Chasing Weak Forces: Hierarchically Assembled Helicates as a Probe for the Evaluation of the Energetics of Weak Interactions

Article abstract of DOI:10.1021/jacs.7b10098

London dispersion forces are the weakest interactions between molecules. Because of this, their influence on chemical processes is often low, but can definitely not be ignored, and even becomes important in cases of molecules with large contact surfaces. Hierarchically assembled dinuclear titanium(IV) helicates represent a rare example in which the direct observation of London dispersion forces is possible in solution even in the presence of strong cohesive solvent effects. Hereby, the dispersion forces do not unlimitedly support the formation of the dimeric complexes. Although they have some favorable enthalpic contribution to the dimerization of the monomeric complex units, large flexible substituents become conformationally restricted by the interactions leading to an entropic disadvantage. The dimeric helicates are entropically destabilized.

Full text of DOI:10.1021/jacs.7b10098

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Article
Chasing weak forces: hierarchically assembled helicates as a
probe for the evaluation of the energetics of weak interactions
David Van Craen, Wolfgang Hubertus Rath, Marina Huth, Laura Kemp, Christoph Räuber,
Jan Wollschläger, Christoph Schalley, Arto Valkonen, Kari Rissanen, and Markus Albrecht
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.7b10098 • Publication Date (Web): 25 Oct 2017
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Chasing weak forces: hierarchically assembled helicates as a probe
for the evaluation of the energetics of weak interactions
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David Van Craen,† Wolfgang Hubertus Rath,† Marina Huth,† Laura Kemp,† Christoph Räuber,†
Jan Wollschläger,‡ Christoph Schalley,‡ Arto Valkonen,§ Kari Rissanen§ and Markus Albrecht*†
† Institut für Organische Chemie, RWTH Aachen University, Landoltweg 1, 52074 Aachen, Germany, E-mail:
markus.albrecht@oc.rwth-aachen.de; ‡ Institut für Chemie und Biochemie - Organische Chemie, Freie Universität
Berlin, Takustr. 3, 14195 Berlin, Germany; § University of Jyvaskyla, Department of Chemistry, Nanoscience Center,
Survontie 9 B, 40014 Jyväskylä, Finland
KEYWORDS Helicate, self-assembly, London dispersion, thermodynamics
ABSTRACT: London dispersion forces are the weakest interactions between molecules. Because of this, their influence on
chemical processes is often low, but can definitely not be ignored and even becomes important in case of molecules with
large contact surfaces. Hierarchically assembled dinuclear titanium(IV) helicates represent a rare example in which the
direct observation of London dispersion forces is possible in solution even in the presence of strong cohesive solvent ef-
fects. Hereby, the dispersion forces do not unlimitedly support the formation of the dimeric complexes. Although they
have some favorable enthalpic contribution to the dimerization of the monomeric complex units, large flexible substitu-
ents become conformationally restricted by the interactions leading to an entropic disadvantage. The dimeric helicates
are entropically destabilized.
2
Shimizu1 and others.13 Especially, Hunter pointed out
that the measured interaction between the alkyl substitu-
1. Introduction
Weak inter- or intramolecular interactions1 are essen-
tial for the properties of molecules. For example, bio-
ents is strongly influenced by solvent effects like sol-
vophobicity and coherence of the solvent molecules.11, 4
1
materials are built from covalently connected sub-units
(e.g. amino acids) adopting an overall structure which is
mainly controlled by weak non-covalent interactions
including dispersion forces, solvophobic/-philic effects
(e.g. hydrophobicity), or dipole-dipole interactions which
finally may result in a special function.2 Weak forces are
essential in chemical reactions and catalysis by stabilizing
transition states and thus lead to specific products with
high selectivity.3
Scheme 1. A molecular balance developed by Wilcox
for the determination of weak interactions between
substituents R and R’ (a) and the dissociation of a t-
butyl substituted hexaphenyl ethane derivative sta-
bilized by London dispersion interaction of the t-
butyl groups.
In the solid, crystal structure analysis reveals many in-
termolecular contacts which indicate weak London dis-
,
persion forces.4 5 Those even can stabilize unusual spe-
cies.6 Here, such weak interactions are driving forces e.g.
for a specific crystal packing. On the other hand, in the
gas phase, non-covalent aggregates based on weak inter-
actions can be observed relatively easily by different tech-
niques and can be characterized7 by e. g. microwave spec-
troscopy.8
In contrast to this, the situation is much more compli-
cated in solution as in the other two states, due to the
presence of many competing interactions like London
dipolar interactions and solvent effects. In an intriguing
early approach, Wilcox introduced a molecular balance
for the determination of weak interactions9 (Scheme 1, a)
Thus, in order to study weak forces like Van der Waals
interactions and London dispersion in solution, strong
competitive solvent effects have to be considered. One
0
1
which was further applied by Diederich,1 Hunter,1
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way to separate the weak binding forces from the latter is
to measure solvent-dependent energetics of the process in
were investigated by Hannon and Nitschke within the
2
context of subcomponent self-assembly.2
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question.1 However, variation of the solvent obviously
In 2005, we described hierarchically assembled dimeric
helicates which in solution are in equilibrium with the
reveals the energetics of the solvent effects and allows
only a rough estimation of binding energies, e.g. due to
London dispersion. In order to measure London disper-
sion forces more directly, the focus should be on the mol-
ecule which can be varied in a stepwise fashion and is
measured in only one solvent. This way, energetics due to
London dispersion interactions may become observable.
3
corresponding monomers.2 Those helicates are easy to
obtain by self-assembly from synthetically readily availa-
ble components and provide an ideal platform for the
study of weak interactions between appending substitu-
ents following the concept presented in Scheme 2. Here-
by, a monomeric titanium triscatecholate unit can dimer-
ize in the presence of lithium ions to yield the corre-
sponding dinuclear helicate. The monomer-dimer equi-
librium can be easily observed by NMR spectroscopy and
Kdim as well as other thermodynamic parameters are
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Recently, the Schreiner et al reported
a hexa-
phenylethane derivative which is stable in the solid state
due to London dispersion interaction between t-butyl
groups as substituents.6a Upon dissolution in benzene, the
“dimer” partly dissociates into the monomeric radicals
revealing a monomer-dimer equilibrium (Scheme 1, b).
The dissociation energies are determined and it is found
that dissociation is entropically highly favored due to
restriction of t-butyl rotation by attractive London disper-
4
readily measured.2 In the monomer the ligands equili-
brate fast between syn and anti orientation and the three
alkyl groups are well separated, while upon dimerization
of the syn isomer to the helicate ester groups of the two
monomeric units come into close contact and are able to
interact.
6
sion.1
The latter example may act as a blueprint for the devel-
opment of a new probe for the determination of weak
forces in solution. Therefore an easily available and ob-
servable dimer-monomer system has to be made and the
substituents at the basic units have to be systematically
varied. Interaction between the substituents will modu-
late the monomer-dimer equilibrium in addition to the
Scheme 3. Monomer-dimer equilibrium of ester-
substituted catecholate-based hierarchically formed
triply lithium-bridged helicates.
O
O
O
Ti
O
O
O
O
O
O
Kdim
RO
OR
OR
O
O
Ti
Li
O
O
Li
O Li
direct interaction between the two monomers.16,
17
O
Li2
Li
O
O
O
RO
O
O
O
O
RO
O
OR
O
OR
Ti
Scheme 2. Schematic representation of a monomer-
dimer equilibrium which allows the determination
of weak interactions between substituents located at
the rim of the molecular components.
O
O
O
In order to determine the dimerization constants of the
helicates, some restrictions need to be considered: (i) The
complexes are not soluble in non-polar solvents. (ii) In
some solvents (e.g. THF, methanol) only the dimer can be
observed by NMR spectroscopy due to high dimerization
constants. Here, a reliable determination of equilibrium
constants is not possible. (iii) Protic solvents (e. g. water,
methanol) strongly interfere with dimer formation (by
forming hydrogen bonds to the catecholate and ester
oxygen atoms) and make the spectroscopic identification
of subtle interactions impossible.23 As an advantage, on
the other hand, over Wilcox’ molecular balance, the di-
meric complexes possess threefold symmetry, leading to a
threefold interaction and make very weak energies ob-
servable by triplication.
In 1987, Lehn introduced the term "helicate" for self-
assembled coordination compounds with one or more
covalently connected ligand strands twisting around two
2. Results and discussion
8
or more metal centers.1 Hierarchically assembled heli-
Four different series of alkyl-type ester ligands 1-4-H2
and the corresponding titanium complexes Li[Li3(1-4)6Ti2]
have been prepared and characterized.25 Subsequently,
thermodynamic studies (determination of Kdim, van’t Hoff
analyses26) have been performed in DMSO-d6.
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cates with metal ion1 or hydrogen bridged ligands20 ap-
peared a few years later. Here, the assembly of the heli-
cates is based on two recognition events: (1) formation of
a Werner-type complex and (2) dimerization. In addition,
cluster helicates with two terminal complex units being
connected by a central metal cluster have to be men-
We are not aware, that similar studies with a systematic
variation of the chain length have been performed in case
of n-alkyl substituted molecular balances. In case of the
1
tioned.2 Related covalently linked imine-type helicates
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deed become possible between the peripheral parts of the
Wilcox-type molecular balances, either a restricted num-
1
2
3
4
ber of compounds was investigated in many different
solvents or modifications have been done at aromatic
substituents to alter their electronics or sterics. Alkyl
groups have not been studied with a systematic varia-
tion.9-13
alkyl groups. In case of the branched secondary alkyl ester
the ability for alkyl-alkyl interactions highly depends on
9
the CH2-CH-CH2 angle2 controlling the bulkiness of the
substituent.
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O
O(CH2)nCH3
OH
O
O(CH2)2(CF2)nCF3
OH
n = 0, 1, 3
2a-c-H2
n = 0-10
1a-k
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-H2
OH
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OH
n-alkyl esters
n-fluoroalkyl esters
H3C(H2C)n
O
(CH2)n
(CH2)nCH3
O
O
O
n = 1-5
n = 0, 1
3a,b-H2
OH
OH
4a-e-H2
OH
OH
branched alkyl esters
cycloalkyl esters
Figure 1. Four different series of ligands as building blocks of
hierarchically formed triply lithium-bridged helicates.
Crystal structures of hierarchically formed helicates.
Crystals of sufficient quality for the single X-ray diffrac-
tion analysis of the ethyl Li[Li3(1b)6Ti2], cyclobutyl
Li[Li3(4a)6Ti2] and cyclopentyl esters Li[Li3(4b)6Ti2] have
been obtained by slow evaporation of the mother solvent.
The corresponding structures of methyl Li[Li3(1a)6Ti2]23
and isopropylesters Li[Li3(3a)6Ti2]24e were published earli-
er. For the ethyl compound Li[Li3(1b)6Ti2], close contacts
of the ethyl substituents to neighboring catechol units are
observed, while no interactions between adjacent ethyl
…
groups can be found (CHethyl Caryl = 2.78, 2.90 or 3.05 Å,
closest CHethyl…CHethyl = 5.41 Å). The more bulky isopropyl
substituents of Li[Li3(3a)6Ti2] are filling up the cleft of the
helicate much better and alkyl-alkyl contacts are observed
…
in addition to short alkyl-aryl distances (CHiPr Caryl = 3.34
Å, CHiPr…CHiPr = 2.62 Å). In the cyclobutyl derivative
Li[Li3(4a)6Ti2], the CH2-CH-CH2 angle at the methine
carbon (CH2-CH-CH2 = 90°) is smaller as in isopropyl
(CH2-CH-CH2 = 110°) due to the small ring size. This com-
pression at the secondary carbon atom leads to longer
distances between neighboring cyclobutyl groups (CHcy-
Figure 2. Structures of the anions [Li3(1b)6Ti2]- (a),
[Li3(3a)6Ti2]- (b), [Li3(4a)6Ti2]- (c), and [Li3(4b)6Ti2]- (d). Side
view (top) and view down the Ti-Ti axis. Ti: yellow, Li: blue,
C: grey, H: white, C-atoms of representative neighboring
alkyl groups are colored in purple and green.
…Caryl = 2.92, 3.03 Å, shortest CHcyBu…CHcyBu = 3.97 Å).
The cyclopentyl substituent of Li[Li3(4b)6Ti2] is a bit more
expanded (CH2-CH-CH2 = 106°) than the corresponding
four membered ring, but somewhat smaller than isopro-
Bu
Thermodynamic investigations
pyl.
Short
alkyl-alkyl
contacts
are
observed
Thermodynamic studies of the dimerization process are
mainly performed by NMR spectroscopy (DMSO-d6). Kdim
of the monomer dimer equilibrium Li2[(1-4)3Ti]/Li[Li3(1-
4)6Ti2] are shown in Figure 3. In the n-alkyl ester series,
the methyl ester Li[Li3(1a)6Ti2] possesses the lowest di-
merization constant which rises upon elongation of the
(CHcyPent…CHcyPent = 2.66, 2.88 Å, CHcyPent Caryl = 3.01 Å).
…
The results of X-ray diffraction studies indicate London
dispersion interactions between the ester side chains in
the solid state.27 However, they highly depend on the size
of the corresponding moiety. In the described examples,
ethyl groups are not ideal for interalkyl London interac-
tions because they are too separated in the dimeric com-
chain and reaches
a
maximum with heptyl
(Li[Li3(1g)6Ti2]), beyond which it drops again. The dra-
matic change from the methyl (Li[Li3(1a)6Ti2]) to the ethyl
8
plex. However, they show some CH-π interactions.2 In
case of longer n-alkyl chains dispersion interactions in-
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(Li[Li3(1b)6Ti2]) derivative can be explained with different stant of Li[Li3(4b)6Ti2] is found somewhere inbetween the
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inductive effects of the alkyl groups on the lithium coor-
dination at the ester carbonyl. This electronic effect be-
comes less important upon elongation of the chain and
does not play a significant role starting with propyl or
one of the isopropyl and the 3-pentyl-substituted com-
plexes. For the cycloalkane esters, a dimerization constant
similar to the isopropyl derivative Li[Li3(3a)6Ti2] is only
reached starting with the cycloheptyl derivative
Li[Li3(4d)6Ti2]. Obviously, isopropyl fills up the cleft of
the helicate as efficiently as cycloheptyl does, while the
smaller rings cannot do this due to the smaller angles
within the ring.
0
butyl.3 Fluorination of the outer alkyl chain leads to
complexes Li[Li3(2)6Ti2] with dimerization constants Kdim
much lower than those of the non-fluorinated analogues.
In the fluorinated series, Kdim increases somewhat from
the trifluoropropane derivative to the nonafluoro hexane.
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For open chain branched systems Li[Li3(3)6Ti2], Kdim
drops from the isopropyl ester to the 3-pentyl derivative
for sterical reasons. In case of the cyclic esters, Kdim in-
creases from smaller (cyclobutyl) Li[Li3(4a)6Ti2] to bigger
(cyclooctyl) ring size Li[Li3(4e)6Ti2].
Interestingly, the sterically highly demanding isopropyl
ester Li[Li3(3a)6Ti2] possesses the same dimerization con-
stant as the corresponding n-propyl ester Li[Li3(1c)6Ti2].
The even bigger t-butyl ester-substituted complex is steri-
cally so congested that the dimer cannot be formed any-
more while the dimerization constant drops dramatically
for the 3-pentyl ester Li[Li3(3b)6Ti2] as compared to iso-
propyl Li[Li3(3a)6Ti2].
Table 1. Kdim [L/mol] as well as ꢀG0, ꢀH0 and -TΔS0
[kJ/mol] measured by 1H NMR for the monomer-
dimer equilibrium of Li[Li3(L)6Ti2].
Figure 3. Dimerization constants Kdim [L/mol] of n-alkyl
(blue), branched acyclic alkyl (orange), cycloalkyl (red) and
fluorinated alkyl (green) ester derivatives of [Li3L6Ti2]- de-
pending on the number of carbon atoms of the ester side
chain. Kdim was determined by NMR at 298 K in DMSO-d6
containing 0.12 ± 0.04 mol/l of water. Concentrations were
0.002 mol L-1, except for the nonyl-, decyl- and undecyl-
substituted helicates, for which the concentration had to be
decreased due to low solubility.
KDim
ΔG0
ΔH0
-TΔS0
-1,87
0,67
0,83
1,32
1,14
2,89
1,27
3,59
4,02
4,47
5,31
Complex
Li[Li3{(1a)3Ti}2]
Li[Li3{(1b)3Ti}2]
Li[Li3{(1c)3Ti}2]
Li[Li3{(1d)3Ti}2]
Li[Li3{(1e)3Ti}2]
Li[Li3{(1f)3Ti}2]
Li[Li3{(1g)3Ti}2] 2690±345 -19,58 -20,78
Li[Li3{(1h)3Ti}2] 2330±300 -19,22 -22,75
Li[Li3{(1i)3Ti}2]
Li[Li3{(1j)3Ti}2]
Li[Li3{(1k)3Ti}2]
175±20
-12,82 -10,95
-16,67 -17,32
-17,35
830±100
1095±135
1195±145
1920±240 -18,74 -19,83
1530±190 -18,17 -20,92
-18,13
-17,57 -18,82
In order to get a more profound insight into the ther-
modynamics, Van’t Hoff analyses were performed by
NMR.26 It is found that the dimerization of the n-alkyl
Li[Li3(1)6Ti2] as well as fluoroalkyl esters Li[Li3(2)6Ti2] are
enthalpically more favored with increasing chain length.
The plateau and eventually the slight increase in ꢀH0 for
the very long alkyl substituents (1j,k) is tentatively as-
signed to their ability to backfold.31 For the fluoroalkyl
esters, Li[Li3(2)6Ti2] only minor changes can be observed
depending on the chain length. The cycloalkane deriva-
tives also show the increase of ꢀH0 with bigger ring size.
Only in case of the branched systems Li[Li3(3)6Ti2] a de-
crease of enthalpic dimer stabilization is observed due to
a strong steric effect in case of the 3-pentyl esters.
2410±300 -19,30 -23,28
1080±125
810±90
-17,32
-16,60 -21,76
-21,71
Li[Li3{(2a)3Ti}2]
Li[Li3{(2b)3Ti}2]
Li[Li3{(2c)3Ti}2]
200±20
205±20
750±90
-13,15
-13,21
-16,41
-15,83
-14,70
-17,12
-2,67
-1,46
-0,75
Li[Li3{(3a)3Ti}2]
Li[Li3{(3b)3Ti}2]
1010±120
50±5
-17,14
-9,79
-17,91
-14,65
0,85
4,85
Li[Li3{(4a)3Ti}2]
Li[Li3{(4b)3Ti}2]
Li[Li3{(4c)3Ti}2]
Li[Li3{(4d)3Ti}2]
Li[Li3{(4e)3Ti}2]
140±15
560±65
415±50
970±120
1145±140
-12,29
-9,58
-2,68
-1,12
0,52
-0,16
1,14
-15,67 -14,49
-14,94 -15,42
-17,04 -16,89
-17,46 -18,50
The liberation of lithium bound solvent molecules is an
entropic advantage for dimerization.23 In case of the ethyl
ester Li[Li3(1b)6Ti2], however, the restrictions of alkyl
group flexibility override this effect and entropy becomes
unfavorable. Surprisingly, it becomes even more unfavor-
able by the stepwise elongation of the alkyl chain, even
upon elongation far out of the cleft of the molecule. This
can be explained by an “attractive” interaction between
the alkyl groups leading to an enthalpic favorization of
The 3-pentyl derivative Li[Li3(3b)6Ti2] may be compared
with the cyclopentane ester Li[Li3(4b)6Ti2], in which the
terminal groups of 3-pentyl are tethered within the ring
system. However, the corresponding dimerization con-
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the dimerization, but restricting the flexibility of the
chains.
For the fluorinated compounds, effects of chain varia-
tion are very small. Dimerization becomes enthalpically
slightly more favorable and slightly less favored entropi-
cally with longer chain length. The very small energetic
differences indicate that here no strong interactions be-
tween the side groups occur and that parts pointing out
of the cleft are not restricted in flexibility by interaction
with other chains.
Open-chain branched alkyl derivatives: The decrease
of Kdim from the isopropyl to the 3-pentyl ester is domi-
nated by the increasing steric demand of the substituents.
1
2
3
4
5
6
7
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Cycloalkyl derivatives: The cycloalkyl derivatives pos-
sess only restricted flexibility at the substituents and the
enthalpic contribution becomes dominant over the en-
tropic contribution. The latter becomes slightly unfavora-
ble with larger ring size. Enthalpically, the dimer for-
mation is favored with increasing ring size due to higher
contact areas for weak interactions and due to more fa-
vorable angles at the methine carbon atom of the ring in
order to allow efficient interactions between the substitu-
ents. This is also observed in the alkyl-alkyl contacts
found in the crystal structures of the cyclobutyl versus the
cyclopentyl complexes.
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Kinetic studies in THF by ESI mass spectrometry.
Differences in weak interactions may not only be ex-
pressed thermodynamically in binding constant differ-
ences, but can also have a kinetic effect on the barriers
and thus the rates for the exchange of monomers. Such an
exchange reaction in solution can easily be monitored by
ESI mass spectrometry as the dimeric helicates are singly
negatively charged after the abstraction of the lithium
counterion that is not incorporated in the helicate struc-
ture.23 This technique opens up a way to study the effect
of minor changes of the substituents on the dimerization
behavior in solvents which are not appropriate for NMR
studies (e.g. THF).
The exchange mechanisms at the dimeric helicates are
quite complex as no direct exchange of single catecholate
ligands is observed for the dimers. Instead, the dimeric
helicates first dissociate into the two monomeric titanium
tris-catecholate complexes, which then undergo ligand
exchange reactions. Depending on the nature of the sol-
vent, the relative rates of the dimer-to-monomer dissocia-
tion and the ligand exchange on the monomers differ. In
aprotic solvents, the first reaction is usually faster than
the latter, while protic solvents speed up the ligand ex-
change on the monomers.23 Irrespective of these details,
any exchange – that of intact monomers without a subse-
quent fast ligand exchange as well as the fast exchange of
individual ligands on the monomers – begins with the
dissociation of the dimeric helicates into the monomeric
titanium tris-catecholates as the rate determining step.
These two exchange reactions should therefore both be
affected in the same manner by differences in weak forces
affecting the transition state for the dimer-to-monomer
dissociation.
Figure 4. Gibbs free energy (ꢀG0, enthalpy (ꢀH0), as well
as entropy (−ΤꢀS0) changes for the dimerization of substi-
tuted complexes [Li3L6Ti2]- in DMSO-d6.
The thermodynamic trends within series of different es-
ter substituted complexes can thus be summarized in the
following way:
n-Alkyl derivatives: In the dimers, the ester alkyl
groups undergo weak interactions with each other adding
some enthalpic stabilization to the dimer which increases
with the length of the alkyl chain. The entropy of dimeri-
zation becomes more unfavorable with increasing chain
length due to the restriction of the chain mobility.
n-Fluoroalkyl derivatives: In case of the fluorinated
compounds, hardly any interaction occurs between the
side chains leading to no significant difference in the
enthalpic contribution. Entropy of dimerization is always
favorable which is traced back to the liberation of solvent
molecules upon dimerization. However, a slight increase
of –TꢀS0 is based on slight steric restrictions of the chain
mobility.
When two separately generated homodimeric helicates
[Li3LA Ti2]- and [Li3LB Ti2]- are mixed, the signal intensity I
6
6
for the [Li3(LA Ti)(LB Ti)]- heterodimeric helicate will
3
3
increase between [Li3LA Ti2]- and [Li3LB Ti2]-, when the
6
6
exchange of intact monomers is significantly faster than
the exchange of individual ligands on the monomers. If
instead the ligand exchange on the monomers is fast
compared to the dissociation of the dimers into mono-
mers, the signal for [Li3(LA Ti)(LB Ti)]- at the same m/z
3
3
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will also grow together with a statistical distribution of all Li[Li3(2)6Ti2] as well as of the sterically highly congested
1
2
3
4
other possible complexes. Without the need to distin-
guish both processes, we can therefore follow the trends
caused by weak interactions by monitoring the signal for
the 3:3 heterodimer [Li3(LA Ti)(LB Ti)]-.
derivative Li[Li3(3b)6Ti2], this trend cannot be observed.
Parallel to the increase of enthalpy with substituent size
the entropic contribution to the dimerization becomes
unfavorable.
3
3
5
6
7
8
As shown in Figure 5, an exchange parameter Qex can
be defined as the quotient of the intensity I of the ex-
change product [Li3(LA Ti)(LB Ti)]- divided by the product
This behavior shows that the ester substituents under-
go some weak interaction overall stabilizing the dimer
but resulting in a restriction of chain flexibility leading to
a “negative” entropic effect.
3
3
of the intensities of the homodimeric helicate ions
9
[Li3LA Ti2]- and [Li3LB Ti2]-. The smaller this parameter at
6
6
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
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36
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43
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48
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50
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53
54
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57
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60
a given reaction time, the slower the exchange proceeds
and the higher is thus the dissociation barrier for the
dimeric helicate into monomeric tris-catecholate com-
plexes.
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
Figure 5 visualizes the progress of the ligand exchange
reaction after 60 minutes reaction time over the average
chain length of the helicate side chains for homologous
pairs of n-alkyl substituted helicates (i.e. Me/Et: chain
length 1.5, Et/Pr: chain length 2.5 etc.). Clearly, the Qex
parameter decreases with chain length and thus the dis-
sociation barriers increase in the same series. This indi-
cates stabilizing weak interactions to have an observable
effect on the transition state for dimer-to-monomer dis-
sociation. Very interestingly, the decrease of Qex is more
pronounced for side chains of medium length, while the
effect decreases for the longer chains. This parallels the
thermodynamic contributions of the weak interactions to
the stability of the dimeric helicates discussed above.
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
Figure 6. Schematic representation of the alkyl-alkyl
interaction upon dimerization of the titanium triscate-
cholate complexes involving solvent (S) alkyl contact
areas which are reduced in the dimer. The green bonds
are located within the cleft formed in the dimer and do
not have significant solvent contacts.
The question remains as to what the nature of the in-
teraction between the alkyl side groups is. Two different
effects can be responsible for the weak interaction which
has been observed: (i) London dispersion and (ii) sol-
vophobic effects due to cohesive properties of the solvent.
The latter should be especially pronounced in DMSO, but
should not be strong in THF which has been used for the
2
ESI MS study.3
An answer to the question cannot be given by interpre-
tation of the four separate series of complexes with lig-
ands 1-4 as shown in Figures 3 and 4. However, compari-
son of well-selected examples from the different series
provides valuable information. Therefore, complexes from
the four different classes of compounds with similar di-
merization constants have to be considered. Dimerization
constants between 1000 M-1 and 1150 M-1 have been ob-
served for the n-propyl Li[Li3(1c)6Ti2], isopropyl
Li[Li3(3a)6Ti2], cyclooctyl Li[Li3(4e)6Ti2] and n-decyl
Figure 5. Based on the equation in the inset, an exchange
parameter Qex is defined, which expresses the progress of
the exchange reaction after a certain reaction delay (here
60 min). The lengths of the n-alkyl side chains attached to
the helicates is expressed as the averaged chain length.
Data points are plotted for the Me/Et, Et/Pr, Pr/Bu, etc.
pairs.
Li[Li3(1j)6Ti2] substituted systems. The n-propyl as well as
nPr
isopropyl esters show dimerization constants of Kdim
=
1095 M-1 and Kdim = 1010 M-1 with similar enthalpic
iPr
(ꢀH0 = -18.13 kJ/mol, ꢀH0 = -17.91 kJ/mol ) as well as
nPr
iPr
entropic contributions (-TꢀS0 = 0.83 kJ/mol, -TꢀS0
=
nPr
iPr
0.85 kJ/mol). From the crystal structure of Li[Li3(3a)6Ti2],
it can be seen that the isopropyl substituent is well em-
bedded in the cavity which is formed in the dimer. Thus,
solvent exposure is much lower in the dimer as in the
monomer. Based on this, the dimerization, which mini-
mizes contact areas, should be favored by solvophobicity
of the alkyl groups especially in DMSO.11,13f Simple models
of the n-propyl derivative Li[Li3(1c)6Ti2] as well as the X-
The nature of the inter-substituent interaction in the
dimer
The studies described above show that the ester sub-
stituents of the titanium catecholates interact with each
other in the dimers giving some enthalpic contribution to
the dimerization which increases with increasing “size” of
the alkyl group. Only in case of the fluorinated complexes
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strongly disfavored (-TꢀS0
ray structure of the corresponding ethyl compound
= 4.47 kJ/mol). This is due
nDec
1
Li[Li3(1b)6Ti2] show that with short alkyl groups like ethyl
or n-propyl no effective inter-alkyl London dispersion can
take place, but some strong interaction occurs between
the alkyl groups and adjacent catecholates. Because of
their bulkiness, isopropyl groups come in close contact to
each other and enable strong alkyl-alkyl London disper-
sion interactions. On the other hand, the steric demand
of isopropyl might reduce the dimerization energy.
to strong London dispersion interactions between the
2
3
4
5
6
7
8
alkyl side chains supported by cohesive forces of the sol-
3
vent molecules.3 The mobility of the alkyl chains is re-
duced by the interaction leading to the entropic penalty.
3. Conclusion
The energetics of lithium cation-dependent dimeriza-
tion of titanium(IV) triscatecholates bearing esters as
substituents in the 3-position of the catecholate ligands is
strongly influenced by the nature of the ester substituent.
Thermodynamic investigations reveal that side chains
weakly interact. In solution, interacting groups may be
highly dynamic and their interaction is strongly covered
by solvent effects (e.g. solvophobicity). In the case of the
hierarchically assembled helicates discussed here, the
interaction energies are amplified by the 3-fold symmetry
of the system leading to a 3-fold interaction and corre-
spondingly to a much larger interaction energy. This en-
ergy contribution to the dimerisation can be observed in
the trends of the equilibrium constants depending on
chain lengths and structures and thermodynamic as well
as exchange parameters can be determined. In case of the
linear alkyl substituents, London dispersion forces are
observed with more than three or four carbon atoms in
the chain. Starting from this chain length, the through-
bond inductive effects do not anymore alter the binding
of the lithium cations and the groups diverge from the
complex. Thus, they have negligible different steric de-
mand in respect to the dimerization. The detailed study
of hierarchically assembled dimeric helicates reveals that
alkyl substituents typically – and superficially – thought
of as innocent, show significant solvophobicity-supported
London dispersive interactions in solution. However,
enthalpic stabilization is accompanied by a destabilising
entropic effect due to conformational fixation of the chain
getting more pronounced with longer chain length. Fluor-
inated derivatives cannot undergo such interactions sig-
nificantly and do not show this effect. With the more
rigid cycloalkanes the entropic effect is significantly re-
duced. In summary, London dispersion forces are enthal-
pically beneficial for stabilizing chemical structures, but
some significant entropic cost has to be paid.34
9
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41
42
43
44
45
46
47
48
49
50
51
52
53
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56
57
58
59
60
Figure 7. Overlayed structures of the isopropyl
Li[Li3(1c)6Ti2] (green) and the cyclo-butyl derivatives
Li[Li3(4a)6Ti2] (magenta) showing similar sizes of the
ester substituents.
Following this, a similar dimerization constant as for
isopropyl Li[Li3(1c)6Ti2] would be expected for the cyclo-
butyl Li[Li3(4a)6Ti2] and cyclopentyl derivatives
Li[Li3(4b)6Ti2] if the observed enhancement of the dimer-
ization is based on solvophobic effects. However, the
cyBu
small ring systems show dramatically lower Kdim (Kdim
= 140 M-1, Kdim
= 560 M-1) which is mainly due to a
cyPent
much lower enthalpic contribution to the dimerization
while entropy even is favorable for the relatively rigid
rings (ꢀH0
= -9.6 kJ/mol, -TꢀS0
= -2.7 kJ/mol;
cyBu
cyBu
(ꢀH0cyPent = --14.5 kJ/mol, -TꢀS0cyPent = -1.1 kJ/mol). Because
of the similar space requirements of the isopropyl and
cyclobutyl / cyclopentyl derivatives in the cleft (Figure 7),
solvophobic effects cannot cause such a big difference in
dimerization energies. The differences can be rather ex-
plained by London dispersion interaction between the
substituents within the cleft for the cyclic compared to
the isopropyl derivative. Upon expansion of the ring size
to cycloheptyl or cyclooctyl, the substituent becomes
bulky enough for strong London dispersion interactions
ASSOCIATED CONTENT
Supporting Information. Synthetic procedures, details on
the thermodynamic studies, spectroscopic and spectrometric
investigations and on the crystal structures. This material is
available free of charge via the Internet at
http://pubs.acs.org.” For instructions on what should be
included in the Supporting Information as well as how to
prepare this material for publication, refer to the journal’s
Instructions for Authors.
and the dimerization constant becomes similar to those
cyOct
of the n-/isopropyl substituted complexes (Kdim
= 1145
M-1) with a strong enthalpic contribution on dimerization
(ꢀH0cyOct = -18.50 kJ/mol). In this case, the London disper-
sion interactions probably experience some support by
alkyl solvophobicity.
nDec
The n-decyl derivative Li[Li3(1j)6Ti2] shows Kdim
=
1145 M-1. In contrast to the earlier discussed examples, a
very strong enthalpic stabilization (ꢀH0
= -21.71
kJ/mol) occurs while the dimerization is entropically
AUTHOR INFORMATION
Corresponding Author
nDec
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Journal of the American Chemical Society
Page 8 of 9
* Markus Albrecht, RWTH Aachen University, Institut für
1497; (d) Leopold, K. R.; Canagaratna, M.; Phillips, J. A.
1
2
3
4
5
6
7
8
Organische Chemie, Landoltweg 1, 52074 Aachen, Germany;
markus.albrecht@oc.rwth-aachen.de
Acc. Chem. Res. 1997, 30, 57ꢀ64; (e) Leopold, K. R.;
Fraser, G. T.; Novick, S. E.; Klemperer, W. Chem. Rev.
1994, 94, 1807ꢀ1827.
Author Contributions
9
(a) Kim, E.; Paliwal, S.; Wilcox, C. S. J. Am. Chem. Soc.
The manuscript was written through contributions of all
authors. All authors have given approval to the final version
of the manuscript.
1998, 120, 11192ꢀ11193.
10
Gardarsson, H.; Schweizer, W. B.; Trapp, N.; Diederich,
F. Chem. Eur. J. 2014, 20, 4608ꢀ4616;
11 (a) Cockroft, S. L.; Hunter, C. A. Chem. Commun., 2006,
3806ꢀ3808; (b) Cockroft, S. L.; Hunter, C. A. Chem. Soc.
Rev. 2007, 36, 172ꢀ188.
Funding Sources
9
Deutsche Forschungsgemeinschaft (DVC, MA), Academy of
Finland (K.R.: grants no. 263256, 265328 and 292746)
10
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12
(a) Carroll, W. R.; Pellechia, P.; Shimizu, K. D. Org.
Lett. 2008, 10, 3547ꢀ3550; (b) Chong, Y. S.; Carroll, W.
R.; Burns William, G.; Smith, M. D.; Shimizu, K. D.
Chem. Eur. J. 2009, 15, 9117ꢀ9126; (c) Carroll, W. R.;
Zhao, C.; Smith, M. D.; Pellechia, P. J.; Shimizu, K. D.
Org. Lett. 2011, 13, 4320ꢀ4323; (d) Hwang, J.; Li, P.;
Smith, M. D.; Shimizu, K. D. Angew. Chem. Int. Ed. 2016,
55, 8086ꢀ8089; (e) Maier, J. M.; Li, P.; Vik, E. C.; Yehl, C.
J.; Shimizu, K. D; Strickland, S. M. S. J. Am. Chem. Soc.
2017, 139, 6550ꢀ6553.
ACKNOWLEDGMENT
We are grateful for funding by the international gradu-
ate school Seleca (Deutsche Forschungsgemeinschaft)
and the Collaborative Research Center 765 (Deutsche
Forschungsgemeinschaft) the Academy of Finland (K.R.:
grants no. 263256, 265328 and 292746) and the University
of Jyväskylä. We thank Prof. Gerhard Raabe for collection
of the data set of Li[Li3(1b)6Ti2].
13
(a) Jennings, W. B.; Farrell, B. M.; Malone, J. F. Acc.
Chem. Res. 2001, 34, 885ꢀ894; (b) Cornago, P.; Claramunt,
R. M.; Bouissane, L.; Elguero, J. Tetrahedron 2008, 64,
3667ꢀ3673; (c) Alkorta, I.; Blanco, F.; Elguero, J. Tet. Lett.,
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Malone, J. F.; Boyd, D. R. Org. Biomol. Chem. 2013, 11,
5278ꢀ5291; (f) Yang, L.; Adam, C.; Nichol, G. S.; Cockꢀ
roft, S. L. Nat. Chem. 2013, 5, 1006ꢀ1010; (g) Yamada, S.;
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