Synthesis and alkali metal complexation studies of novel cage-functionalized cryptands Tatjana Sumanovac Ramljak a , Ines Despotovi c a, * , Branimir Berto sa b , Kata Mlinari c-Majerski a, * a Department of Organic Chemistry and Biochemistry, RuCer Boskovic Institute, Bijenicka Cesta 54, 10 000 Zagreb, Croatia b Division of Physical Chemistry, Department of Chemistry, Faculty of Science, Horvatovac 102A, 10000 Zagreb, Croatia article info Article history: Received 4 July 2013 Received in revised form 24 September 2013 Accepted 14 October 2013 Available online 18 October 2013 Keywords: Adamantane functionalized cryptands Metal ion complexation Metal ion transport Monte Carlo conformational search Stability constant Quantum chemical calculations abstract The synthesis of novel cage-functionalized cryptands 1e5 containing adamantane-, 2-oxaadamantane- or noradamantane-moiety [i.e., 1,3-diethyladamantano[2.2.0]cryptand (1), 1,3-diethoxyadamantano [2.2.2]cryptand (2), 1,3-di[(ethyloxy)methyl]adamantano[2.2.2]-cryptand (3), 1,3-di[(ethyloxy)methyl]- 2-oxaadamantano[2.2.3]cryptand (4), and 1,2-diethyloxynoradamantano[2.2.2]cryptand (5)] and their alkali metal binding properties are reported. The results obtained by extraction experiments showed that all the cryptands displayed lower extraction capabilities than the parent [2.2.2]cryptand. However, cryptands 1 and 2 showed much higher selectivity toward K þ than the reference [2.2.2]cryptand. When the third bridge is enlarged by two additional CH 2 -groups as well as by two oxygen atoms, as in cryptands 3 and 4, the complexational abilities for bigger cations (K þ , Rb þ and Cs þ ) are enhanced. Cryptand 5 displayed very good extraction capabilities of all cations, but showed practically no selectivity towards any of the alkali metal cation. The experimental findings are corroborated by calculation studies consisting of force field based conformational search using Monte Carlo method followed by in- vestigation of the stabilities of the complexes of cryptands with Na þ and K þ metal ions in chloroform by means of quantum chemical calculations at the density functional theory level. Ó 2013 Elsevier Ltd. All rights reserved. 1. Introduction Hosteguest chemistry, first introduced by Pedersen’s discovery of crown ethers, 1 has led to the development of understanding the geometric and electronic requirements necessary for selective complexation of cations. 2 Many different modifications of crown ethers, such as changing the ring size, the kind of substituents, and the type of donor atoms, have been made to enhance their com- plexation properties. 3 When an additional ring is incorporated into the crown ether, cryptands are obtained. 4 These macrobicyclic li- gands are capable of ion encapsulation due to their cage-like structure and they represent an ideal model system for the stud- ies of molecular recognition and inclusion phenomena. 5 Different kinds of cryptands have also been synthesized in order to find host compounds with superior properties and proper application in various areas, for example, as receptors for binding cations, 6 in transport of cations through organic membranes, 7 as receptors for anions 8 as well as parts of supramolecular structures. 9 In recent years there are a number of papers describing the oxa and aza crown ethers, which contain polycyclic moieties, such as 4- oxahexacyclo[5.4.1.0 2,6 .0 3,10 .0 5,9 .0 8,11 ]dodecane, 10 adamantane, and 2-oxaadamantane, 11 but in the case of cryptands we found just a few examples with 4-oxahexacyclo[5.4.1.0 2,6 .0 3,10 .0 5,9 .0 8,11 ] dodecane unit incorporated into the cryptand structure. 12 In- corporation of a rigid polycyclic molecule into the skeleton of host molecules should affect their conformational mobility and there- fore their complexation abilities. The lipophilic polycyclic moiety should also increase the solubility of the ionophores in nonpolar media and thereby increase their ability for ion transport. An ad- ditional oxygen atom in some polycyclic units, like in 2- oxaadamantane, can participate in complexation and thus en- hance the complexation abilities of macrocyclic ligand. 13 In this paper we report the synthesis of five novel cryptands 1e5 containing adamantane-, 2-oxaadamantane- or noradamantane- moiety, and the study of their binding properties. Cryptand 1 , in which the adamantane moiety is incorporated in its third chain, does not possess donor atoms in this added chain, so it should not be considered as a cryptand but as some kind of a bridged diaza- crown ether. Cryptands 2 and 3 belong to the [2.2.2]cryptand family since they have two oxygen atoms in the third chain. The difference between cryptands 2 and 3 is in the length of third chain. * Corresponding authors. Tel.: þ385 1 456 0951 (I.D.); tel.: þ385 1 468 0196; fax: þ385 1 4680195 (K.M.-M.); e-mail addresses: [email protected](I. Despotovic), [email protected](K. Mlinaric-Majerski). Contents lists available at ScienceDirect Tetrahedron journal homepage: www.elsevier.com/locate/tet 0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.tet.2013.10.039 Tetrahedron 69 (2013) 10610e10620
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Tetrahedron 69 (2013) 10610e10620
Contents lists avai
Tetrahedron
journal homepage: www.elsevier .com/locate/ tet
Synthesis and alkali metal complexation studies of novelcage-functionalized cryptands
Tatjana �Sumanovac Ramljak a, Ines Despotovi�c a,*, Branimir Berto�sa b,Kata Mlinari�c-Majerski a,*aDepartment of Organic Chemistry and Biochemistry, RuCer Bo�skovi�c Institute, Bijeni�cka Cesta 54, 10 000 Zagreb, CroatiabDivision of Physical Chemistry, Department of Chemistry, Faculty of Science, Horvatovac 102A, 10000 Zagreb, Croatia
a r t i c l e i n f o
Article history:Received 4 July 2013Received in revised form 24 September 2013Accepted 14 October 2013Available online 18 October 2013
Keywords:Adamantane functionalized cryptandsMetal ion complexationMetal ion transportMonte Carlo conformational searchStability constantQuantum chemical calculations
0040-4020/$ e see front matter � 2013 Elsevier Ltd.http://dx.doi.org/10.1016/j.tet.2013.10.039
a b s t r a c t
The synthesis of novel cage-functionalized cryptands 1e5 containing adamantane-, 2-oxaadamantane-or noradamantane-moiety [i.e., 1,3-diethyladamantano[2.2.0]cryptand (1), 1,3-diethoxyadamantano[2.2.2]cryptand (2), 1,3-di[(ethyloxy)methyl]adamantano[2.2.2]-cryptand (3), 1,3-di[(ethyloxy)methyl]-2-oxaadamantano[2.2.3]cryptand (4), and 1,2-diethyloxynoradamantano[2.2.2]cryptand (5)] and theiralkali metal binding properties are reported. The results obtained by extraction experiments showed thatall the cryptands displayed lower extraction capabilities than the parent [2.2.2]cryptand. However,cryptands 1 and 2 showed much higher selectivity toward Kþ than the reference [2.2.2]cryptand. Whenthe third bridge is enlarged by two additional CH2-groups as well as by two oxygen atoms, as incryptands 3 and 4, the complexational abilities for bigger cations (Kþ, Rbþ and Csþ) are enhanced.Cryptand 5 displayed very good extraction capabilities of all cations, but showed practically no selectivitytowards any of the alkali metal cation. The experimental findings are corroborated by calculation studiesconsisting of force field based conformational search using Monte Carlo method followed by in-vestigation of the stabilities of the complexes of cryptands with Naþ and Kþ metal ions in chloroform bymeans of quantum chemical calculations at the density functional theory level.
� 2013 Elsevier Ltd. All rights reserved.
1. Introduction
Hosteguest chemistry, first introduced by Pedersen’s discoveryof crown ethers,1 has led to the development of understanding thegeometric and electronic requirements necessary for selectivecomplexation of cations.2 Many different modifications of crownethers, such as changing the ring size, the kind of substituents, andthe type of donor atoms, have been made to enhance their com-plexation properties.3 When an additional ring is incorporated intothe crown ether, cryptands are obtained.4 These macrobicyclic li-gands are capable of ion encapsulation due to their cage-likestructure and they represent an ideal model system for the stud-ies of molecular recognition and inclusion phenomena.5 Differentkinds of cryptands have also been synthesized in order to find hostcompounds with superior properties and proper application invarious areas, for example, as receptors for binding cations,6 intransport of cations through organic membranes,7 as receptors foranions8 as well as parts of supramolecular structures.9
In recent years there are a number of papers describing the oxaand aza crown ethers, which contain polycyclic moieties, such as 4-oxahexacyclo[5.4.1.02,6.03,10.05,9.08,11]dodecane,10 adamantane, and2-oxaadamantane,11 but in the case of cryptands we found justa few examples with 4-oxahexacyclo[5.4.1.02,6.03,10.05,9.08,11]dodecane unit incorporated into the cryptand structure.12 In-corporation of a rigid polycyclic molecule into the skeleton of hostmolecules should affect their conformational mobility and there-fore their complexation abilities. The lipophilic polycyclic moietyshould also increase the solubility of the ionophores in nonpolarmedia and thereby increase their ability for ion transport. An ad-ditional oxygen atom in some polycyclic units, like in 2-oxaadamantane, can participate in complexation and thus en-hance the complexation abilities of macrocyclic ligand.13
In this paper we report the synthesis of five novel cryptands 1e5containing adamantane-, 2-oxaadamantane- or noradamantane-moiety, and the study of their binding properties. Cryptand 1, inwhich the adamantane moiety is incorporated in its third chain,does not possess donor atoms in this added chain, so it should notbe considered as a cryptand but as some kind of a bridged diaza-crown ether. Cryptands 2 and 3 belong to the [2.2.2]cryptandfamily since they have two oxygen atoms in the third chain. Thedifference between cryptands 2 and 3 is in the length of third chain.
T. �Sumanovac Ramljak et al. / Tetrahedron 69 (2013) 10610e10620 10611
In cryptand 2 the oxygen atoms are directly bonded to positions 1and 3 of adamantane moiety while in cryptand 3 there are addi-tional CH2 groups between the adamantane moiety and the oxygenatoms. Cryptand 4 is structurally analogous to cryptand 3 in whichthe adamantane unit is replaced with 2-oxaadamantane moiety, soit possesses an additional oxygen atom in the third chain and it
N NO OO O
O O
N NO OO O
O O
N NO OO O
O O
HN
O
NH
O
OO O
N NO OO O
O O
N NO OO O
O
OOTs
OTs
OO OTs
O OTs
O
O
OTs
OTs
O OTs
O OTs
OTsOTs
1 2
3 5
4
6 7
8
9
10
Scheme 1.
should be considered as a [2.2.3]cryptand. The replacement of theadamantane moiety in cryptand 2with the noradamantane moietygave us cryptand 5, which is structurally analogous to the reference[2.2.2]cryptand.
Complexational abilities of these new ligands 1e5 were studiedby alkali picrate extraction experiments and by potassium and so-dium picrate transport experiments through a model organicmembrane. The obtained results are supported by a computationalstudy consisting of force field based conformational search fol-lowed by investigation of complexation ability employing quantumchemical studies with density functional theory in its B3LYP rep-resentation. Solvent effects were taken into account using the po-larized continuum model.
2. Results and discussion
2.1. Synthesis
The synthesis of cryptands 1e5 was based on the coupling re-actions of diaza-18-crown-6 with corresponding ditosylates: 1,3-
bis(2-tosyloxyethyl)adamantane (6), 1,3-bis(2-tosyloxyethyloxy)adamantane (7), 1,3-bis[(2-tosyloxyethyloxy)methyl]adamantane(8), 1,3-bis[(2-tosyloxyethyloxy)methyl]-2-oxaadamantane (9), and1,2-bis(2-tosyloxyethyloxy)noradamantane (10) in acetonitrile inthe presence of Na2CO3 affording cryptands 1e5 in the yields of 50,50, 74, 67, and 54%, respectively (Scheme 1).
It is interesting to note that during purification of crude productsobtained in the synthesis of cryptands1 and 2, wewere able to isolatetheir complexes with Na-tosylate, but cryptands 3, 4, and 5 we ob-tained only as the free ligands. However, from the results of the pic-rate extraction experiments we observed that cryptands 1 and 2showed lower extraction values for the extraction of Naþ than for Kþ.Most probably Naþ is bonded more strongly and thus cannot leaveeasily from the complex. This is in accord with a published observa-tion that for the synthesis of [2.2.2]cryptand,Naþ is usedasa templatecation although [2.2.2]cryptand is the best for the extraction of Kþ. Inthe case when the template cation is Naþ, reaction yields were verygood, but in the cases with Kþ yields were almost negligible.14
1,3-bis(2-tosyloxyethyloxy)adamantane (7),17 and 1,3-bis[(2-tosyloxyethyloxy)methyl]-2-oxaadamantane (9)17 were preparedaccording to previously published procedures. Since 1,3-bis[(2-tosyloxyethyloxy)methyl]adamantane (8) and 1,2-bis(2-tosyloxyethyloxy)noradamantane (10) were not known in the litera-ture, we prepared these compounds from the corresponding 1,3-bis(hydroxymethyl)adamantane18 and 1,2-noradamantanediole19
T. �Sumanovac Ramljak et al. / Tetrahedron 69 (2013) 10610e1062010612
using the same procedure as for the preparation of oxaadamanta-nediol 917 (Scheme 2).
OH
OH O O
O O
O OH
O OH
O OTs
O OTs
OH
OH
O O
O O
O OH
O OH
O OTs
O OTs
OOTs
NaH, DMF
H2, Pd/C
8
10
11 12
13 14
EtOHTsClpyridine
OOTs
NaH, DMF
H2, Pd/C
EtOHTsClpyridine
Scheme 2.
Table 1Extractions of alkali picrates with CHCl3 containing cryptands 1e5
a Defined as percent of picrate extracted into organic phase. Each value is theaverage of five independent extraction experiments.
b The extraction experiments were performed by using 5�10�3 M CHCl3 solutionof cryptands and 5�10�3 M H2O solution of alkali metal picrates. The picrate ionconcentrations were determined by UV.
0
20
40
60
80
100
120
1 2 3 4 5 [2.2.2]cryptand
% o
f extractio
n
Cryptands
Li+
Na+
K+
Rb+
Cs+
Fig. 1. Extractions of alkali picrates with CHCl3 containing cryptands 1e5.
1,3-Bis[(2-tosyloxyethyloxy)methyl]adamantane (8) was pre-pared starting from 1,3-bis(hydroxymethyl)adamantane.18 NaH pro-moted reaction of 1,3-bis(hydroxymethyl)adamantane with 1-tosyloxy-2-benzyloxyethane20 in DMF afforded 1,3-bis[(2-benzyloxyethyloxy)methyl]adamantane (11) in 55% yield. Subsequent hy-drogenation of the obtained product gave 1,3-bis[(2-hydroxyethyloxy)methyl]adamantane (12) in 97% yield. Standardprocedure that employedTsClepyridine afforded the desiredproduct1,3-bis[(2-tosyloxyethyloxy)methyl]adamantane (8) in 85% yield.
The same synthetic strategy was employed for the preparation of1,2-bis(2-tosyloxyethyloxy)noradamantane (10) from 1,2-noradamantanediol.19 The reaction of 1,3-bis(hydroxymethyl)ada-mantane18 with 1-tosyloxy-2-benzyloxyethane20 in the presence ofNaH in DMF afforded 1,2-bis(2-benzyloxyethyloxy)noradamantane(13) in 53% yield. 1,2-Bis(2-hydroxyethyloxy)noradamantane (14)was prepared by hydrogenation of compound 13 in 92% yield. 1,2-Bis(2-tosyloxyethyloxy)noradamantane (10) was obtained via thewell known reactionwith TsCl and pyridine, thereby affording 91% ofthe desired product.
2.2. Extraction experiments
In order to investigate cation binding abilities of cryptands 1e5,extraction experiments were carried out by solvent extraction ofalkali metal picrates from aqueous solution into chloroform. Sincepicrate ion concentrations can easily be determined by UV mea-surement, extractions of aqueous alkali metal picrates (Liþ, Naþ, Kþ,Rbþ, and Csþ; 5�10�3 M) were carried out at room temperaturewith chloroform solutions of cryptands 1e5 (5�10�3 M). In addi-tion, ‘blank’ experiments in which CHCl3 contained no host com-poundwere carried out for each alkali metal picrate salt. The resultsthereby obtained were compared with the corresponding resultsobtained for the referent [2.2.2]cryptand. The extraction tech-nique17,21 used in this study are described in Experimental section.The obtained results are shown in Table 1 and Fig. 1. From the datashown in Table 1 and Fig. 1, it is obvious that all synthesizedcryptands 1e5 showed lower extraction abilities towards all alkalimetal cations compared to the referent [2.2.2]cryptand.
Cryptand 5, which is structurally similar to the parent [2.2.2]cryptand with noradamantane moiety incorporated into the thirdchain of the cryptand, displayed the best extraction capabilities of all
synthesized cryptands 1e5, but showed practically no selectivity to-wards any of the alkali metal cations studied.
Cryptands 1, 2, and 4 as well as the reference [2.2.2]cryptandshowed the best extraction of Kþ. Although their extraction capa-bilities were lower, cryptands 1 and 2 showed much higher selec-tivity toward Kþ than the [2.2.2]cryptand and cryptands 3, 4, and 5.Cryptands 4 and 5 displayed the highest values of extraction to-wards Kþ but the measured values were approximately 20% lowerthan the corresponding values obtained for the [2.2.2]cryptand.
When the third bridge is enlarged by two additional CH2-groupsas well as two additional oxygen atoms, as in cryptands 3 and 4,
0
2
4
6
8
10
12
14
3 4 5 [2.2.2]cryptand
10^
-8 R
ate o
f tran
sp
ort
Cryptands
Na+
K+
Fig. 2. Transport rate of sodium and potassium picrate through CHCl3 membranecontaining cryptands 3, 4, 5, or [2.2.2]cryptand.
T. �Sumanovac Ramljak et al. / Tetrahedron 69 (2013) 10610e10620 10613
extraction abilities for bigger cations (Kþ, Rbþ, and Csþ) are en-hanced but they showed practically no selectivity towards any ofthe three cations. Therefore cryptand 3 extracted approximately36% of Kþ but extractions of Rbþ and Csþ were also about 36%, andcryptand 4 extracted 78% of Kþ as well as 73% of Rbþ and 74% of Csþ.
Considering Naþ cation, the parent [2.2.2]cryptand also showedthe best extraction abilities. Cryptand 5 displayed 20% lower valuesthan the referent compound while cryptand 4 extracted approxi-mately 60% of Naþ. The values measured for cryptands 1, 2, and 3were significantly lower.
Cryptand 5 showed higher value for the extraction of Liþ andthat value was approximately 40% higher than the one obtained forthe [2.2.2]cryptand. For cryptands 1 and 4 the obtained values wereabout 10% higher than for the reference compound. On the otherhand, cryptands 2 and 3 showed slightly lower values compared tothe reference compound.
Cryptands 4 and 5 extracted Csþ better than the [2.2.2]cryptand,the values obtained for the extraction of Csþ for cryptand 3 wereabout the same as the ones obtained for the referent compoundwhile the values measured for cryptands 1 and 2 were slightlylower than for the [2.2.2]cryptand.
For the extraction of Rbþ the reference compound displayed thebest results, cryptands 4 and 5 showed approximately 20% lowervalues while the results obtained for cryptands 1, 2, and 3 weresignificantly lower.
2.3. Transport experiments
It has been found that there is no direct correlation between thelog Kex and transport rate through liquid membrane.17,22 How ef-fectively the cation is transported depends on how well it fits intothe macrocyclic cavity as well as how easily it can leave from thehost carrier at the membrane interface. In order to obtain con-vincing evidence regarding this point, we carried out a series of iontransport studies. We studied the transport rates (jc, in mol h�1)through an organic liquid membrane (H2OeCHCl3eH2O) for so-dium and potassium picrate by cryptands 3, 4, 5, and [2.2.2]crypt-and. The results are shown in Table 2.
Table 2Transport rate of Naþ and Kþ picrate through chloroform membrane containingcryptands 3, 4, 5, and [2.2.2]cryptand
Cryptandsa (jc)b mol h�1�10�8 (n)c mol�10�7 in 24 h
a Chloroformmembrane contained 7.5�10�4 mol of corresponding cryptand. Themolar ratio of cryptand:M picrate was 1:10.
b Each value is the average of three independent measurements with deviationless than �5%.
c Measured value.
A plot of moles of cation transported into aqueous phase versustime was constructed for each carrier-containing system. Linearincrease in concentration in the receiving phase with increasingtime was observed throughout the first 7 h (Fig. 2, Figs. S2 and S3).In each case, the transport rate (jc) could be obtained from the slopeof the line and was in accordance with the data reported earlier.22
The results obtained from transport experiments (Table 2, Fig. 2,Figs. S2, S3) showed that the reference [2.2.2]cryptand displayedthe best transport capabilities for the Naþ and a significant differ-ence in transport rates between the Naþ and Kþ in favor of Naþ. Thetransport rates obtained for both cations with cryptands 4 and 5 arenotably lower compared to the [2.2.2]cryptand. On the other hand,
although cryptand 3 showed significantly lower transport rates forboth cations than the reference compound, in this case the trans-port rate for Kþ was higher than for Naþ however the difference intransport rates is not as notable as in the case of the [2.2.2]cryptand.
2.4. Modeling
Monte Carlo (MC) conformational searches were performedwith goals of investigating conformational flexibility of studiedcompounds and finding the most stable conformers that will beused for studding complexation ability of the investigated com-pounds by quantum chemical calculations.
For each compound, at least 50,000 MC steps were accom-plished. Since some of the conformers were found several dozentimes (in some cases evenmore than a hundred times), the selectednumber of steps was considered sufficient for extensive MC con-formational search. Number of conformers found during the MCsearches of compounds 3 and 4 were several times larger com-paring to the MC searches of compounds 1 and 2, and two timeslarger than in case of compound 5 (Table 3). Larger number ofconformers found during the MC searches of compounds 3 and 4points to their larger conformational flexibility comparing tocompounds 1, 2, and 5. The later result is consequence of the longerlinker between crown ether and adamantane units (the thirdbridge). The lower flexibility of compounds 1 and 2 might be thereason for their higher selectivity toward Kþ cation (Fig. 1, Table 1).Compound 1 has greater flexibility than compound 2, which im-plies that the presence of oxygen atom in the third bridge decreasesflexibility. In case of the [2.2.2]cryptand, conformational searchrevealed that the most stable conformer is the symmetrical con-formation in which all six oxygen atoms and both nitrogen atomsare oriented towards the center of the crown ether ring (Fig. S4).That conformation is 11 kJ mol�1 more stable than any other con-formation found during the MC search. Extension of energy win-dow to 50 kJ mol�1 during the MC search of [2.2.2]cryptandresulted in 1754 diverse conformations.
In order to gain deeper insight into conformational distributionand to group conformers found during the MC searches, clusteranalysis of MC results was performed. Cluster analysis revealed thatmore than 90% of the conformations found during the MC searchesof compounds 1 and 2 can be represented with one cluster repre-sentative (Table 3, Fig. S4). In cases of compounds 3 and 4, sucha difference in percentage of conformations represented by eachcluster structure was not found. These results again point to thelarger flexibility of compounds 3 and 4 compared to compounds 1and 2. Due to the low number of structures found within
Table 3Monte Carlo conformational searches of compounds 1e5 and [2.2.2]cryptand
a Number of structures found within the energy window of 10 kJ mol�1.b Number of structures found within the energy window of 20 kJ mol�1.c Number of clusters found by the cluster analysis of the structures found within the energy window of 10 kJ mol�1.d Percentage of conformations found within the energy window of 10 kJ mol�1 that are represented by each cluster; cluster structures have the same names as on the Fig. S4
in Supplementary data.e Force field energy of the energetically most favorable conformation found by the MC search.f Solvation energy in chloroform for the energetically most favorable conformation.
Table 5Selected geometrical parameters obtained by B3LYP/6-31G(d) method for sodiumand potassium complexes of cryptands 1e5 and reference [2.2.2]cryptand (in �A)
T. �Sumanovac Ramljak et al. / Tetrahedron 69 (2013) 10610e1062010614
10 kJ mol�1 energy window, cluster analysis was not performed forcompound 5 and [2.2.2]cryptand.
The stability constants of complexes of cryptands 1e5, and[2.2.2]cryptand with Naþ and Kþ metal cation in chloroform solu-tion are presented in Table 4. The gas phase free energies of for-mation, DfG�, and solvation free energies, DG*sol for uncomplexedcryptands, cryptand complexes andmetal ions are given in Table S1in Supplementary data. The gas phase and solution phase reactionfree energies are given in Table S2 in Supplementary data.
Table 4The stability constants of complexes of cryptands 1e5, and [2.2.2]cryptand with Naþ
The perusal of results in Table 4 reveal that cryptand 5 shows thestrongest binding affinity for Naþ and Kþ. It follows that the nor-adamantane unit incorporated in the third chain increases log K by3.03 and 1.53 units for complexes with Naþ and Kþ, respectively,compared with the [2.2.2]cryptand. All others synthesized crypt-ands display lower binding affinity for Naþ as well as for Kþ thanthe reference system.
Cryptand 1 shows the lowest cation-binding ability. Moreover,cryptand 1 shows a slightly lower affinity for Kþ then for Naþ, whileall other cryptands show higher binding ability for Kþ than for Naþ.The reference [2.2.2]cryptand displays the highest selectivity, whilethe selectivity is shown to be the lowest for cryptand 1, being onlyabout 10% of the value obtained for the [2.2.2]cryptand. Cryptand 5,with the highest binding affinity shows a moderate selectivity of1.75 units.
In order to give more insight into the binding affinities, struc-tural parameters were considered. The structures of uncomplexedand complexed cryptands are depicted, and Cartesian coordinatesare given in Fig. S1. The selected geometrical parameters are givenin Table 5.
T. �Sumanovac Ramljak et al. / Tetrahedron 69 (2013) 10610e10620 10615
The calculations revealed that the Kþ ion is completely encap-sulated by [2.2.2]cryptand, being situated at the center of thecryptand cavity. Despite a greater Lewis basicity of the N lone pair,KþeN distances are longer than KþeO distances (the average dis-tances are: KþeN¼3.093 �A and KþeO¼2.863 �A). The six oxygenbinding sites appear to favor interaction with the metal ion at theexpense of the two nitrogen binding sites. Cryptand 1 shows con-siderably lower binding ability for Kþ compared to the referentcryptand obviously due to the lack of two donor oxygen atomswithin the third chain of the cryptand.
Cryptand 2 has two oxygen atoms in the third chain, but onlyone of them is included in the coordination sphere as indicated bydistances KþeO7¼4.296 �A and KþeO8¼3.820 �A. When the thirdbridge is enlarged by two additional CH2 groups, as in cryptand 3,both oxygen atom from the bridge containing the adamantane unitget closer to the Kþ atom (KþeO7¼3.645�A, KþeO8¼3.568�A), thustaking part in coordination of Kþ. Cryptand 4 possesses one oxygenatomwithin the adamantane unit, thus having three oxygen atomsin the third chain. The distances of three oxygen atoms from thechain with oxaadamantane unit to the Kþ ion are KþeO7¼3.086 �A,KþeO8¼3.124 �A, and KþeO9¼2.992 �A, indicating that all threeoxygen atoms from the bridge containing the oxaadamantane unitparticipate in the complexation. In cryptand 5, two oxygen atomsfrom the third chain are closest to the Kþ ion. The distances are:KþeO7¼2.806 �A and KþeO8¼2.809 �A.
Due to its smaller size, the Naþ ion does not match the cavity asis the case with Kþ ion, so in the complex with cryptand 2 bothoxygen atoms in the third chain are excluded from the coordinationsphere, as indicated by the distances NaþeO7 and NaþeO8 being4.440 �A and 4.176 �A, respectively. The distances from the oxygenatoms to the Naþ ion in complex with cryptand 3 areNaþeO7¼2.571 �A and NaþeO8¼4.839 �A indicating that now oneoxygen atom from the third chain is included in the coordinatesphere. In the complex with cryptand 4 two of the three oxygenatoms from the chain containing oxaadamantane unit are includedin coordination sphere. The distances from the oxygen atoms to theNaþ ion are: NaþeO7¼2.515 �A, NaþeO8¼3.510 �A, andNaþeO9¼2.661 �A. In cryptand 5, the two oxygen atoms from thebridge containing noradamantane unit are, as in the case of Kþ ion,closest to the Naþ ion (NaþeO7¼2.457 �A and NaþeO8¼2.457�A).
A useful insight into electronic structure of the complexes isgiven by atomic densities. We employed Hirshfeld’s atomic densi-ties obtained by the stockholder principle.23 This provides one ofthe most reliable methods of describing the electron redistribution
in molecules.24 The atomic densities of the cations in question andoxygen as well as nitrogen cryptand atoms are given in Table S3.One observes that there is a large charge transfer from the ligand tothe cation, ranging from 0.68e to 0.72e for Naþ, and from 0.62e to0.76e for Kþ. It is interesting to note that cryptand nitrogens as wellas oxygens retrieve all the electron density lost to the trappedcation. Their atomic density remains practically constant as thedata presented in Table S3 clearly show.
Another factor that influences binding affinity is structural dis-tortion of the cryptand host needed to accommodate the metal ion.A quantitative way to examine the energy cost for structural ac-commodation is to consider complexation as a process where, atfirst, the host cryptand is distorted from its equilibrium geometryso as to accommodate the metal cation. The energy change en-countered in the structural distortion is a measure of the strainenergy, DEstrain, required to accommodate themetal ion. The resultsof the analysis of the strain energy, DEstrain, are presented in TableS4. It is easy to see that greater structural deformations are re-quired in order to accommodate Naþ ion, which has a radius of95 pm than to accommodate Kþ, which has a radius of 138 pm. It isobvious from these results that the cavity size of the investigatedcryptands most closely matches the size of the larger Kþ ion, so thecryptand has to undergo smaller structural changes to accommo-date Kþ than Naþ. The only exception is cryptand 1 where a re-versed trend is observed.
In spite of the fact that the DEstrain is greater to accommodateNaþ than Kþ, in all cryptands except in cryptand 1, cryptands 1e5 aswell as the referent cryptand more strongly bind Naþ in the gasphase then Kþ as shown by the DrG�
(g) values (Table S2). Obviously,stabilization resulting from complexation of Naþ ion is greater thanthat from complexation of Kþ ion, recovering in both cases theenergy cost of structural deformation.
Finally, it has to be noted that the selectivity for alkali metal ionsin the condensed phase is the result of a balance between the in-trinsic affinity and the influence of solvent, i.e., desolvation of themetal ion and free ligand, and the solvation of the complex. Thecontinuum solvation energies of the neutral cryptands and thepositively charged cryptand-metal ion complexes, as well as that ofthe free metal ion are given in Table S1. PCM continuum methodpredicts positive solvation free energies for all host molecules. Thesolvation energies of the neutral host are in the range from25.5 kJ mol�1e39.3 kJ mol�1. The solvation free energies for thecomplexes are predicted to be negative spanning the range from�79.5 kJ mol�1 to�49.4 kJ mol�1. It has to be noted that there is nosignificant difference in solvation free energies of Naþ and Kþ
complexes for the particular case of the cryptand (Table S1).However, the solvation energy of the uncomplexed Mþ changessignificantly from Naþ to Kþ, with solvation energy decreasing asthe ion size increases (DG*sol (Naþ)¼�364.5 kJ mol�1, DG*sol(Kþ)¼�287.1 kJ mol�1). It appears that the solvation energy dif-ference between Naþ and Kþ ion is enough, except for complexa-tion by cryptand 1, to reverse the gas-phase trend so that overallcomplexation process is more favorable for a larger ion than fora smaller one.
3. Conclusion
A number of new adamantane-, 2-oxaadamantane-, andnoradamantane-containing cryptands 1e5 have been synthesizedand their cation-binding abilities were evaluated using a solventextraction technique as well as transport experiments of Naþ andKþ picrate through the liquid membrane. Conformational analysisof investigated compounds was performed using force field basedMonte Carlo conformational search, which showed that the con-formational space of compounds 3 and 4 consists of larger numberof diverse conformations compared to the other investigated
T. �Sumanovac Ramljak et al. / Tetrahedron 69 (2013) 10610e1062010616
compounds. The complex stability was investigated by means ofquantum chemical calculations, using density functional theoryapproach in conjunction with polarized continuum model chosenfor modeling of solvent effects. The results were compared withthose obtained for the parent [2.2.2]cryptand.
The extraction experiments showed that cryptands 1e5 dis-played lower extraction capabilities than the parent [2.2.2]crypt-and. Although their complexation abilities are lower, cryptands 1and 2 showed much higher selectivity toward Kþ than the [2.2.2]cryptand and cryptands 3, 4, and 5, which might be consequence oftheir low conformational flexibility. When the third bridge is en-larged by two additional CH2-groups as well as by two oxygenatoms, as in cryptands 3 and 4, the complexation abilities for biggercations (Kþ, Rbþ, and Csþ) are enhanced. Cryptand 5 displayed thebest extraction capabilities of all cage-substituted cryptands butshowed practically no selectivity towards any of the alkali metalcations.
The experiments of transport of potassium and sodium picratethrough the liquid membrane by ionophores 3, 4, 5, and [2.2.2]cryptand showed that the transport rate with [2.2.2]cryptand forNaþ is much larger than for Kþ. Even though cryptands 4 and 5 havemuch lower transport rates than the [2.2.2]cryptand, they transportKþ faster than Naþ, but with less difference in the transport rates.On the other hand, cryptand 3 also has significantly smallertransport rates than the [2.2.2]cryptand, but transports Kþ fasterthan Naþ with a slightly larger difference in transport rates com-pared to cryptands 4 and 5.
The results obtained from quantum chemical calculations of thestability constants are in good agreement with the experimentalresults and revealed that the most stable complexes with Naþ aswell as Kþ are formed by the cryptand 5. The selectivity toward Kþ
is displayed by all cryptands, except by cryptand 1, which showedselectivity toward Naþ. All cryptands displayed lower selectivitythan [2.2.2]cryptand. The lowest selectivity was shown by cryptand1, moderate selectivity by cryptand 5, while noticeable selectivitywas displayed by cryptand 4.
4. Experimental section
4.1. General
1H and 13C NMR spectra were recorded on a Bruker AV- 300 or600 MHz. All NMR spectra were taken in CDCl3 using tetrame-thylsilane as a reference and chemical shifts are reported in partsper million. The assignment of the NMR signals was done bya combination of 2D NMR techniques. IR spectra were recorded ona FT-IR-ABB BomemMB 102 spectrophotometer in KBr. HRMSwereobtained on an Applied Biosystems 4800 Plus MALDI TOF/TOF in-strument (AB, Foster City, CA). Elemental analyses were performedon a PerkineElmer 2400 elemental analyzer and a PerkineElmerseries II CHNS analyzer 2400. Solvents for chromatography were ofHPLC purity. All compounds were routinely checked by TLC withFluka aluminum oxide on TLC-PET foils.
1,3-bis(2-tosyloxyethyloxy)adamantane (7),17 and 1,3-bis[(2-tosyloxyethyloxy)methyl]-2-oxaadamantane (9)17 were preparedaccording to the procedure described in the literature.
4.2. General procedure for the synthesis of cryptands 1e5
Diaza-18-crown-6 (1 mmol) and ditosylate (1 mmol) were dis-solved in dry acetonitrile under nitrogen atmosphere. Na2CO3(4 mmol) was added and the reaction mixture was refluxed for5 days. The reaction mixture was then cooled to ambient temper-ature and concentrated in vacuo. The solid residue was suspendedin CH2Cl2 and filtered through a plug of Celite. The combined
filtrates were concentrated under reduced pressure to afford thecrude product, which was purified by column chromatography.
4.2.1. 1,3-Diethyladamantano[2.2.0]cryptand (1). By following thegeneral procedure, compound 1 was obtained by reaction of 1,3-bis(2-tosyloxyethyl)adamantane (2.50 g, 4.80 mmol), 4,13-diaza-18-crown-6 (1.30 g, 4.80mmol), and Na2CO3 (2.04 g,19.20mmol) inacetonitrile (280 mL). The crude product was purified by columnchromatography on silica gel using 2/20%MeOHeCH2Cl2, therebyaffording 1.55 g (50%) of a very viscous oily product, which isa complex of cryptand 1 with Na-tosylate. IR (KBr/CDCl3 film) nmax/cm�1: 2900 (s), 2850 (s), 1450 (w), 1350 (w), 1220 (m), 1195 (m),1120 (s), 1035 (m), 1010 (m). 1H NMR (CDCl3) d/ppm: 1.20e1.60 (m,16H, 2H C-2þ12H C-3), 1.93 (br s, 2H, C-5), 2.26 (s, 3H, eCH3),2.40e3.10 (m, 12H, 4H C-7þ8H C-8), 3.52 (br s, 16H, 8H C-9þ8H C-10), 7.08 (d, J¼7.7 Hz, 2H, eOTs), 7.70 (d, J¼7.7 Hz, 2H, eOTs). 13CNMR (CDCl3) d/ppm: 20.85 (1C, eOTs), 28.41 (2C-2), 32.49 (2C-4),36.24 (1C-1), 38.41 (2C-6), 42.09 (4C-3), 44.61 (1C-5), 48.89 (2C-7),55.01 (4C-8), 66.11 (4C-9), 68.84 (4C-10), 125.72 (2C, eOTs), 128.34(2C, eOTs), 139.04 (1C, eOTs), 143.10 (1C, eOTs). Anal. Calcd forC33H53N2O7SNa: C, 61.47; H, 8.28; N, 4.34. Found: C, 61.50; H, 8.44;N, 4.47.
A solution of Na-complex of cryptand 1 (0.32 g, 0.50 mmol) inCH2Cl2 (30 mL) was placed in the separatory funnel and extractedwith water (5�60 mL). CH2Cl2 extract was concentrated under re-duced pressure and then dissolved in hexane using the ultrasoundbath, filtered, and the filtrate was then concentrated in vacuo togive 0.10 g (45%) of cryptand 1 as colorless oil. IR (KBr/CDCl3 film)nmax/cm�1: 2900 (s), 2840 (s), 1450 (m), 1350 (m), 1290 (w), 1260(w), 1105 (s), 1070 (m), 940 (w). 1H NMR (CDCl3) d/ppm: 1.20e1.30(m, 8H, 4H C-3þ4H C-6), 1.50e1.62 (m, 8H, 4H C-3þ2H C-5þ2H C-1), 1.99 (br s, 2H, C-2), 2.50e2.70 (m, 8H, 4H C-7þ4H C-8),2.70e2.85 (m, 4H, C-8), 3.50e3.70 (m, 16H, 8H C-9þ8H C-10). 13CNMR (CDCl3) d/ppm: 29.22 (2C-2), 32.88 (2C-4), 37.09 (1C-1), 41.00(2C-6), 42.86 (4C-3), 44.59 (1C-5), 49.70 (2C-7), 54.56 (4C-8), 70.06(2C-9), 71.23 (6C, 2C-9þ4C-10). Anal. Calcd for C26H46N2O4: C,69.29; H, 10.29; N, 6.22. Found: C, 69.40; H, 10.51; N, 6.33. HRMS,calculated for C26H46N2O4þH: 451.3530; observed: 451.3517.
4.2.2. 1,3-Diethoxyadamantano[2.2.2]cryptand (2). By following thegeneral procedure, compound 2 was obtained by reaction of 1,3-bis(2-tosyloxyethyloxy)adamantane (2.14 g, 3.80 mmol), 4,13-diaza-18-crown-6 (1.00 g, 3.80 mmol), and Na2CO3 (1.61 g,15.20 mol) in acetonitrile (220 mL). The crude product was purifiedby column chromatography on silica gel using 2/20%MeOHeCH2Cl2, thereby affording 1.30 g (50%) of a very viscous oilyproduct, which is a complex of cryptand 2with Na-tosylate. IR (KBr/CDCl3 film) nmax/cm�1: 2900 (s), 2810 (m), 1450 (m), 1355 (m), 1210(s), 1120 (s), 1035 (m), 1010 (m), 920 (s). 1H NMR (CDCl3) d/ppm:1.49 (br s, 2H, C-1), 1.50e1.80 (m, 8H, C-3), 1.86 (br s, 2H, C-5), 2.33(br s, 5H, eCH3þ2H C-2), 2.50 (br s, 8H, C-8), 2.79 (br s, 4H, C-7),3.45e3.65 (m, 20H, 4H C-6þ8H C-9þ8H C-10), 7.12 (d, J¼7.9 Hz, 2H,eOTs), 7.81 (d, J¼7.9 Hz, 2H, eOTs). 13C NMR (CDCl3) d/ppm: 20.79(1C, eCH3), 30.57 (2C-2), 34.95 (1C-1), 40.18 (4C-3), 46.64 (1C-5),54.71 (2C-7), 55.59 (4C-8), 58.69 (2C-6), 68.35 (4C-9), 69.80 (4C-10), 74.22 (2C-4), 125.97 (2C, eOTs), 127.99 (2C, eOTs), 138.26 (1C,eOTs), 144.56 (1C, eOTs). Anal. Calcd for C33H53N2O9SNa: C, 58.56;H, 7.89; N, 4.14. Found: C, 58.57; H, 7.73; N, 4.38.
A solution of Na-complex of cryptand 2 (0.56 g, 8.20 mmol) inCH2Cl2 (30 mL) was placed in the separatory funnel and extractedwith water (5�60 mL). CH2Cl2 extract was concentrated under re-duced pressure and then dissolved in hexane using the ultrasoundbath, filtered, and the filtrate was then concentrated in vacuo togive 0.27 g (68%) of cryptand 2 as yellow oil. IR (KBr/CD3Cl film)nmax/cm�1: 2900 (s), 2850 (m), 1350 (m), 1130 (s), 1100 (s), 730 (w).1H NMR (CDCl3) d/ppm: 1.45e1.60 (m, 6H, 4H C-3þ2H C-1),
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4.2.3. 1,3Di[(ethyloxy)methyl]adamantano [2.2.2]cryptand (3). Byfollowing the general procedure, compound 3 was obtained byreaction of 1,3-bis[(2-tosyloxyethyloxy)methyl]adamantane (8)(0.63 g, 1.10 mmol), diaza-18-crown-6 (0.26 g, 1.00 mmol), andNa2CO3 (0.43 g, 4.00 mmol) in acetonitrile (120 mL). The crudeproduct was purified by column chromatography on Al2O3 (act.IIeIII) using 2/10% MeOHeCH2Cl2 thereby affording 0.38 g (74%)of cryptand 3 as viscous yellow oil. Analytically pure sample wasobtained by rechromatography on a column of Al2O3 (act. IIeIII)using 0/10% MeOHeCH2Cl2. IR (KBr) nmax/cm�1: 2899 (s), 2849(s), 1652 (m), 1453 (m), 1356 (m), 1301 (w), 1264 (w), 1107 (s), 945(m). 1H NMR (CDCl3) d/ppm: 1.30e1.35 (m, 4H, C-3), 1.50e1.55 (m,6H, 4H C-3þ2H C-1), 1.64 (br s, 2H, C-5), 2.03 (br s, 2H, C-2),2.70e2.75 (m, 4H, C-8), 2.75e2.80 (m, 8H, C-9), 3.05 (br s, 4H, C-6),3.45e3.50 (m, 4H, C-10), 3.60e3.70 (m, 12H, 4H C-10þ4H C-8þ4HC-11), 3.75e3.80 (m, 4H, C-11). 13C NMR (CDCl3) d/ppm: 28.13 (2C-2), 34.34 (2C-4), 37.15 (1C-5), 39.23 (4C-3), 41.73 (1C-1), 54.85 (2C-8), 55.28 (4C-9), 69.39 (4C-10), 69.51 (2C-8), 70.70 (4C-11), 81.78(2C-6). HRMS, calculated for C28H50N2O6þH: 511.3742; observed:511.3725.
4.2.4. 1,3-Di[(ethyloxy)methyl]-2-oxaadamantano[2.2.3]cryptand(4). By following the general procedure, compound 4 was ob-tained by reaction of 1,3-bis[(2-tosyloxyethyloxy)methyl]-2-oxaadamantane (0.67 g, 1.13 mmol), diaza-18-crown-6 (0.30 g,1.13 mmol), and Na2CO3 (0.48 g, 4.52 mmol) in acetonitrile(600 mL). The crude product was purified by column chroma-tography on Al2O3 (act. IIeIII) using 2/10% MeOHeCH2Cl2,thereby affording 0.38 g (67%) of cryptand 4 as viscous yellowoil. Analytically pure sample was obtained by rechromatographyon a column of Al2O3 (act. IIeIII) using 0/10% MeOHeCH2Cl2. IR(KBr) nmax/cm�1: 2921 (s), 2854 (s), 1655 (m), 1458 (m), 1359 (m),1112 (s), 940 (m). 1H NMR (CDCl3) d/ppm: 1.38e1.44 (m, 4H, C-3),1.78e1.84 (m, 6H, 4H C-3þ2H C-1), 2.22 (br s, 2H, C-2),2.68e2.84 (m, 12H, 4H C-7þ8H C-8), 3.30 (br s, 4H, C-5),3.46e3.74 (m, 20H, 4H C-6þ8H C-9þ8H C-10). 13C NMR (CDCl3)d/ppm: 26.99 (2C-2), 35.60 (1C-1), 36.26 (4C-3), 55.04 (2C-7),55.23 (4C-8), 70.04 (4C-9), 70.82 (6C, 2C-6þ4C-10), 72.71 (2C-4),78.71 (2C-5). HRMS, calculated for C27H48N2O7þH: 513.3534;observed: 513.3547.
4.2.5. 1,2-Diethyloxynoradamantano[2.2.2]cryptand (5). By follow-ing the general procedure, compound 5was obtained by reaction of1,2-bis(2-tosyloxyethyloxy)noradamantane (10) (0.63 g,1.15 mmol), diaza-18-crown-6 (0.30 g, 1.15 mmol), and Na2CO3(0.49 g, 4.60 mmol) in acetonitrile (600 mL). The crude product waspurified by column chromatography on Al2O3 (act. IIeIII) using2/10%MeOHeCH2Cl2, thereby affording 0.31 g (54%) of cryptand 5as viscous yellow oil. Analytically pure sample was obtained byrechromatography on a column of Al2O3 (act. IIeIII) using 0/10%MeOHeCH2Cl2. IR (KBr) nmax/cm�1: 2920 (s), 1637 (m), 1459 (m),1352 (m), 1301 (m), 1260 (m), 1155 (s), 1134 (s), 1101 (s), 980 (m),941 (m). 1H NMR (CDCl3) d/ppm: 1.45 (br s, 2H, C-1), 1.85e1.90 (m,4H, C-3), 2.00e2.10 (m, 4H, C-3), 2.40 (br s, 2H, C-2), 2.60e2.70 (m,12H, 4H C-6þ8H C-7), 3.55e3.70 (m, 20H, 4H C-5þ8H C-8þ8H C-9).13C NMR (CDCl3) d/ppm: 32.83 (1C-1), 34.10 (2C-2), 47.19 (4C-3),52.95 (4C-7), 54.60 (2C-6), 61.38 (2C-5), 67.52 (4C-8), 68.54 (4C-9),
85.67 (2C-4). HRMS, calculated for C25H44N2O6þNa: 469.3272;observed: 469.3271.
4.2.6. 1,3-Bis[(2-benzyloxyethyloxy)methyl]adamantane (11). A so-lution of 1,3-bis(2-hydroxymethyl)adamantane (3.00 g,15.30mmol) in dry DMF (25mL) was added to a stirred, cooled (ice/water) suspension of NaH (2.90 g, 60.00 mmol; 50% in mineral oil)in dry DMF (40 mL) under a nitrogen atmosphere. The cooling bathwas removed after 30min, the reactionmixturewas stirred at roomtemperature for 3 h and then cooled again with an ice/water bath.The solution of 2-benzyloxy-1-tosyloxyethane20 (10.20 g,33.00 mmol) in dry DMF (25 mL) was added to the cooled reactionmixture, which was then stirred for an additional 48 h, and water(200 mL) was added. The reaction mixture was extracted withCH2Cl2 (4�100mL) and organic extracts were dried over anhydrousMgSO4. The solvent was evaporated and the obtained residue waspurified by column chromatography on silica gel with 10/30%EtOAc/CH2Cl2 as the eluant to afford 3.88 g (55%) of 1,3-bis[(2-benzyloxyethyloxy)methyl]adamantane (11) as a slightly yellowoil. IR (KBr/film) nmax/cm�1: 2880 (s), 1600 (w), 1580 (w), 1500 (m),1450 (s), 1350 (s), 1290 (m), 1240 (m), 1200 (m), 1110 (s). 1H NMR(CDCl3) d/ppm: 1.37 (br s, 2H), 1.45e1.60 (m, 8H), 1.64 (br s, 2H),2.07 (br s, 2H), 3.09 (s, 4H), 3.62 (br s, 8H), 4.59 (s, 4H), 7.25e7.40(m,10H). 13C NMR (CDCl3) d/ppm: 28.06 (2C), 34.35 (2C), 36.53 (1C),39.07 (4C), 41.45 (1C), 69.23 (2C), 71.04 (2C), 72.96 (2C), 82.01 (2C),127.43 (2C), 127.59 (4C), 128.26 (4C), 138.47 (2C). Anal. Calcd forC30H40O4: C, 77.55; H, 8.68; O, 13.77. Found: C, 77.65; H 8.48.
4.2.7. 1,3-Bis[(2-hydroxyethyloxy)methyl]adamantane (12). A sus-pension of 1,3-bis[(2-benzyloxyethyloxy)methyl]adamantane (11)(3.88 g, 8.40 mmol) and 10% PdeC (1.44 g) in dry ethanol (50 mL)was hydrogenated for 96 h. The reaction mixture was filtered andthe filtrate was evaporated under reduced pressure to give 2.30 g(97%) of 1,3-bis[(2-hydroxyethyloxy)methyl]adamantane (12) asa colorless viscous oil. IR (KBr/film) nmax/cm�1: 3300 (s), 2900 (s),2840 (s), 1450 (m), 1360 (m), 1350 (m), 1235 (w), 1125 (s), 1075 (s),1010 (w), 890 (w). 1H NMR (CDCl3) d/ppm: 1.34 (br s, 2H), 1.40e1.55(m, 8H), 1.60 (br s, 2H), 2.03 (br s, 2H), 2.94 (br s, 2H), 3.05 (br s, 4H),3.45e3.55 (m, 4H), 3.65e3.75 (m, 4H). 13C NMR (CDCl3) d/ppm:27.96 (2C), 34.37 (2C), 36.52 (1C), 39.01 (4C), 41.33 (1C), 61.44 (2C),72.45 (2C), 81.66 (2C). Anal. Calcd for C16H28O4: C, 67.57; H, 9.92; O,22.50. Found: C, 67.66; H, 9.73.
4.2.8. 1,3-Bis[(2-tosyloxyethyloxy)methyl]adamantane (8). To a stir-red, cooled (ice/water) suspension of TsCl (0.95 g, 5.00mmol) in drypyridine (2.00 mL), 1,3-bis[(2-hydroxyethyloxy)methyl]ada-mantane (12) (0.57 g, 2.00 mmol) was added in small portionsduring 3 h. The reaction mixture was stirred overnight at w4 �C,diluted with water (50 mL) and extracted with CH2Cl2 (3�50 mL).The combined organic extracts were washed with 6 M HCl(3�100 mL) and dried over anhydrous MgSO4. The solvent wasevaporated under reduced pressure and 1.01 g (85%) of 1,3-bis[(2-tosyloxyethyloxy)methyl]adamantane (8) was obtained as color-less viscous oil. IR (KBr/film) nmax/cm�1: 2900 (s), 1595 (m), 1445(m), 1350 (s), 1290 (m), 1180 (s), 1125 (s), 1095 (s), 1010 (s), 915 (s),810 (s). 1H NMR (CDCl3) d/ppm: 1.16 (br s, 2H), 1.25e1.45 (m, 8H),1.54 (br s, 2H), 1.96 (br s, 2H), 2.42 (s, 6H), 2.93 (s, 4H), 3.50e3.60(m, 4H), 4.05e4.15 (m, 4H), 7.32 (d, 4H, J¼8.0 Hz), 7.76 (d, 4H,J¼8.0 Hz). 13C NMR (CDCl3) d/ppm: 21.33 (2C), 27.81 (2C), 34.09(2C), 36.27 (1C), 38.67 (4C), 40.98 (1C), 68.42 (2C), 69.13 (2C), 81.61(2C), 127.61 (4C), 129.56 (4C), 132.64 (2C), 144.48 (2C). Anal.Calcd for C30H40O8S2: C, 60.79; H, 6.80; O, 21.59; S, 10.82. Found: C,60.69; H, 6.59.
4.2.9. 1,2-Bis(2-benzyloxyethyloxy)noradamantane (13). A solutionof noradamantan-1,2-diole (0.10 g, 0.65 mmol) in dry DMF
T. �Sumanovac Ramljak et al. / Tetrahedron 69 (2013) 10610e1062010618
(1.50 mL) was added to a stirred, cooled (ice/water) suspension ofNaH (0.13 g, 2.60 mmol; 50% in mineral oil) in dry DMF (5 mL)under a nitrogen atmosphere. The cooling bath was removed after30 min, the reaction mixture was stirred on the room temperaturefor 3 h and then cooled again with an ice/water bath. The solutionof 2-benzyloxy-1-tosyloxyethane20 (0.44 g, 1.43 mmol) in dry DMF(1.50 mL) was added to the cooled reaction mixture, which wasthen stirred for additional 48 h, and then water (100 mL) wasadded. The reaction mixture was extracted with CH2Cl2 (3�50 mL)and organic extracts were dried over anhydrousMgSO4. The solventwas evaporated and the obtained residue was purified by columnchromatography on silica gel with 0/30% EtOAc-CH2Cl2 as theeluant to afford 0.14 g (53%) of 1,2-bis(2-benzyoxyethyloxy)nor-adamantane (13) as a slightly yellow oil. IR (KBr) nmax/cm�1: 3432(w), 2949 (m), 2869 (w), 1720 (s), 1453 (w), 1315 (m), 1277 (s), 1161(m), 1071 (w), 1028 (w). 1H NMR (CDCl3) d/ppm: 1.45 (br s, 2H), 1.80(d, J¼9.9 Hz, 4H), 2.07 (d, J¼9.9 Hz, 4H), 2.31 (br s, 2H), 3.62 (t,J¼5.4 Hz, 4H), 3.73 (t, J¼5.4 Hz, 4H), 4.54 (s, 4H), 7.20e7.40 (m,10H).13C NMR (CDCl3) d/ppm: 33.62 (1C), 33.71 (2C), 47.01 (4C), 63.79(2C), 69.85 (2C), 73.09 (2C), 84.42 (2C), 127.33 (2C), 127.57 (4C),128.16 (4C), 138.38 (2C).
4.2.10. 1,2-Bis(2-hydroxyethyloxy)noradamantane (14). A suspen-sion of 1,2-bis(2-benzyloxyethyloxy)noradamantane (13) (0.38 g,0.90 mmol) and 10% PdeC (0.15 g) in dry ethanol (40 mL) washydrogenated for 96 h. The reaction mixture was filtered and thefiltrate was evaporated under reduced pressure to give 0.20 g (92%)of 1,2-bis(2-hydroxyethyloxy)noradamantane (14) as a colorlessviscous oil. IR (KBr) nmax/cm�1: 3405 (s), 2945 (s), 2869 (m), 1459(w), 1315 (m), 1255 (w), 1225 (w), 1161 (m), 1142 (m), 1088 (m),1062 (m), 985 (w). 1H NMR (CDCl3) d/ppm: 1.48 (br s, 2H), 1.86 (d,J¼9.8 Hz, 4H), 2.03 (d, J¼9.8 Hz, 4H), 2.36 (br s, 2H), 3.60e3.85 (m,10H). 13C NMR (CDCl3) d/ppm: 33.46 (1C), 33.79 (2C), 46.95 (4C),61.85 (2C), 65.99 (2C), 84.11 (2C). HRMS, calculated forC13H22O4þHþ: 265.1410; observed: 265.1417.
4.2.11. 1,2-Bis(2-tosyloxyethyloxy)noradamantane (10). To a stirred,cooled (ice/water) suspension of 1,2-bis(2-hydroxyethyloxy)nor-adamantane (14) (0.32 g, 1.32 mmol) in dry pyridine (2.50 mL), TsCl(0.51 g, 2.64 mmol) was added in small portions during 3 h. The re-action mixture was stirred overnight at w4 �C, diluted with water(100 mL), and extracted with CH2Cl2 (4�50 mL). The combined or-ganic extracts were washed with 6 M HCl (3�50 mL) and dried overanhydrous MgSO4. The solvent was evaporated under reduced pres-sure and 0.66 g (91%) of 1,2-bis(2-tosyloxyethyloxy)noradamantane(10) was obtained as colorless viscous oil. IR (KBr) nmax/cm�1: 2952(m), 2939 (m), 2873 (w), 1598 (w), 1449 (w), 1357 (s), 1311 (m), 1190(s), 1174 (s), 1160 (s), 1092 (m), 1014 (m), 921 (s). 1H NMR (CDCl3) d/ppm: 1.42 (br s, 2H),1.71 (d, J¼9.7 Hz, 4H),1.92 (d, J¼9.7 Hz, 4H), 2.29(br s, 2H), 2.44 (s, 6H), 3.65e3.70 (m, 4H), 4.05e4.15 (m, 4H), 7.34 (d,J¼8.1 Hz, 4H), 7.79 (d, J¼8.1 Hz, 4H). 13C NMR (CDCl3) d/ppm: 21.48(2C), 33.28 (1C), 33.48 (2C), 46.67 (4C), 62.07 (2C), 69.65 (2C), 84.56(2C), 127.67 (4C), 129.62 (4C), 132.85 (2C), 144.44 (2C). HRMS, calcu-lated for C27H34O8S2þK: 589.1327; observed: 589.1328.
4.3. Alkali metal picrate extraction experiments
Alkali metal picrates (Lþ, Naþ, Kþ, Rbþ, and Csþ) were freshlyprepared by reacting each of the respective alkali metal hydroxides,MþOH�, with picric acid.22c Due to its high solubility in water andEtOH, Liþ picrate was prepared in situ and subsequently used. Allother alkali metal picrates were isolated and dried prior to use.Alkali metal picrates are highly explosive compounds and shouldbe handled very carefully.
An aqueous solutions of 5.0 mM in alkali metal picrate wereprepared. Reagent grade CHCl3 was washed three times with
redistilled water and then utilized to prepare 5.0 mM solutions ofcryptands 1e5.
A CHCl3 solution (0.5 mL) of the corresponding cryptand wasplaced into a 5mL screw-top vial, and the aqueous solution of alkalimetal picrate (0.5 mL) was added. Another portion of alkali metalpicrate solution (0.5 mL) was added to the second vial to the CHCl3(0.5 mL), which contained no host compound (blank probe) Thevials were stoppered, shaken on a Termolyne Maxy-Mix III Type65,800 mixer for 4 min and then allowed to stand at ambienttemperature for 1 h. A 0.1 mL aliquot of the aqueous phase wastaken with automatic pipette and diluted in volumetric flask viaaddition of redistilled water to a total volume of 10 mL. UVevisiblespectra were obtained for the two solutions, and the percent ofpicrate extracted in each case was calculated from the absorbancemeasured on 355 nm. For each combination of cryptand and alkalimetal picrate, the picrate extractionwas conducted on five differentsamples, and the average value of percent picrate extracted wascalculated. In the absence of cryptand, no metal picrate extractionwas detected.
4.4. Transport of alkali metal picrates across bulk chloroformmembrane
The transport studies were conducted at ambient temperaturein ‘hollow-tube-within-a-vial’ cells. A hollow glass tube (20mm ID)was suspended vertically within a glass vial (40 mm ID) so that thebottom of the glass tube extended below the surface of CHCl3membrane, which separated the aqueous source phase (7.5 mmolof alkali metal picrate in 3 mL of redistilled water) from aqueousreceiving phase (10 mL of redistilled water). The liquid membraneconsisted of 0.75 mmol of cryptand in 10 mL CHCl3. The molar ratioof cryptand to alkali metal picrate was 1:10. The organic phase wasstirred at ca. 200 rpm by means of internal small magnetic stirringbar. During first 7 h, aliquot of the aqueous receiving phase (3 mL)was taken at 1 h intervals, and the concentration of alkali metalpicrate was determined by recording UVevisible spectra (percentof picrate transported was calculated from the absorbance mea-sured on 355 nm with ε¼14,400). Aliquot was returned to the re-ceiving phase and transport experiment was continued. Transportrate was calculated as a slope of moles of picrate transported versustime data, fitted to the straight line. After first 7 h transport ex-periment was continued for another 17 h (total of 24 h), and totalamount of alkali metal picrate transported in 24 h was determined.
4.5. Computational methods
4.5.1. Monte Carlo conformational search. Conformational searchwas performed for compounds 1e6 using Macromodel25 software,which enables efficient conformational search of cyclic compounds.The initial 3D molecular structures were obtained by submittingthe smile codes to the online 3D structure generator (http://cac-tus.nci.nih.gov/translate/). Allinger’sMM3 force field26 was used forparameterization of the molecules and solvent effect was modeledusing the generalized Born-solvent accessible surface area contin-uum solvent model (GB/SA) for chloroform.27 For each compound,the conformational search was performed using at least 50,000steps of Monte Carlo multiple minimum (MCMM) procedure. Ineach step, generated conformation was initially energy minimizedusing 500 steps of Polak-Ribi�ere conjugate gradient algorithm. Theconformations that were found within 20 kJ mol�1 from the ener-getically most favorable conformation were additionally energyminimized using 300 steps of Truncated Newton conjugate gradi-ent algorithm. In order to make the search as extensive as possible,the conformation that has been found the least times (within20 kJ mol�1 from the most favorable conformation) was used as thestarting one in the subsequent run. Even so, the most stable
T. �Sumanovac Ramljak et al. / Tetrahedron 69 (2013) 10610e10620 10619
conformations of each compound were found several tens of timesleading to the conclusion that the conformational space was thor-oughly sampled. Gromacs28 software was used for the clusteranalysis, which was performed on the set of conformations foundwithin 10 kJ mol�1 from the most favorable conformation foundduring the search.
4.5.2. Quantum chemical calculations. Complexes of cryptands1e5 and parent [2.2.2]cryptand with Naþ and Kþ cations werebuilt using the most stable conformers found during the MCsearches. The geometries of those initial conformations werefully optimized using the density functional theory (DFT) in itsB3LYP representation29 This level of theory was chosen becauseit is a good compromise between accuracy and feasibility whendealing with large systems, yielding reasonably accurate struc-tures and energies of interactions between neutral moleculesand metal monocations if a flexible basis set is provided.30 Themolecular structures were calculated using the efficient 6-31G(d) basis set, whereas the final molecular energies wereobtained with the large B3LYP/6-311þG(3df,2p) basis setemploying single point calculations B3LYP/6-311þG(3df,2p)//B3LYP/6-31G(d). The structure of each complex was built upfrom those of optimized cryptands by placing the metal cationinside the cavity and then fully optimized. All calculated struc-tures were verified by the vibrational frequency analysis carriedout using the harmonic oscillator approximation to be trueminima on the potential energy surface, which means that noimaginary vibrational frequencies were found. The zero-pointvibrational energy correction (ZPVE) and thermal correction tothe free energy were derived from the same vibrational analysiswithout scaling. The energies of the host-metal complexes werecorrected for basis set superposition errors using the counter-poise correction method of Boys and Bernardi31 at the B3LYP/6-311þG(3df,2p)//B3LYP/6-31G(d) level. Solvent effects were takeninto account using the polarized continuum model (PCM) in-troduced by Scrocco, Tomasi, and Miertu�s.32 The continuummodel places a solute molecule in a solvent cavity surrounded bya polarizable continuum, whose reaction field modifies the en-ergy and properties of the solute. The chloroform solvent isrepresented by an infinite dielectric continuum characterized bya dielectric constant of 4.71. The solute cavity is constructedusing atom-centered spheres of ua0 radii. Geometries for thesolutes were taken from B3LYP/6-31G(d) gas phase optimizationand were kept frozen during the B3LYP/6-311þG(d,p) free en-ergy solvation calculation. Gaussian 0333 and Gaussian 0934
program packages were employed.The stability constant was calculated utilizing the well-known
relation, DrG*¼�RT ln K. The thermodynamics is based on the fol-lowing process:
MþðCHCl3Þ þ LðCHCl3Þ/LMþ
ðCHCl3Þ (1)
where ‘Mþ’ stands for the metal cation, ‘L’ stands for the cryptandligand, whereas ‘CHCl3’ indicates continuum solvation in chloro-form solvent. Using thermodynamic cycle given in Scheme S1 in theSupplementary data, DrG
�ðCHCl3Þ is calculated via gas phase com-
plexation free energy, DrG�(g), which, in turn, is calculated as stated
in Eq. 2:
DrG�ðgÞ ¼ Df G
��LMþ��
hDf G
� ðLÞ þ Df G��Mþ�i (2)
where DfG� is the free energy of the formation. It involves theelectronic energy, the zero-point vibrational energy contributionand thermal corrections to 298.15 K. All species were immersed inthe chloroform solvent and their solvation free energies wereadded to the gas phase reaction free energy to get DrG
�ðCHCl3Þ:
DrG�ðCHCl3Þ ¼ DrG
�ðgÞ þ DG�
sol�LMþ�� DG�
solðLÞ � DG�sol
�Mþ�
� DG�/� (3)
where DG*sol(LMþ) is the solvation free energy of complex inchloroform solvent, DG*sol(L) is solvation free energy of cryptand inchloroform solvent, DG*sol(Mþ) is solvation free energy of metalcation in chloroform solvent, and DG�/* represents the free en-ergy change of 1 mol of an ideal gas from 1 atm to 1 M standardstate. It was applied to each gas phase reactant and product. At298 K, DG�/* has value of 7.91 kJ mol�1. It has to be noted that theeffects of counter ions were neglected during the stability constantcalculations, which was necessary to keep the size of the molecularsystems manageable so that relatively high levels of theory and anadequate basis set could be used.
Acknowledgements
The financial support of The Croatian Ministry of Science, Edu-cation and Sports (Grants no. 098-0982933-2911, 098-0982933-2932, 098-1191344-2860) is gratefully acknowledged.
Supplementary data
Supplementary data related to this article can be found at http://dx.doi.org/10.1016/j.tet.2013.10.039.
References and notes
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