CNRS, Université de Paris Saclay, CEA Saclay, 91191 Gif-sur-Yvette, France.
#Shanghai Key Laboratory of Green Chemistry and Chemical Processes, School of Chemistry and
Molecular Engineering, East China Normal University, Shanghai 200062, China.
Abstract
Hierarchically nested hosts offer new opportunities to control the guest binding of the inner host,
functionalize the cavity of the outer host, and investigate communication between different layers.
Here we report a self-assembled triazatruxene-based FeII L4 capsule, which was able to
4
encapsulate a covalent cage, cryptophane-111 (CRY). The resulting cage-in-cage complex was
capable of accommodating a cesium cation or xenon atom with altered guest binding behavior
compared to the CRY alone. A crystal structure of the Russian doll complex [Cs+⊂CRY]⊂FeII L4
4
unambiguously demonstrated the unusual encapsulation of a cation within a capsule bearing a
8+ charge. Moreover, the binding of enantiopure CRY occurred with high enantioselectivity (530-
fold) between the two enantiomers of the tetrahedron. This discrimination resulted in
stereochemical information transfer from the inner covalent cage to the outer self-assembled
capsule, leading to the formation of enantiopure [guest⊂cage]⊂cage complexes. The
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stereochemistry of the tetrahedron persisted even after displacement of CRY with an achiral
guest.
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Introduction
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Russian-doll-like superstructures1 consisting of nested host-in-host complexes2 as essential
precursors, have intrigued supramolecular chemists for over a decade.3 Besides the beauty of
the hierarchical architectures, the binding properties of the inner host, ensconced within the outer
host, may be changed through outer-host encapsulation.1d,1g,4 This effect evokes the
encapsulation of enzymes in nanometer-sized protein compartments to enhance and control
enzymatic activity.5 This strategy also offers a new approach to internally functionalize larger
capsules,6 endowing them with the ability to bind molecules that are not otherwise encapsulated.
These newly designed Russian dolls, which consist of robust, multiple three-dimensional nested
hosts, thus compliment and build upon the foundations of those involving two-dimensional
macrocycles1a-j,1l or single assemblies with multi-layered walls.1k,2e,2f
Coordination-driven self-assembled capsules7 are excellent outer hosts because they may be
designed to be large and to have wide-ranging guest binding abilities. They also exhibit structural
adaptability as a consequence of the reversibility of their coordinative bonds.8 In contrast,
cryptophanes,9 a type of covalent cage built from two cyclotribenzylene units,10 serve very well as
inner hosts. They encapsulate small molecules such as methane or xenon, as well as cations and
anions.9 Furthermore, many cryptophanes are inherently chiral.9 When used in enantiopure form,
they enable the investigation of the stereochemical communication between the different layers
of Russian doll complexes, allowing a new class of enantiopure nested hosts to be investigated.
Here we show the encapsulation of cryptophane-111 (CRY)11 within a self-assembled FeII L4
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capsule constructed from a triazatruxene-based subcomponent, and demonstrate how cage-in-
cage formation alters the binding behavior of the inner cage and endows the outer tetrahedron
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with new binding ability. Cesium cations and xenon atoms are bound within the host-in-host
complex to form Russian doll-like superstructures. Stereochemical communication occurred
between layers when enantiopure CRY was employed, resulting in the handedness of the
tetrahedron host framework becoming fixed by the CRY guest stereochemistry and allowing
further fabrication of enantiopure three-component Russian doll complexes. The stereochemical
configuration of the outer host was robustly maintained even following the displacement of the
CRY by an achiral guest.
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Results and Discussion
Triazatruxene-based subcomponent A was synthesized in four steps from commercially available
starting materials (Figure S1). The reaction of subcomponent A (4 equiv) with iron(II)
bis(trifluoromethanesulfonyl)imide (triflimide, Tf2N−) (4 equiv) and 2-formylpyridine (12 equiv) in
acetonitrile afforded tetrahedron 1 with one triazatruxene capping each face (Figure 1). The FeII4L4
composition of the assembly was confirmed by ESI-MS (Figure S12). Due to the possibility of
either clockwise (C) or anticlockwise (A) orientation of the triazatruxene panels around the center
of each face, as well as the Λ or Δ handedness at the tris-chelated octahedral vertices of the
tetrahedron, a series of stereoisomers might be envisaged.12 The 1H NMR spectrum of FeII L4 1
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displayed only one set of ligand signals (Figure 1), suggesting the exclusive formation of a pair of
T-symmetric tetrahedral enantiomers with homochiral faces and vertices. We infer that the
homochiral configuration of 1 arises from the rigid three-fold symmetric ligands, which provide
conformational rigidity to the cage framework, as has been observed for cages built from other
C3-symmetric ligands.13 Based upon the crystal structure discussed below, we infer these to be
A4Δ4-1 and C4Λ4-1, with anticlockwise (A) triazatruxene panels always paired with Δ handedness
of the iron(II) stereocenters, and clockwise (C) triazatruxene with Λ iron(II). We thus refer to these
stereoisomers as Δ4-1 and Λ4-1, henceforth.
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b
c
FeII L4 1
4
rac-CRY⊂FeII L4 1
*
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* *
*
DOSY of rac-CRY⊂FeII L4 1
4
D = 5.7 10-6 cm2 s-1
ppm
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Figure 1. (a) Subcomponent self-assembly of 1. (b) Enantioselective encapsulation of rac-CRY by 1. (c) 1H
NMR spectra (CD3CN, 500 MHz, 25 °C) of 1 and CRY⊂1, and DOSY spectrum of CRY⊂1. The peaks of
the encapsulated CRY have been highlighted with a light orange background. Solvent peaks from diethyl
ether, water and acetonitrile are indicated by asterisks. DOSY NMR indicated that the signals from 1 and
the bound CRY diffuse at the same rate.
Addition of racemic CRY (rac-CRY) to a solution of 1 in acetonitrile led to formation of the cage-
in-cage complex, CRY⊂1, after 70 °C for 12 h. This complex was isolated in pure form by
precipitation with diethyl ether. Encapsulation was signaled by the disappearance of the 1H NMR
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peaks of free 1 and the concurrent appearance of a new set of peaks for the tetrahedron and its
CRY guest, which were shifted upfield. All signals had the same diffusion coefficient (Figure 1c),
which correspond to the CRY⊂1 complex. As enantiomers of both 1 and CRY were present, and
no diastereomeric species were observed by NMR after host-guest complexation, we infer
stereoselective encapsulation to have taken place, forming a mixture of two enantiomeric host-
guest complexes, which we infer to be PP-CRY⊂Δ4-1 and MM-CRY⊂Λ4-1 from the crystal
structure discussed below. NOESY and ESI-MS spectra further indicated the formation of the 1:1
host-guest complex (Figures S19 and S23). The binding constant of 1 for CRY was too high to be
determined directly; we thus employed di(p-tolyl)fluorine as an intermediate guest (Figure S24),
allowing the determination of Ka = (9.5±0.4)×106 M-1 through competitive guest displacement
(Figure S27).
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We then tested the binding ability of the host-in-host complex, CRY⊂1, for the cesium cation,
which is a known guest of other cryptophanes.14 Slow vapor diffusion of ethyl acetate into an
acetonitrile solution of a mixture of CRY⊂1 and CsCB11H12 provided crystals suitable for X-ray
crystallographic analysis (Figure 2). Carborate was used as the counter-anion of Cs+ in order to
obtain X-ray quality crystals.15 Two enantiomers, [Cs+⊂PP-CRY]⊂Δ4-1 and [Cs+⊂MM-CRY]⊂Λ4-
1, are present in the unit cell (Figure S13). A single Cs+ cation is located close to the centroid of
the CRY cage with an average refined occupancy of 36%. Each FeII L4 cage encapsulates a CRY
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in its cavity, displaying contacts consistent with the presence of CH-π interactions. The structure
provided unambiguous assignment of the relative stereochemical orientations of the triazatruxene
faces and tris-chelated octahedral vertices within 1. The iron(II) centers are separated by
distances of 20.0-20.9 Å. The volume of the central cavity was calculated to be 1010 and 913 Å3
for the two crystallographically independent cages in the asymmetric unit (Figure S15). The
degree of outward bending of some triazatruxene faces and the number of their internally oriented
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ethyl groups accounted for the different volumes. The cavity was thus suitable for the
accommodation of a CRY guest with an estimated volume of 694 Å3.
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Figure 2. Crystal structure of [Cs+⊂CRY]⊂1 illustrating the [Cs+⊂PP-CRY]⊂Δ4-1 enantiomer. The bound
Cs+, CRY and the front triazatruxene face are colored yellow, orange and cyan, respectively. Disorder,
unbound counterions, and solvent of crystallization are omitted for clarity and only one of the two
crystallographically independent complexes is shown.
Cesium binding by CRY⊂1 was also observed in solution, in slow exchange on the NMR
timescale. In this case, cesium triflimide was employed in order to match the counter-anions of
the assembled cage. Upon progressive addition of CsNTf2 to an acetonitrile solution of CRY⊂1,
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the initial H NMR peaks gradually diminished with the appearance of a new set of signals
corresponding to [Cs+⊂CRY]⊂1, allowing a binding constant of 34±3 M-1 to be determined (Figure
S28). The other alkali metal ions, including Li+, Na+, K+, and Rb+, were also tested, with no binding
observed by 1H NMR spectroscopy (Figure S29). Encapsulation of cesium was also demonstrated
by 133Cs NMR experiments. As shown in Figure 3a, after addition of Cs+, a new peak appeared
at -316 ppm alongside the free Cs+ peak at 32 ppm. This new peak was assigned to the Cs+ inside
CRY⊂1, experiencing a strong shielding effect.14 In contrast, without the outer tetrahedral host,
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CRY was observed to bind Cs+ in fast exchange on the NMR timescale, showing gradual shifts
of the host proton signals during titrations (binding constant, 23±1 M-1) and only a single 133Cs
peak (Figures S34 and S35). The binding behavior of CRY had thus been altered through
encapsulation, increasing the barrier to Cs+ exchange and bringing about a slight amplification in
binding strength. This enhancement in Cs+ binding is counterintuitive, because the binding of CRY
within 1 results in an 8+ charge surrounding the CRY-bound cesium cation. [Cs+⊂CRY]⊂1 thus
represents an unusual example of encapsulation of a charged species within a capsule of the
same charge.16
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a
free Cs+
[Cs+⊂CRY]⊂1
ppm
b
free Xe
[Xe⊂CRY]⊂1
ppm
Figure 3. (a) 133Cs NMR (CD3CN, 66 MHz, 60 °C) spectrum of CRY⊂1 in the presence of excess Cs+. (b)
129Xe NMR (CD3CN, 138 MHz, 25 °C) spectrum of CRY⊂1 in the presence of excess Xe.
Bubbling xenon gas through an acetonitrile solution of CRY⊂1 also resulted in clear changes
to its 1H NMR spectrum (Figure S36), which were particularly significant in the region of the bound
CRY, indicating encapsulation of Xe by CRY⊂1. 129Xe NMR experiments using hyperpolarized
Xe were then carried out. As shown in Figure 3b, in addition to the peak assigned to free Xe at
179 ppm, a new upfield peak at 47 ppm was observed, corresponding to Xe within CRY⊂1.
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Addition of excess CRY into the same sample gave rise to another peak of CRY-caged xenon, at
50 ppm with much weaker intensity due to the low solubility of CRY in acetonitrile (Figure S37).
The outer tetrahedral layer thus contributes to the shielding effect experienced by caged xenon,
in addition to the CRY core. 1D selective inversion 129Xe EXSY experiments with variable mixing
time gave an exchange rate between [Xe⊂CRY]⊂1 and free Xe of 11±2 Hz (Figure S38).17
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We then set about investigating stereochemical communication between 1 and CRY in their
host-guest complex (Figure 4). After adding enantiopure PP-CRY to 1 and heating to 70 °C for
12 h, two diastereomeric host-guest complexes, PP-CRY⊂Δ4-1 and PP-CRY⊂Λ4-1, formed in a
1
1:1 ratio, as indicated by the presence of two sets of signals in the H NMR spectrum (Figure
S39). Maintaining the mixture at 70 °C for a further three days resulted in no change in the ratio
between the two diastereomers, consistent with a high energy barrier for diastereomer
interconversion. After the removal of excess CRY in solution by precipitating the host-guest
complexes with diethyl ether and redissolution in CD3CN, selective release of PP-CRY from Λ4-1
was observed after three days at 25 °C, resulting in diastereomeric enrichment of PP-CRY⊂Δ4-1
(Figure 4 and Figure S39). A binding constant of (1.8±0.1)×104 M-1 between PP-CRY and Λ4-1
was determined from 1H NMR integration (Supplementary section 7.1, Figure S40), which is 530
times smaller than the affinity of (9.5±0.4)×106 M-1 between PP-CRY and Δ4-1 noted above,
indicating high enantioselectivity of binding.
Heating the initially-formed mixture of PP-CRY⊂Λ4-1 and PP-CRY⊂Δ4-1 to 150 °C for four
hours in a microwave reactor, however, resulted in the conversion of the mixture to 97% PP-
CRY⊂Δ4-1 (Figure S41). The high temperature required and complete inversion of the chirality of
all vertices suggest a mechanism of conversion involving a significant degree of cage disassembly
and reassembly. Starting from MM-CRY resulted in the formation of the enantiomeric cage-in-
cage product, MM-CRY⊂Λ4-1, in a comparable yield (Figure S42). These enantiopure Russian
doll precursors were isolated and purified by precipitation with diethyl ether. We infer that this
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efficient stereochemical information transfer18 reflects the high degree of enantioselectivity in
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binding between PP-CRY and the two enantiomers of rac-1.
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Guest release
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25 C
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+
PP-CRY⊂Λ4-1
150 C Stereochemical
70 C
induction
+
Host-guest
complexation
rac-1
PP-CRY
Stereochemical
memory
70 C
PP-CRY⊂Δ4-1
C60⊂Δ4-1
Figure 4. Stereochemical information transfer from CRY to 1. The presence of excess PP-CRY and
racemic 1 at 70 °C produced two diastereomeric host-guest complexes, but PP-CRY⊂Λ4-1 was observed
to spontaneously lose guest at 25 °C after removal of excess CRY, and converted to the more stable PP-
CRY⊂Δ4-1 upon heating to 150 °C. Subsequent treatment with C60 resulted in displacement of chiral CRY
but maintenance of the stereochemical definition of 1.
CD spectroscopy also confirmed stereochemical communication within the CRY⊂1 system. As
shown in Figure 5a, strong Cotton effects in the triazatruxene absorption region (300-350 nm)
and for metal-to-ligand charge-transfer (MLCT) (500-650 nm) were observed in CD spectra of the
host-guest complexes when using enantiopure CRY. The positive CD MLCT band corresponds
to induction of Δ handedness of the metal center by PP-CRY, as observed in the crystal structure.
This assignment is also consistent with previous observations.13 No optical activity was observed
when rac-CRY was used as the guest.
When achiral fullerene C60 displaced chiral CRY within 1 (Figures S43 and S44), strong Cotton
effects as well as the sign, in particular of the MLCT region, persisted in the CD spectrum of the
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new C60⊂1 host-guest complex (Figure 5b), suggesting a stereochemical memory effect.13 No
decrease in the intensity of the CD signals was observed after a month in solution (13 μM) at
room temperature (Figure S45). We infer that the persistent stereochemical memory is a
consequence of the structural integrity of the whole tetrahedral framework. This integrity is
maintained by the rigid tritopic ligands of 1 during guest displacement, allowing this process to
proceed without racemization.13
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a
b
20
10
0
20
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0
PP-CRY⊂Δ4-1
MM-CRY⊂Λ4-1
C60⊂Δ4-1
C60⊂Λ4-1
-10
-20
-10
-20
rac-CRY⊂rac-1
C60⊂rac-1
300
400
500
600
700
300
400
500
600
700
Wavelength (nm)
Wavelength (nm)
Figure 5. (a) CD spectra of PP-CRY⊂Δ4-1 (orange), MM-CRY⊂Λ4-1 (green) and rac-CRY⊂rac-1 (purple).
(b) CD spectra of C60⊂Δ4-1 (orange), C60⊂Λ4-1 (green) and C60⊂rac-1 (purple), formed following CRY
guest displacement.
Addition of Cs+ or xenon to the enantiopure cage-in-cage complexes allowed us to construct
enantiopure three-component Russian dolls, [Cs+/Xe⊂PP-CRY]⊂Δ4-1 and [Cs+/Xe⊂MM-
CRY]⊂Λ4-1 (Figures S49 and S50). Cs+ was able to serve as a probe to discriminate between
diastereomeric complexes by NMR. Its addition to a solution containing the two diastereomers
PP-CRY⊂Δ4-1 and PP-CRY⊂Λ4-1 gave a 133Cs NMR spectrum with peaks at 256 and 311 ppm
(Figure 6a). Similarly, bubbling xenon into a solution of the same two diastereomeric nested hosts
gave a 129Xe NMR spectrum with host-guest resonances at 47 and 54 ppm. (Figure 6b). The 133Cs
and 129Xe nuclei thus were able to sense the chirality of the outermost cage, even though the
inner CRY cage was always of PP stereochemistry.14,19 Moreover, the peak of xenon
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encapsulated within CRY alone is located at 50 ppm (Figure S37), between the above two
diastereomeric Xe signals, indicating that the outer capsule 1 is capable of either strengthening
or weakening the shielding effect of the inner CRY core, depending on its stereochemistry.
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free Cs+
[Cs+⊂PP-CRY]⊂Δ4-1
[Cs+⊂PP-CRY]⊂Λ4-1
ppm
b
free Xe
[Xe⊂PP-CRY]⊂Δ4-1
[Xe⊂PP-CRY]⊂Λ4-1
ppm
Figure 6. (a) 133Cs NMR (CD3CN, 66 MHz, 60 °C) spectrum of CRY⊂1 containing the two diastereomers
PP-CRY⊂Δ4-1 and PP-CRY⊂Λ4-1 in the presence of excess Cs+. (b) 129Xe NMR (CD3CN, 138 MHz, 25
°C) spectrum of CRY⊂1 containing two diastereomers PP-CRY⊂Δ4-1 and PP-CRY⊂Λ4-1 in the presence
of excess Xe. In both NMR spectra, the peaks of encapsulated guests within PP-CRY⊂Δ4-1 are of higher
intensity than those within PP-CRY⊂Λ4-1 due to the release of more weakly-bound PP-CRY from Λ4-1
during the NMR measurement (Figure S39).
Conclusion
The new [guest⊂cage]⊂cage complexes presented herein comprise a new class of enantiopure
Russian dolls, building upon the foundations of previous host-in-host complexes involving two-
dimensional macrocycles.1a-j,1l As Cs+ was initially bound by CRY in fast exchange on the NMR
timescale and Xe was insufficiently encapsulated by the poorly acetonitrile-soluble CRY, our
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results demonstrate that encapsulation of a host can improve its guest binding performance. Inner
“functionalization” of the large cavity of 1 through binding of CRY also enabled the encapsulation
of a cation within a capsule bearing a high positive charge. The stereochemical induction effect
of CRY upon the framework of 1, followed by the displacement of the chiral guest, also represents
a novel means to fix the stereochemistry of a host framework. These phenomena could prove
useful for molecular-recognition-based applications, such as catalysis, separations, drug delivery
and sensing.
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Associated Content
Supporting Information
The Supporting Information is available free of charge on the ACS Publications website.
Complete experimental details (PDF)
X-ray data for [Cs+⊂CRY]⊂1 (CCDC 1894903)
Author Information
Corresponding Author
*J.N. jrn34@cam.ac.uk
ORCID
Dawei Zhang: 0000-0002-0898-9795
Tanya K. Ronson: 0000-0002-6917-3685
Jonathan R. Nitschke: 0000-0002-4060-5122
Acknowledgements
This work was supported by the European Research Council (695009) and the UK Engineering
and Physical Sciences Research Council (EPSRC, EP/P027067/1). The authors thank the
Department of Chemistry NMR facility, University of Cambridge for performing some NMR
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experiments, Diamond Light Source (UK) for synchrotron beamtime on I19 (MT15768) and the
EPSRC UK National Mass Spectrometry Facility at Swansea University for carrying out high
resolution mass spectrometry. D. Z. acknowledges the Herchel Smith Research Fellowship from
the University of Cambridge. The authors acknowledge Dr Roy Lavendomme (University of
Cambridge) for useful discussions and help in cryptophane-111 volume calculation, Dr Nicolas
Vanthuyne (Aix-Marseille University) for the separation of the racemic cryptophane-111, and Dr
Derrick A. Roberts (University of Cambridge) for assistance with the production of graphical
material.
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[Cs+⊂PP-cryptophane]⊂Δ4-FeII4L4
[Cs+⊂MM-cryptophane]⊂Λ4-FeII4L4
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Figure 1. (a) Subcomponent self-assembly of 1. (b) Enantioselective encapsulation of rac-CRY by 1. (c) 1H
NMR spectra (CD3CN, 500 MHz, 25 °C) of 1 and CRY⊂1, and DOSY spectrum of CRY⊂1. The peaks of the
encapsulated CRY have been highlighted with a light orange background. Solvent peaks from diethyl ether,
water and acetonitrile are indicated by asterisks. DOSY NMR indicated that the signals from 1 and the bound
CRY diffuse at the same rate.
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Figure 2. Crystal structure of [Cs+⊂CRY]⊂1 illustrating the [Cs+⊂PP-CRY]⊂Δ4-1 enantiomer. The bound
Cs+, CRY and the front triazatruxene face are colored yellow, orange and cyan, respectively. Disorder,
unbound counterions, and solvent of crystallization are omitted for clarity and only one of the two
crystallographically independent complexes is shown.
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Figure 3. (a) 133Cs NMR (CD3CN, 66 MHz, 60 °C) spectrum of CRY⊂1 in the presence of excess Cs+. (b)
129Xe NMR (CD3CN, 138 MHz, 25 °C) spectrum of CRY⊂1 in the presence of excess Xe.
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Figure 4. Stereochemical information transfer from CRY to 1. The presence of excess PP-CRY and racemic 1
at 70 °C produced two diastereomeric host-guest complexes, but PP-CRY⊂Λ4-1 was observed to
spontaneously lose guest at 25 °C after removal of excess CRY, and converted to the more stable PP-
CRY⊂Δ4-1 upon heating to 150 °C. Subsequent treatment with C60 resulted in displacement of chiral CRY
but maintenance of the stereochemical definition of 1.
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Figure 5. (a) CD spectra of PP-CRY⊂Δ4-1 (orange), MM-CRY⊂Λ4-1 (green) and rac-CRY⊂rac-1 (purple). (b)
CD spectra of C60⊂Δ4-1 (orange), C60⊂Λ4-1 (green) and C60⊂rac-1 (purple), formed following CRY guest
displacement.
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Figure 6. (a) 133Cs NMR (CD3CN, 66 MHz, 60 °C) spectrum of CRY⊂1 containing the two diastereomers PP-
CRY⊂Δ4-1 and PP-CRY⊂Λ4-1 in the presence of excess Cs+. (b) 129Xe NMR (CD3CN, 138 MHz, 25 °C)
spectrum of CRY⊂1 containing two diastereomers PP-CRY⊂Δ4-1 and PP-CRY⊂Λ4-1 in the presence of excess
Xe. In both NMR spectra, the peaks of encapsulated guests within PP-CRY⊂Δ4-1 are of higher intensity than
those within PP-CRY⊂Λ4-1 due to the release of more weakly-bound PP-CRY from Λ4-1 during the NMR
measurement (Figure S39).
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