Hemiacetals in dynamic covalent chemistry: Formation, exchange, selection, and modulation processes

Article abstract of DOI:10.1021/jo9009886

(Chemical Equation Presented) A reversible formation of hemiacetals represents a useful tool in covalent dynamic chemistry. Heterocyclic hemiacetals can be stabilized effectively via either protonation or metal cation coordination. The resulting hemiaceta

Full text of DOI:10.1021/jo9009886

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We present here some of our results on the implementation
Hemiacetals in Dynamic Covalent Chemistry:
Formation, Exchange, Selection, and Modulation
Processes
of hemiacetals as the functional group of interest for DCC.
Hemiacetals are formed from the reversible condensation of
alcohols with a carbonyl group. Generally, they are rather
unstable species, forming in only very small amounts, except
when they are stabilized by structural effects as in the cyclic
carbohydrates.4,5 On the other hand, they may be expected
to present fast exchange kinetics, thus allowing a rapid
establishment of the equilibrium dynamic library. A major
task is thus to search for means of increasing and controlling
their formation.
ꢀ
Dusan Drahonovsky and Jean-Marie Lehn*
ꢀ
ꢁ
ISIS, Universiteꢁ de Strasbourg, 8 Alleꢁe Gaspard Monge,
67083 Strasbourg, France
lehn@isis.u-strasbg.fr
Received May 24, 2009
Building on the fact that nucleophilic addition to the
carbonyl group increases in the presence of electron-with-
drawing units, we have explored the reactions of alcohols with
aldehydes of nitrogen heterocycles, in particular pyridine and
pyrimidine. Such electron-deficient groups activate the carbo-
nyl function and furthermore may provide a means to increase
hemiacetal formation by protonation or metal cation coordi-
nation at the nitrogen site. In addition, the hemiacetals formed
may also be stabilized by H-bonding between the OH group
and the neighboring nitrogen in the heterocyclic ring. We now
report some of our results on hemiacetal formation between
the heterocyclic aldehydes 1-3 and various alcohols, in the
absence as well as in the presence of added protons or metal
ions. The processes involved are represented in Schemes 1-3.
Some significant results are listed in Tables 1-4. They lead to
the following comments.
A reversible formation of hemiacetals represents a useful
tool in covalent dynamic chemistry. Heterocyclic hemi-
acetals can be stabilized effectively via either protonation
or metal cation coordination. The resulting hemiacetal
systems are highly dynamic, show fast response, and
display component selection.
1. Hemiacetal Formation from Heterocyclic Aldehydes and
Alcohols. We first investigated, by proton NMR, hemiacetal
formation from pyridine-2-carboxaldehyde (1) and various
alcohols in chloroform. Pyridine-2,6-dicarboxaldehyde (2)
and 2-phenylpyrimidine-4,6-dicarboxaldehyde (3) may be ex-
pected to be more reactive than 1. Scheme 1 represents the
different compounds and equilibria involved. Primary alcohols
yield a small amount of hemiacetal, which increases with
equivalents of alcohol added in chloroform solutions (Table 1).
For instance, 1-butanol (6 equiv) produces up to 11%
Chemical entities of molecular or supramolecular nature
may adapt their constitution in response to physical or
chemical effectors by exchange, incorporation, exclusion,
or reorganization of their components via formation or
breaking of reversible covalent bonds or of noncovalent
interactions, respectively. Such behavior defines constitu-
tional dynamic chemistry (CDC) on both the supramolecu-
lar and molecular levels.1 The latter represents a dynamic
covalent chemistry (DCC)2,3 and rests on the introduction
into molecules of bonds formed through reversible chemical
reactions. It has exploited mainly the use of imine and
disulfide functional groups, although some other functions
have also been investigated.2,3 To broaden the scope of DCC,
it is necessary to explore other reversible reactions presenting
controllable formation efficiency and exchange kinetics.
hemiacetal with 1 (0.15 mol dm-3) in chloroform at room
3
temperature. With more reactive difunctional aldehydes
such as 2 and the even more reactive 3, the amount of hemi-
acetals in the equilibrated solutions can reach 43% and 56%
(monohemiacetals) and 1% and 27% (bis-hemiacetals), res-
pectively. The less nucleophilic 2-methoxyethanol affords
just a trace amount of the hemiacetal with 1, and 3% of
the monohemiacetal of 2, whereas 3 yields almost the
same results as with 1-butanol. A mixture of 1-butanol and
2-methoxyethanol (6 equiv of each) with 1 gives 11% of 4a
and 5% of 4b. The sterically more demanding secondary
alcohol 2-propanol forms just a trace amount of hemiacetal
with the tested pyridine aldehydes. No hemiacetals were
observed with the tertiary alcohol t-BuOH or with phenol.
2. Effect of Protonation on Hemiacetal Formation. Addi-
tion of acid enhances markedly the formation of the
hemiacetals. Protonation at nitrogen should increase the
(1) Lehn, J.-M. Chem. Soc. Rev. 2007, 36, 151.
(2) (a) Rowan, S. J.; Canrill, S. J.; Cousins, G. R. L.; Sanders, J. K. M.;
Stoddart, J. F. Angew. Chem., Int. Ed. 2002, 41, 898. (b) Corbett, P. T.;
Leclaire, J.; Vial, L.; West, K. R.; Wietor, J.-L.; Sanders, J. K. M.; Otto, S.
Chem. Rev. 2006, 106, 3652. (c) Ladame, S. Org. Biomol. Chem. 2008, 6, 219.
(3) Lehn, J.-M. Chem.;Eur. J. 1999, 5, 2455.
(4) Acetals undergo acid-catalyzed exchange of carbonyl and alcohol
components and have been used for generation of dynamic combinatorial
libraries; see: (a) Berkovic-Berger, D.; Lemcoff, N. G. Chem. Commun. 2008,
1686. (b) Fuchs, B.; Nelson, A.; Star, A.; Stoddart, J. F.; Vidal, S. Angew.
Chem., Int. Ed. 2003, 42, 4220. (c) Cacciapaglia, R.; Di Stefano, S.;
Mandolini, L. J. Am. Chem. Soc. 2005, 127, 13666. (d) For a very recent
reference on hemiacetals, see: Soutullo, M. D.; O’Brien, R. A.; Gaines, K. E.;
Davis, J. H., Jr. Chem. Commun. 2009, 2529.
(5) Hemiaminals are labile intermediates in imine formation and their use
in DCC has been explored recently. They may be stabilized by a synthetic
receptor; see: Iwasawa, T.; Hooley, R. J.; Rebek, J. Science 2007, 317, 493.
8428 J. Org. Chem. 2009, 74, 8428–8432
Published on Web 10/02/2009
DOI: 10.1021/jo9009886
r
2009 American Chemical Society

JOCNote
SCHEME 1. Formation of Hemiacetals from Alcohols and Heterocyclic Aldehydesa
a6 and 8 can in principle be a mixture of D, L, and meso forms.
SCHEME 2. Structures of Hemiacetalsa
aPart a: Two plausible structures of the protonated bis-hemiacetal 6b. Part b: Zinc(II) complex of hemiacetal 4a. Part c: Zinc(II) complex of hemiacetal
6a. Part d: Oligo/polymeric zinc(II) complex of hemiacetal 6g.
reactivity of the pyridine aldehydes. Indeed, addition of
trifluoroacetic acid (TFA) to 1:1 mixtures of the aldehyde
1 and alcohols in chloroform results in greatly increased
formation of hemiacetal products (for instance from 3% to
35% for 1 and 1 equiv of 1-butanol in the presence of 1 equiv
of TFA), with similar yields for the different alcohols studied
(Table 2). An excess of the alcohols (3 equiv) shifts the
equilibrium significantly toward hemiacetals (Table S2,
SI), but the trend remains the same.
The less basic 2 is less effectively activated compared to 1.
For dialdehyde/alcohol 1:2 ratios, the maximum yields of
the hemiacetals do not exceed 37% for both 1-butanol and
2-methoxyethanol (Table 2, middle). 2-Propanol gives only
about 8% of bis-hemiacetals. A larger excess of the alcohols
(6 equiv) pushes the equilibrium toward the hemiacetals, but
the activation in not as strong as for 1 (Table S2b, SI). An
interesting effect has been observed in the case of 2-methox-
yethanol. The proton NMR spectra of the hemiacetal region
show only one sharp singlet of the bis-hemiacetal, whereas
the same experiment with 1-butanol gives split signals, in
agreement with the presence of two diastereomeric chiral
centers at the hemiacetal carbon atoms. Unless there is an
accidental overlap, this means that the monohemiacetal of
2-methoxyethanol 5b probably induces chirality at the sec-
ond carbon atom to form the corresponding bis-hemiacetal
species 6b diastereoselectively. A plausible explanation
may lie in the interactions of the proton at nitrogen with
the oxygen atoms of the two 2-methoxyethanol units
(Scheme 2a, 6bHþ). Difunctional alcohols (3 equiv), namely
diethylenglycol, triethylenglycol, and tetraethylenglycol,
form complex mixtures of bis-hemiacetal species with 2.
The yields of the hemiacetals (containing possibly macro-
cyclic as well as oligo and/or polymeric species as well) are
very similar for all the glycols, about 70% in the presence of
8 equiv of TFA. This result points to the possibility of
generating highly dynamic covalent polymers.
Protonic amplification of hemiacetal formation is not
effective in the case of the relatively reactive and nonbasic
aldehyde of 3. Thus, the sequentional addition of TFA to 3
decomposes the hemiacetals formed in favor of the starting
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JOCNote
SCHEME 3. Component Selection by Metal Cations
Part a: Lead(II) ions lead to the formation of the macrocycle of tetraethyleneglycol. Part b: Zinc(II) ions yield the bis-dibutoxy hemiacetal complex.
TABLE 1. Equilibrated Solutions of Alcohols with Aldehydesa
ald. (%)
monohemiac. (%)
bis-hemiac. (%)
equiv of aOH
1
2
3
4a
5a
7a
6a
1
8a
1.0
4.0
6.0
97
92
89
87
64
56
68
27
17
3
8
11
13
36
43
32
56
56
17
27
ald. (5)
monohemiac. (%)
bis-hemiac. (%)
equiv of bOH
1
2
3
4b
5b
7b
6b
8b
1.0
4.0
6.0
>99
99
98
>99
98
97
70
29
18
<1
1
2
<1
2
3
29
52
50
1
19
32
aCDCl3 solutions of alcohols aOH and bOH (a = 1-butyl, b = 2-methoxyethyl) with 1, 2, and 3 giving corresponding hemiacetals.
TABLE 2. Proton Modulated Formation of Hemiacetalsa
ald. (%) þ 1 equiv ROH
1 þ bOH
hemiac. (%)
equiv of TFA-D
1 þ aOH
1 þ cOH
4a
4b
4c
1.0
2.0
5.0
65
46
24
70
54
28
80
66
44
35
54
76
30
46
72
20
34
56
diald. (%) þ 2 equiv ROH
monohemiac. (%)
bis-hemiac. (%)
equiv of TFA-D
2 þ aOH
2 þ bOH
2 þ cOH
5a
5b
5c
6a
6b
6c
1.0
2.0
5.0
80
77
64
88
86
74
93
92
89
13
8
9
6
6
7
5
3
7
15
36
3
8
20
3
8
dial. (%) þ 2 equiv ROH
monohemiac. (%)
bis-hemiac. (%)
equiv of TFA-D
3 þ aOH
3 þ bOH
7a
7b
8a
8b
0.1
0.5
3.0
34
42
70
40
43
60
57
51
30
53
51
40
9
7
7
6
aBy deuterated TFA from alcohols ROH (aOH = 1-butanol, bOH = 2-methoxyethanol, cOH = 2-propanol). Hemiacetal formation equilibria of
(top) 1 with 1 equiv of ROH, (middle) 2 with 2 equiv of ROH, and (bottom) 3 with 2 equiv of ROH.
dialdehyde (Table 2, bottom). The ratios are very similar
for both 1-butanol and 2-methoxyethanol; however, the
hemiacetals of the latter show slightly higher stability,
possibly due to the higher basicity of 1-butanol compared to
2-methoxyethanol.
3. Effect of Metal Ion Coordination on Hemiacetal Forma-
tion. Of particular interest is the fact that the formation and
the stabilization of the hemiacetal species also may be
promoted via coordination of metal ions. The activation of
the selected aldehydes by Zn2þ and Pb2þ salts (triflates,
trifluoroacetates) has been tested in acetonitrile solution at
room temperature. Thus, the hemiacetals are present in the
solutions as ionic metal complexes of defined stoichiometry.
Effect of Zinc(II) Coordination. For 1, the most effective
activation has been achieved for a 2:1 1/Zn2þ ratio. It is
comparable to that produced by addition of 1 equiv of TFA
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JOCNote
TABLE 3. Effect of Zinc(II) Ions in the Formation of Hemiacetalsa
ald. (%) þ 1 eq. ROH
hemiac. (%)
eq. Zn2þ
1 þ aOH
1 þ bOH
1 þ cOH
1 þ dOH
4a
4b
4c
4d
0.2
0.5
1.0
67
59
68
74
67
78
80
69
77
94
92
99
33
41
32
26
33
22
20
31
23
6
8
1
diald. (%) þ 2 equiv ROH
monohemiac.
bis-hemiac.
equiv of Zn2þ
2 þ aOH
2 þ bOH
2 þ cOH
2 þ dOH
5a
5b 5c
5d
6a
6b
6c
6d
0.2
0.5
1.0
40
19
18
47
30
30
51
30
27
76
57
50
4
56
81
82
53
70
70
49
70
73
24
43
50
aROH (aOH = 1-butanol, bOH = 2-methoxyethanol, cOH = 2-propanol, dOH = tert-butyl alcohol): (top) 1 with 1 equiv of ROH, (bottom) 2 with
2 equiv of ROH.
TABLE 4. Formation of Hemiacetals with Mixture of Alcohols
equiv of Zn2þ
ald. 1 (%)
hemiac. 4a (%)
hemiac. 4b (%)
hemiac. 4c (%)
0.2
0.5
1.0
62
5
5
19
46
45
8
21
21
11
28
29
equiv of TFA-D
ald. 1 (%)
hemiac. 4a (%)
hemiac. 4b (%)
hemiac. 4c (%)
0.5
1.0
2.0
79
60
33
16
26
40
3
9
17
2
5
10
1 with a mixture of alcohols ROH (3 equiv of each, aOH = 1-butanol, bOH = 2-methoxyethanol, cOH = 2-propanol): (top) presence of Zn(II) ions,
(bottom) presence of TFA.
(Table 2, top). Further addition of zinc(II) salt decreases the
amount of the hemiacetal species. The trend is general for all
zinc(II) complexes of the hemiacetals of 1. An excess of the
alcohols shifts the equilibrium toward hemiacetals, but the
2:1 ligand/Zn2þ ratio remains the optimal one. The reac-
tivity of the alcohols has been found in the expected order:
1-butanol > 2-methoxyethanol > 2-propanol > tert-butyl
alcohol (Table 3, top). 2-Pyridylmethanol yields up to 29%
of the hemiacetal. Phenol is unreactive for all tested sub-
strates. According to the optimal ratio, the zinc(II) coordina-
tion center should be surrounded by at least two hemiacetal
ligands (Scheme 2b, (4a)2Zn2þ). The 2:1 hemiacetal complex
may be transformed to other coordination species by higher
amounts of zinc(II) ions.
of the amount of hemiacetal species. The two hemiacetal
ligands probably form a hexacoordinated complex with the
zinc(II) metal centers in an octahedral coordination geome-
try as represented by (6a)2Zn2þ (Scheme 2c). Such complexes
are expected to be much more stable than those of the
monohemiacetals of 1. However, they remain highly dy-
namic. The NMR spectra display rather broad bands,
signaling the occurrence of exchange processes among the
complexes.
Reactions with diols give complex mixtures of oligo-/
polymeric hemiacetals in contrast to 1. In this case, based
on the proton NMR experiments showing generally broad
signals and very broad hemiacetal signals, we expect forma-
tion of the oligomeric species. The di-, tri-, and tetraethy-
lenglycols as well as 1,5-pentanediol, 1,6-hexanediol, 1,7-
heptanediol, and 1,8-octanediol give complex mixtures of
hemiacetals (that may contain macrocyclic entities) in yields
up to 80% for the aliphatic diols (dial/diol, 1:1, 1 equiv of
Zn2þ) (e.g., Scheme 2d, (6g)2Zn2þ). Less nucleophilic glycols
give up to 50% complex hemiacetals under the same condi-
tions. The composition of the sample remains stable even
after 7 days.
Effect of Lead(II) Coordination. Lead(II) salts are also
capable of activating effectively 2 toward formation of
hemiacetals. Activation by lead(II) ions is highest at 1:1
aldehyde/cation ratio, as compared to 2:1 for zinc(II) ca-
tions, and it gives usually lower yields in comparison to
zinc(II) under the same conditions (e.g., 6 equiv of 1-butanol
give 83% of bis-hemiacetal complex in the presence of Pb2þ
and 97% in the presence of Zn2þ, respectively). In addition,
the NMR spectra show very broad signals, indicating even
much more fluctuating character of the lead(II) complexes
compared to that of the zinc(II) complexes. Glycols yield
macrocyclic complexes. Thus, tetraethyleneglycol forms
with 1 equiv of 2 a macrocycle of aza-18-crown-6 type in
up to 82% yield (Scheme 3a, (6h)Pb2þ, proton NMR, see the
The formation of such 2:1 complexes suggests that oligo-
and/or polymeric species might be formed in the presence of
diols. Thus, 1 and 1,6-hexanediol (2:1) yield 42% hemiacetal,
but the formation of polymers (the proton NMR spectra
shows sharp well-resolved signals and about 58% of 1 re-
maines untouched in the solution) has not been observed under
these conditions (concentration of 1 c = 0.15 mol dm-3)!
3
Due to its tridentate nature, 2 may be expected to form
much more stable zinc(II) complexes of the hemiacetals
compared to 1. A combination of the higher reactivity of 2
itself with zinc(II) activation results indeed in much higher
yields of hemiacetals. The reactivity of the alcohols follows
the same order as for the reaction with 1 (Table 3, bottom).
The yields of the hemiacetals with 1-butanol and 2-methoxy-
ethanol reach average values as high as about 80% and 70%,
respectively, for a 1:2 2/alcohol ratio. An excess of alcohol
may increase the yields over 90% (Table S3b, SI). A second-
ary alcohol such as 2-propanol gives up to 73% yield, and
even the sterically demanding tert-butyl alcohol shows a
rather good yield up to 50% (Table 3, bottom). All the
indicated yields are for the bis-hemiacetals. An excess of
zinc(II) ions above over 2:1 ratio does not result in a decrease
J. Org. Chem. Vol. 74, No. 21, 2009 8431

JOCNote
SI), increasing to over 95% with 2 equiv of tetraethylenegly-
col. The macrocycle is formed immediately after mixing
the components with lead(II) ions. Herein, lead(II) ions
play at least two important roles: activation of the aldehyde
and stabilization of the final macrocyclic structure by com-
plexation.
As mentioned above, the same mixture of 2 (1 equiv) and
tetraethyleneglycol (1 equiv) can also be activated by lead(II)
ions, giving the macrocyclic complex (6h)Pb2þ
.
The switching between the Zn(II) and Pb(II) modes may be
extended to involve component selection by the combination
of the two last systems. The addition of 2 equiv of 1-butanol to
the 2:tetraethyleneglycol 1:1 mixture changes the dynamic
equilibrium of the zinc(II) system in favor of butyl-hemiacetal
complexes (Scheme 3), whereas the preferential formation of
the macrocycle in the presence of lead(II) ions is not affected by
the presence of 1-butanol (Scheme 3).
Thus, metal cation coordination to pyridine carboxalde-
hyde derived DCLs of hemiacetals may regulate both the
formation efficiency and the selection of component alcohols.
The results presented above lead to several conclusions: (i)
hemiacetal formation represents a significant and promising
addition to the set of reversible reactions for covalent
dynamic chemistry;2,3 (ii) the efficiency of formation of
specific hemiacetals may be greatly increased through acti-
vations by protonation or metal ion coordination as well as
by higher concentrations of components; (iii) exchange
dynamics are very fast and may be modulated by such
effectors; (iv) both features ii and iii, as well as component
selection and type of hemiacetal product may be further
modulated by the choice of the metal cation; and (v) applica-
tions may be envisaged in the controlled release of one of the
partners, in particular of bioactive or home and personal
care alcohol partners, as well as in the generation of highly
dynamic hemiacetal-based polymers.
4. Component Exchange Dynamics. Exchange processes
and equilibration in the reaction mixtures of hemiacetals
alone as well as in the proton modulated systems are very
fast, features of much interest in DCC. Dynamic behavior
and exchange processes of zinc(II) and lead(II) complexes
are fast as well. With mixtures of alcohols and hemiacetals,
the equilibria were always established within the time of the
1H NMR experiments (less than a few minutes). Repeated
measurements after another few minutes or hours did not
show further changes. Generally, the formation of the
hemiacetals showed strong concentration dependence under
these conditions. The equilibria are shifted toward starting
aldehydes and alcohols in the case of diluted solutions, e.g.,
the population of the hemiacetal species may vary from 16%
to 94% of (6a)2Zn2þ for diluted (0.01 mol dm-3) and
3
concentrated (0.8 mol dm-3) solutions, respectively (see
3
the SI). Addition of 2-propanol (3 equiv) to a mixture of
1-butanol (3 equiv) and 2-methoxyethanol (3 equiv) with 1
(1 equiv) has been tested under “proton“ and “zinc(II)“
conditions (Table 4). The same equilibrium compositions
were observed when the alcohols have been mixed in differ-
ent order or added in one portion (3 equiv of each) to 1
(Table 4). The formation of the hemiacetal with 1-butanol is
preferred in the equilibria, whereas 2-methoxyethanol and
2-propanol show almost the same hemiacetal ratios.
Experimental Section
A mixture of 2 (1 equiv), 1-butanol (6 equiv), and 2-
methoxyethanol (6 equiv) gave under zinc(II) activation a
complex mixture of the hemiacetal species, as expected. On
the other hand, under activation by protons instead of
zinc(II) cations, the same mixture showed an interesting
selectivity in the formation of the bis-hemiacetals, giving a
31%:16% mixture of bis-butyl (6aHþ) and bis-methoxyethyl
(6bHþ) species. Mixed butyl-methoxyethyl hemiacetals
were not observed in contrast to the “zinc“ case, and the
bis-methoxyethyl hemiacetal was formed diastereoselec-
tively (vide ante) (Scheme 2a, 6bHþ). Thus, combination of
the dynamic behavior of the reaction system and selectivity
in the formation of the hemiacetals allows specific constitu-
ents in the DCL to be expressed.
Fast dynamic behavior and selectivity in favor of more
nucleophilic reagent was shown in the following experiment.
A mixture of 2 (1 equiv) and tetraethyleneglycol (1 equiv)
contains ca. 46% of a complex mixture of hemiacetals of
tetraethylenglycol (oligo/polymeric) in the presence of 0.5
equiv of zinc(II) triflate in acetonitrile. Progressive addition
of 1-butanol to the mixture showed an immediate change in
the equilibrium in favor of (6a)2Zn2þ (Scheme 3b).
All proton NMR experiments (400 MHz) were recorded at
25 °C in either CDCl3 or CD3CN. Samples were prepared by
mixing of aldehydes 1, 2, and 3, respectively, in volumetric flasks
(1 mL) to form solutions of 0.15 mol dm-3 together with
3
respective amount of alcohols and deuterated solvents. Proton-
ation experiments were carried out in chloroform, and deuter-
ated TFA (2 mol dm-3 solution in CDCl3) was added
3
sequentially by microsyringe to 0.5 mL of the solutions of
aldehydes and alcohols in NMR tubes. Metal-mediated experi-
ments were performed in CD3CN (due to solubility of metal
salts) by addition of zinc(II) triflate and lead(II) trifluoroacetate
solutions (both 0.5 mol dm-3 in CD3CN), respectively, to
3
0.5 mL of the solutions of aldehydes and alcohols.
Acknowledgment. This work was supported by the DY-
NAMIC-Marie Curie Research Training Network MRTN-
CT-2005-019561, including a postdoctoral fellowship to D.
ꢀ
Drahonovsky.
ꢁ
Supporting Information Available: Full versions of the
experimental data tables and NMR and MS spectra. This
material is available free of charge via the Internet at http://
pubs.acs.org.
8432 J. Org. Chem. Vol. 74, No. 21, 2009