Design, Synthesis, and X-ray Structural Analyses of Diamantane DiammoniumSalts: Guests for Cucurbit[n]uril (CB[n]) Hosts
Marina Sekutor,[a] Kresimir Molcanov,[b] Liping Cao,[c] Lyle Isaacs,*[c] Robert Glaser,*[d]
and Kata Mlinaric-Majerski*[a]
Keywords: Synthetic methods / Host-guest systems / Polycycles / Diamantane
New bisprimary and bisquaternary diamantane-1,6- and-4,9-diammonium/diaminium salts were synthesized, andcharacterized by NMR spectroscopy and X-ray crystallogra-phy. The impetus for these syntheses were previously re-ported X-ray crystallographic investigations of adamantanemono- and bisquaternary ammonium ions [3,5-diMeAda-1-NH3 or Ada-1,3-di(NMe3)] complexed with cucurbit[n]uril (n= 7, 8). The crystal structures were analyzed to ascertain pos-sible structural hypotheses for high binding affinity guestsbound within various diameter pumpkin-shaped hosts. Al-though Diam-4,9-di(NMe3I) 5 could be readily prepared fromthe bisprimary precursor, corresponding Diam-1,6-di(NMe3I)
IntroductionDiamantane (1) is a naturally occurring polycyclic hydro-
carbon that was first isolated from crude oil,[1] later synthe-sized from Binor-S.[2] Some of its many applications are inpolymers,[3] advanced materials,[4] and as a potential antitu-mor[5] agent. Owing to its diamondoid structure,[6] diaman-tane possesses many physical characteristics typical of ada-mantane, including rigidity, lipophilicity, low strain energy,etc.[7] However, its chemistry differs quite a bit from that ofadamantane. For example, the diamantane skeleton pos-sesses two different types of tertiary C–H bonds: six “me-dial” bonds on a central cyclohexane “belt” and two “api-cal” bonds on top/bottom. Because the reactivity of thesebonds in chemical transformations is markedly different, se-
[a] Department of Organic Chemistry and Biochemistry, RueerBoskovic Institute,Bijenicka cesta 54, 10000 Zagreb, CroatiaE-mail: [email protected]://www.irb.hr/eng/People/Kata-Majerski
[b] Department of Physical Chemistry, Rueer Boskovic Institute,Bijenicka cesta 54, 10000 Zagreb, CroatiaE-mail: [email protected]://www.irb.hr/eng/People/Kresimir-Molcanov
[c] Department of Chemistry and Biochemistry, University ofMaryland,College Park, Maryland 20742, USAE-mail: [email protected]://www.chem.umd.edu/lyle-isaacs
[d] Department of Chemistry, Ben-Gurion University of the Negev,Beer-Sheva 84105, IsraelE-mail: [email protected] information for this article is available on theWWW under http://dx.doi.org/10.1002/ejoc.201301844.
14 could not be obtained even under strong reaction condi-tions. Stereochemical analysis of this situation suggests verysevere steric non-bonding cis-1,3-diaxial type H···H interac-tions between the “axial”-type NMe3 group and neighboring“axial” proton neighbors. These same interactions are foundin Ada-2,6-di(NMe3I) analogues, but they are alleviated inthis smaller polycyclic skeleton through tilting the axialC(methylene)–NMe3 bond away from its axial neighbors.However, similar structural relief for Diam-1,6-di(NMe3I) isnot possible, because the C(methine)–NMe3 bond therein isligated to the diamondoid’s rigid skeleton.
lective functionalizations of certain positions are possible.Unfortunately, this does not always hold true for all syn-thetic procedures, e.g. selective bromination sometimesproves rather tedious.[8]
Our goal was to synthesize diamantane ammonium salts2–5 (see Figure 1) as part of an ongoing study of the geo-metrical binding prerequisites for complexes of ada-mantane-diammonium cation guests bound to cucurbit[n]-uril (CB[n]) hosts of different diameters.[9] Two X-ray crys-tal structures of adamantane ammonium guests complexedwith cucurbit[n]uril (CB[n]) hosts are found in the Cam-bridge Structural Database (CSD). One of the structuresdepicts cucurbit[8]uril complexed with adamantyl bis-quaternary ammonium dication 6, CB[8]·6 (refcode
Figure 1. Chemical structures of CB[n], diamantane guests 2–5, andadamantane guests 6–9.
L. Isaacs, R. Glaser, K. Mlinaric-Majerski et al.FULL PAPERSAXKEI)[9b] and the other portrays cucurbit[7]uril com-plexed with an adamantyl monoammonium cation, CB[7]·7(refcode SULZIJ).[9c] In addition to the hydrophobic inter-actions between CB[n] cavities and adamantyl guests, thesestructures illustrate two different N+ binding modes to thecarbonyl oxygens on the CB[n] portals.
Figure 2 shows one Ada-1,3-di(NMe3I) quaternary tri-methylammonium ion in CB[8]·6 jutting out 0.51 Å fromthe top portal carbonyl oxygen mean plane.[9b] The partiallyexposed adamantyl C(quat)–N+ bond is approximately per-pendicular to the portal plane and is located at almostequal distances to five of the eight carbonyl oxygens on theelliptical portal rim. As a result, multiple strongRMe3N+···δ–O=C quaternary ammonium ion-carbonyl di-pole interactions are formed [four show a 4.34(8) Å+N···O=C average distance and one has a 4.74 Å +N···O=Cdistance, see the dashed lines in upper half of CB[8]·6 de-picted in Figure 2]. The remaining three carbonyl oxygenatoms are at longer distances from N+ owing to the portalrim’s elipticity: 5.70, 5.78, and 6.44 Å. The second quater-nary trimethylammonium ion pushes against the cavity wallcausing it to undergo an ellipsoidal deformation.
Figure 2. X-ray crystal structure of CB[8]·6 complex, refcodeSAXKEI mol A.[9b] The long axis of elongated CB[8] is horizontal,and the RMe3N+···δ–O=C ion-dipole interactions are shown asdashed lines. Atom key: black (nitrogen), dark grey (oxygen), lightgrey (carbon), white (hydrogen).
The 3,5-diMeAda-1-NH3Cl dimethyl groups in CB[7]·7undergo steric interactions with the walls that result in anellipsoidal deformation of the cavity.[9c] One of the impor-tant host-guest attractive forces in this complex are two hy-drogen-bonds which +N···O=C distances are 2.76 Å and2.85 Å. These are shown as dashed lines in Figure 3. A thirdNH proton in the guest undergoes hydrogen-bonding to thehost through a water bridge: 2.85 Å +N···O(water) and2.80 Å O(water)···O=C.
To optimize the hydrogen-bond lengths and locations,the adamantyl-C–N+ bond “tilted” towards two carbonyloxygen atoms on the rim until it attained a 0.18 Å heightabove the carbonyl oxygen mean plane. Counting the waterbridged carbonyl, only three of the seven CB[7] carbonylsundergo strong hydrogen-bonding interactions. These sameprimary and quaternary ammonium binding modes are ob-served in other crystalline CB[n] complexes that were ana-
Figure 3. X-ray crystal structure of CB[7]·7 complex, refcodeSULZIJmol A.[9c] The long axis of elongated CB[7] is horizontal,and the hydrogen bonds are shown as dashed lines. Atom key:black (nitrogen), darkest grey (oxygen), lightest grey (carbon),white (hydrogen).
lyzed. They are also assumed to be present in CB[n] com-plexes containing smaller cross-sectional diameter ada-mantyl monoamines [e.g. Ada-1-NH3Cl (8·HCl) andAda-1-NMe3I (9)]. The Isaacs group[9b] reported relativelyhigh Ka values of (4.23� 1.00)�1012 m–1 and(1.71 �0.40)� 1012 m–1 for CB[7]·8·HCl and CB[7]·9 com-plexes, respectively.
Because the cross-sectional diameters of both ada-mantyl-9 and diamantyl-5 mono- or bisquaternary ammo-nium ions are similar, efficient space filling of the CB[7]cavity should be possible for both diamondoids. TheSAXKEI diamine crystal structure shows one adamantylC–N+ bond approximately parallel to the CB[8] rotationaxis (see Figure 2). A line continuing the C–N bond intothe adamantane rear cyclohexyl mean plane centroid is ap-proximately perpendicular to the CB[8] equatorial plane.The non-bonding distance between the cyclohexyl centroidand N+ is 3.9(1) Å in length. This is approximately one-halfthe 7.8 Å N+···N+ distance in diamines 4 and 5. Only oneof the two CB[n] portals in the SAXKEI/SULZIJ crystalstructures interacts with adamantyl ammonium ionsthrough formation of either multiple +N···O=C ion-dipoleinteractions or by local hydrogen-bonding. The principlesof “crystal structure based molecular design” employed bythe pharmaceutical industry suggest that new inversion-symmetry diammonium guests be appropriately designed sothat each of their cations interacts with different portals.
On the basis of the similar cross-sectional diameters andthe appropriate diamantane N+···N+ distance, it was hy-pothesized that 4,9-diamantane salts would bind to bothportals of CB[7]. Furthermore, the lack of lateral substitu-ents on bisquaternary ammonium 5 could enable its C3-axisto be aligned approximately collinear with CB[7]’s C7-axis.As a result, one could expect a maximum quantity of sevenmultiple ion-dipole interactions on each of the two non-elliptically distorted portal faces. A second probe of struc-tural requirements in CB[n]·amine complexes uses the widercross-sectional diameter of 1,6-diamantane salts that mightenable them to be selective in favor of larger CB[8] molecu-
Diamantane Diammonium Salts
lar containers. These stereochemical analyses were the im-petus for the syntheses of diamantane-1,6-di(NH2) (2), di-amantane-4,9-di(NH2) (4), and their N-methylated ana-logues.
Our recent report of a record ultrahigh Ka =7.2 �1017 m–1 binding constant for CB[7]·5 is in agreementwith a crystal structure showing auspicious diamantane di-ammonium salt interactions encompassing fourteen O-atoms on both portals of the host.[10] As further noted inour findings, the CB[7] macrocycle within CB[7]·5 assumeda nearly circular equatorial cross-section 11.6(2) Å meandiameter, which is similar to the 11.6(2)/11.7(9) Å values ofthe two uncomplexed CB[7] symmetry independent mol-ecules.[11] However, the 8.62(3) Å C=O···O=C portal meandiameter of CB[7]·5 is slightly larger, and with ten timeshigher precision, than the 8.4(4)/8.6(9) Å measurements inuncomplexed CB[7]. This difference probably reflects thenon-sterically demanding constraints of multiple+N(CH3)3···O=C close contacts with portal O-atoms versusthe latter’s increased flexibility within an uncomplexed mo-lecular container.[10]
Results and Discussion
Synthesis of Diamantane-1,6-diamines
The most facile way to obtain 1,6- and 4,9-substituteddiamantanes is to start with selective halogenation of thediamantane-type hydrocarbon 1, see Scheme 1. Bromina-tion of diamantane at reflux temperatures for 16 hours af-forded 1,6-dibromodiamantane 10[12] in a 46 % yield, whichwas sufficient for further synthesis of the 1,6-diamine salts.A mixture of polybrominated derivatives[8] is obtained un-der different conditions. Desired diacetamide 11[13] wasthen successfully prepared from 10 by using a Ritter reac-tion (Scheme 1). However, hydrolysis of this acetamide tocorresponding diamine 2 was problematic. A previously de-scribed procedure[13] involved the use of NaOH in diethyl-ene glycol as a solvent, which made work up difficult.
Furthermore, the hydrolysis itself was often unsuccessfuland only starting diacetamide 11 could be isolated. Acidcatalyzed hydrolysis with concentrated HCl did not enableisolation of the hydrochloride salt of diamine 2, but unex-pected dichlorodiamantane byproduct 12 was produced.These unsuccessful hydrolysis attempts were the reason thatwe turned our attention to a different path that proceededthrough diazide 13.[14] Azidation of 1,6-dibromide 10 byusing trimethylsilyl azide was straightforward, and the sub-sequent reduction of diazide 13 to desired diamine 2 byusing catalytic hydrogenation was successful. The last stepin the synthesis of the 1,6-derivatives was exhaustive meth-ylation[9b] that was expected to produce quaternary ammo-nium salt 14. However, work-up of the crude product, eitherin the presence or absence of excess NaHCO3, afforded onlyN,N,N�,N�-tetramethylated free base 3 or dihydroiodide salt3·2HI.
Although different methods were used in the attempt toproduce quaternary ammonium salt 14, none of them weresuccessful. The procedures that were used are summarizedin Table 1. Regardless of whether diamine 2 or 3·2HI wasused as the starting material, tetramethylated compound3·2HI was always isolated as the sole product (except forTable 1, Entries 4 and 6, in which decomposition occurredand no products were isolated). The reason for these fail-ures appears to be steric in nature (vide infra).
Table 1. Unsuccessful attempts to synthesize quaternary ammo-nium salt 14.
Reactant Base Solvent Conditions Time Product
1 2 NaHCO3 MeOH MeI, reflux 48 h 3·2HI2 2 NaHCO3 MeOH MeI, reflux 120 h 3·2HI3 3·2HI NaOH MeOH MeI, reflux 24 h 3·2HI4 3·2HI NaH THF MeI, reflux, N2 6 h dec.5 3·2HI NaHCO3 toluene MeI, reflux 6 h 3·2HI6 3·2HI NaHCO3 toluene MeI, MW, (200 W) 1 h dec.
Synthesis of Diamantane-4,9-diamines
It was decided not to use the brominated 4,9-derivativeas a starting material because it is normally difficult to ob-tain specificity in the Br2–AlBr3 reaction, and the resultingpolybrominated product mixture is difficult to separate.[8]
Although a recently published work describes a highly se-lective bromination of diamantane at the 4,9-positions withan Fe-catalyst,[15] its use of Freon-113 made this methodless attractive. Instead, a selective chlorination of diaman-tane produced 4,9-dichlorodiamantane 15[16] (Scheme 2).
L. Isaacs, R. Glaser, K. Mlinaric-Majerski et al.FULL PAPERThe dichloro derivative proved to be reactive enough underazidation to afford desired diazide 16 (albeit in a somewhatlower yield than that reported for 4,9-dibromodiamantane).Further elaboration proceeded as planned and diazide 16was successfully reduced to diamine 4, which was thenmethylated to quaternary ammonium salt 5 without diffi-culty.
The reduction of azides 13 and 16 with an excess of 10 %Pd/C in unstabilized THF as a solvent produced two unex-pected byproducts 17 and 19 that were the result of a tetra-hydrofuran ring opening reaction (Scheme 3). Althoughthis reaction is known for aromatic amines,[17] to the bestof our knowledge, there is no example of such a reactionfor aliphatic amines. The free radical mechanism proposedby Russell et al.[17] suggested stabilization of the amino freeradical by aromatic resonance. Although there is no pos-sibility for this to occur for our diamantane amines, we nev-ertheless believe that stabilization of the amine free radicalis possible owing to the presence of the bulky diamantaneskeleton. After the subsequent methylation of these di-amines, we isolated corresponding tertiary ammonium salt18 and quaternary diiodide 20. As mentioned earlier for salt3, the lack of formation of the quaternary ammonium saltupon methylation of 17 is probably owing to steric factorsas described below.
Scheme 3. Synthesis of bis(4-hydroxybutyl)diamantane derivatives17–20; (i) excess of 10% Pd/C, H2, unstabilized THF, 24 h; (ii) MeI,MeOH, NaHCO3, reflux, 48 h, overall yield 66% for 18, 65% for20.
The 1H and 13C NMR spectra of all the diamantane-1,6-and 4,9-compounds reported in this work are in agreementwith their proposed structures.
Solid-State Stereochemistry of Adamantane- andDiamantane-Diamine Salts with Coaxially DisposedSterically Demanding Amino Substituents
At first glance, diamantane-1,6-diamines appear to beara structural resemblance to those of the adamantane-2,6-diamine family. However, the adamantane skeleton is cap-able of undergoing distortion to accommodate increased
“cis-1,3-diaxial strain” arising from bulky substituents (e.g.NMe3) at the 2,6-positions, whereas the 1,6-diamantane an-alog is incapable of doing this. A discussion of the solid-state stereochemistry of Ada-2,6-di(NHMe2Cl) 21, andAda-2,6-di(NMe3X) (in which X = Br or I) 22[18] providesa useful foundation for understanding the unsuccessfulpreparation of Diam-1,6-di(NMe3I) 14. Adamantane meth-ylene positions C(2 and 6) are each located at the fusion oftwo cyclohexyl fragments. Substituents at positions 2 and 6are axially disposed with respect to one of the adamantanecyclohexyl moieties [C(1,2,3,9,7,8)] and equatorial to theother [C(1,2,3,4,5,10)]; see numbering in Figure 4. There-fore, one may expect non-bonding steric interactions as the2- or 6-substituent increases in bulk. cis-1,3-diaxial strainin crystalline 21 and 22 manifests itself by distortions of thenon-bonding angle α and torsion angle β in which α = N–C(2)···C(8 or 9) and β = C(8)–C(1)–C(2)–H(2)/C(9)–C(3)–C(2)–H(2). When 2,6-substituents are not sterically de-manding, the axial C(2)–N bond should be approximatelyparallel to the axial C(8)–H/C(9)–H bonds so that α ≈ 90°and β ≈ 180° owing to a lack of appreciable strain-basedtorque (twist) about the C(1)–C(2)/C(2)–C(3) bonds. InAda-2,6-diamines 21 and 22, N+ tilts away from its nearbytransannular H(8ax & 9ax) neighbors as the amino groupincreases in bulk. For N+HMe2 (in which the NH protonpoints toward the interior of the ring) α = 97.0(6)°, and thisangle is increased to 109(1)° for N+Me3 (Figure 4). Underthese circumstances, the normally antiperiplanar-like ≈ 180°magnitude for torsion angle β distorts to � 180° throughtorque about the C(1)–C(2)/C(2)–C(3) bonds to accommo-date the concurrent outward “tilt” of bulky axial N-substi-tuted groups: e.g. 173.1(5)° for N+HMe2 and 161.4(9)° forN+Me3.
Figure 4. X-ray crystallographically determined structures of Ada-2,6-di(NHMe2Cl) 21 and Ada-2,6-di(NMe3I) 22 showing increas-ing N+ tilt outwards from the interior of the cyclohexyl ring printedin grey as the ammonium substituent increases in bulk.[18]
In contrast, diamantane methine carbons C(1 & 6) areeach located at the fusion of three cyclohexyl fragments.As a result, diamantane 1,6-substituents are equatorial withrespect to two other cyclohexyl fragments [C(1,10,9,8,7,11)and C(1,10,9,14,13,2)] but axial to C(1,2,3,4,12,11), seenumbering in Figure 5. This illustration depicts the X-raycrystallographically determined molecular structures ofDiam-1,6-di(NMe2) free base 3, and Diam-1,6-di(NHMe2I)3·2HI together with a semi-empirical AM1 model of Diam-1,6-di(NMe3) 14. The α non-bonding angles are now num-
Diamantane Diammonium Salts
bered C(3 or 12)···C(1)–N and the β “tilt” torsion anglesbecome C(3)–C(2)–C(1)–C(10)/C(12)–C(11)–C(1)–C(10).The 1,6-positions in diamantane are methine carbons andare constrained against torque about the C(2)–C(1)/C(1)–C(11) bonds, because C(10) is an integral part of the skel-eton [i.e. angle C(1)–C(10)–C(9) cannot be compressedthrough tilting].
Figure 5. X-ray crystallographically determined molecular struc-tures of Diam-1,6-di(NMe2) free base 3, Diam-1,6-di(NHMe2I)3·2HI, (–)-3ax-trimethylammonio-2ax-acetoxy-trans-decalin iodide23, and the calculated AM1 model of Diam-1,6-di(NMe3) 14.
The molecular geometry of crystalline free base 3 is suchthat the non-bonding lone pair electrons of the axial nitro-gen point into the ring interior. Like the lone pair electronsof Diam-1,6-di(NMe2) free base 3, the NH proton alsopoints inwards towards its diaxial proton neighbors inDiam-1,6-di(NHMe2I) 3·2HI. Yet, despite increased cis-1,3-diaxial strain going from :NMe2 �H–N+Me2, the tertiaryammonium salt’s α and β angles are very similar α =91.4(7)° and β = 178(1)° values relative to α = 89.3(2)° andβ = 178.6(1)° for the corresponding free base.
On the other hand, these parameters for Ada-2,6-di(NHMe2Cl) are a more usual α = 97.0(6)° and β =173.1(5)° because N+ tilting outwards is enabled. This com-parison of α and β values for the same NHMe2 substituent
is consistent with our interpretation that Diam–C(10) pro-vides a “buttressing effect” hindering an outward “tilt” ofthe axial substituent required to provide relief from cis-1,3-diaxial interactions. Another indication of the strain inDiam-1,6-di(NHMe2) is seen by its AM1 ≈ 13 kcal mol–1
higher energy relative to the Diam-4,9-di(NHMe2) consti-tutional isomer in which NHMe2 is equatorial to all threefused cyclohexyl moieties. The C(10) skeletal constraint isalso counteracting an outward NMe3 “tilt” in the AM1 cal-culated model of Diam-1,6-di(NMe3) dication of 14 inwhich α and β are only 98(1) and 176(2)°, respectively. Afurther indication of the constraint upon an NMe3 outwardtilt in Diam-1,6-di(NMe3) is seen by its exceptionally largeabout 37 kcal mol–1 higher energy (AM1) relative to Diam-4,9-di(NMe3) constitutional isomer 5 in which NMe3 isequatorial to all three fused cyclohexyl moieties.
Figure 5 also illustrates the molecular geometry of crys-talline (–)-3ax-trimethylammonio-2ax-acetoxy-trans-deca-lin iodide 23, a rigid structural analogue of acetylcholine.[19]
Axial NMe3 groups in these crystals also readily “tilt” out-wards because they are not constrained by the diamantaneskeleton. This is clearly seen by the 112(1)° and 111.0(8)° αnon-bonding angles measured in both polymorphs of 23(refcodes MADECI and TMAXDI, respectively) relative tothe 109(1)° value for Ada-2,6-di(NMe3I) 22. Because thecrystal structures of 23 were reported without protons, theβ “tilt” angles are unknown.
The X-ray crystallographically determined structures ofDiam-4,9-di(NH3Cl) 4·2HCl and Diam-4,9-di(NMe3I) 5are presented in Figure 6. Substituents bonded to the C(4 &9) positions of the diamantane skeleton are in an equatorialdisposition to each of the three fused cyclohexane frag-ments. As a result, their bulk does not result in significantnon-bonding steric interactions.
Figure 6. X-ray crystallographically determined molecular struc-tures of Diam-4,9-di(NH3Cl) 4·2HCl and Diam-4,9-di(NMe3I) 5.
X-ray Crystallography and Hydrogen-Bonding Patterns
Pidcock et al.[20] showed that 99% of molecules havinginversion symmetry as their sole non-trivial symmetry ele-ment maintain this symmetry upon crystallization by occu-pying special positions of inversion. The solution-state C2h
symmetry diamantane-1,6- and D3d symmetry diamantane
L. Isaacs, R. Glaser, K. Mlinaric-Majerski et al.FULL PAPER4,9-derivatives reported in this work undergo desymmetriz-ation in the crystal lattice. Thus, with the exception ofDiam-4,9-di(NMe3I) 5 (asymmetric when within the P1crystal), the other diamantane crystal structures reportedherein [2·2HCl·2H2O, 3, 3·2HI·2H2O, 4(A,B)·2HCl·H2O,10, 12, 13, 16(A,B), and 20·2H2O] show partial desymme-trization to solid-state Ci symmetry because they all occupyspecial positions of inversion symmetry in their respectiveunit cells. Nevertheless, whereas the above nine crystalstructures exhibit only genuine Ci point group symmetryand another structure is asymmetric, the very high fidelityof their C2h- or D3d pseudosymmetry is aesthetically pleas-ing owing to the higher order virtual (non-mathematical)symmetry.
Diam-1,6-di(NH3Cl)·dihydrate 2·2HCl·2H2O crystallizedin the monoclinic space group P21/n (Z = 2, Z� = 0.5) andoccupies a special position of crystallographic inversionsymmetry. Each of the three N–H protons participates in ahydrogen bond: d[+N(1)–H···Cl–(1) {x,y,z}] = 3.273 Å;d[+N(1)–H···Cl�–(1) {1/2 + x,1/2 – y,1/2 + z}] = 3.168 Å;and d[+N(1)–H···O(1) {x,y,z}] = 2.663 Å. Figure 7 shows
Figure 7. R44(8) ring hydrogen-bonding graph sets for Diam-1,6-
di(NH3Cl)·dihydrate 2·2HCl·2H2O. Cl� and O� are symmetryequivalent [1/2 + x,1/2 – y,1/2 + z] and [1/2 + x,1/2 – y, –1/2 + z],respectively. Skeletal protons are eliminated for clarity.
Figure 9. R35(10) ring hydrogen-bonding graph set between Diam-4,9-di(NH3Cl)·dihydrate 4 (molecule A)·2HCl·2H2O (on right) and
Diam-4,9-di(NH3Cl) anhydrate 4 (molecule B)·2HCl (on left) molecules in the P1 crystal. Skeletal protons are eliminated for clarity.
Diam-1,6-di(NHMe2I)·dihydrate 3·2HI·2H2O crys-tallized in the orthorhombic space group Pccn (Z = 4, Z�= 0.5) and occupies a special position of crystallographicinversion symmetry. Figure 8 shows the hydrogen-bondingpatterns for the molecule, and d[+N(1)–H···O(1) {x,y,z}] =2.761 Å; d[O(1)···I–(1) {x,y,z}] = 3.463 Å.
Figure 8. Hydrogen-bonding patterns for Diam-1,6-di(NHMe2I)·dihydrate 3·2HI·2H2O. Skeletal protons are eliminated for clarity.
Both Diam-4,9-di(NH3Cl)·dihydrate 4 (molecule A)·2HCl·2H2O and Diam-4,9-di(NH3Cl) anhydrate 4 (mo-lecule B)·2HCl cocrystallized in the same triclinic spacegroup P1 crystal, and both molecules occupy different spe-cial positions of inversion symmetry. Figure 9 shows theR3
5(10) ring hydrogen-bonding graph set between the Aand B molecules, and d[+N(A)–H···O(A) {x,y,z}] = 2.782 Å;d[+N(A)–H···Cl–(1A) {x,y,z}] = 3.227 Å; d[O(A)···Cl–(1B){x,y,z}] = 3.234 Å; d[+N(1B)–H···Cl–(1B) {1 + x,y,z}] =3.241 Å; d[+N(1B)–H···Cl–(2A) {x,y,z}] = 3.184 Å;d[+N(A)–H···Cl–(2A) {x,y,z}] = 3.149 Å; and d[+N(2B)–H···Cl–(2B) {2 – x,1 – y, –z}] = 3.168 Å. Diam-4,9-
Diamantane Diammonium Salts
Figure 10. Left: side view of Diam-4,9-di(NMe3I) dication (5) encapsulated in a monoclinic prism (distorted rombohedron-pattern) ofblack colored iodide anions [6.9(1) Å] doubly-capped with iodide anions residing at the apexes of square pyramids. The grey color-codedmidpoints of each of the six rhombohedron-like faces are crystallographic centers of inversion symmetry. Right: end view showing adashed line ca. 7.15 Å cross-sectional diameter of 5 perpendicular to the N+···N+ axis.
di(NMe3I) (5) occupies general positions of symmetry in aP1 space group crystal, and thereby is asymmetric. Thisdistortion from its solution-state D3d-symmetry is visuallynegligible, but is significant because the diastereotopic envi-ronments around electron clouds of pairs of pseudosym-metrical nuclei afford no symmetry degeneracies in the dif-fraction pattern of the crystal. In other words, despite theaesthetic appeal of a higher order virtual symmetry, thereare no symmetry related pairs of atomic coordinates in thesolid-state D3d-pseudosymmetric crystal structures. As a re-sult, the asymmetric unit of the unit cell is a full moleculewhereas those for 2·2HCl·2H2O, 3, 3·2HI·2H2O, 4(A,B)·2HCl·H2O, 10, 12, 13, 16(A,B), and 20·2H2O crystals con-tain half-molecules. Eight iodide anions encapsulate thebisquaternary dication of 5 and form a monoclinic prism(distorted rombohedron-arrangement) with all twelve I–···I–
edges being 6.9(1) Å (see Figure 10). When oriented as inFigure 10, the faces in the figure parallel to the gh-axis arealternating squares and rhombi (e.g. a-b-c-d and a-b-f-e,respectively). The midpoint of each of the prism’s four hori-zontal sides (grey circle) is a center of inversion symmetry(0,0,0; 1/2,0,0; 0,1/2,0; 1/2,1/2,0). The ends of the prism arecapped with a square-pyramid arrangement having iodideanions at apices g,h that are 4.97(1) Å above the square baseof four iodides. In Figure 10, the square plane a-b-c-d isskewed to the left by about 10.8° from its parallel rearsquare plane neighbor. This generates an acute complemen-tary b-a-e angle of 79.2° within the adjacent a-b-f-e rhom-bus. The about 7.15 Å cross-sectional diameter perpendicu-lar to the N+···N+ axis of 5 is illustrated on the right sideof Figure 10. This distance suggests that the bisquaternarycation should be able to enter the about 7.2 Å diameter be-tween the peripheral van der Waals radii of the CB[7] por-tal. The 6.89(1) Å long horizontal axis is laterally displacedby only ca. 0.1 Å from the slightly longer N+···N+ axis[d(N+···N+) = 7.81(1) Å] so that the two are almost coaxial.This places the N+ atom 0.46 Å above the inversion centermidpoint of the four-iodide anion base-plane. This distanceis comparable to the about 0.8 Å N+ distance above theportal plane of carbonyl oxygens in CB[7] (Figure 1). As aresult of the base plane’s tilt, electrostatic interaction dis-tances involving base plane anions fall into two groups. On
each end, two of the four base plane anions exhibitd(N+···I–) = 4.77(1) Å whereas two others have d(N+···I–) =5.07(1) Å. These electrostatic interaction distances are sim-ilar to the carbonyl-O···N+ distances of 4.4(2) Å illustratedin Figure 2. Finally, the horizontal electrostatic interactiondistances involving the apex iodide anions are the shortest[d(N+···I–) = 4.53(1) Å] because the anion points into theinterior of a tripod composed of three N+–C(methyl)bonds.
Crystallographic and refinement data for structures2·2HCl·2H2O, 3·2HI·2H2O, 4(A)·2HCl/4(B)·2HCl·2H2O,and 5 are presented in Table 2.[21]
of complexes of CB[7]·7 and CB[8]·6 were analyzed to as-certain possible structural hypotheses for high binding af-finity toward pumpkin-shaped hosts. As a result of thisstereochemical study, new diamantane-1,6- and diaman-tane-4,9-diammonium and diaminium salts were synthe-sized as potential guests for cucurbit[n]uril (CB[n]) hosts ofvarying ring sizes. The results of host·guest binding studieshave been reported separately.[10] Although Diam-4,9-di(NMe3I) 5 could be readily prepared from the bisprimarystarting material, corresponding Diam-1,6-di(NMe3I) 14could not be obtained even under strong reaction condi-tions. Stereochemical analysis of this finding suggests thatthe cause is very severe steric non-bonding cis-1,3-diaxialtype H···H interactions between the “axial”-type NMe3
group and neighboring “axial” proton neighbors that can-not be alleviated by skeletal distortion. These same interac-tions are found in Ada-2,6-diamine analogues 21 and 22,but in this case they are alleviated through tilting the C(me-thylene)–NMe3 bond away from its axial neighbors. How-ever, similar structural relief for Diam-1,6-di(NMe3I) 14 isnot possible because the C(methine)–NMe3 bond therein isligated to the diamondoid’s rigid skeleton.
Experimental Section1H and 13C NMR spectra were recorded with Bruker AV-300 orAV-600 NMR spectrometers. NMR spectra measured in C6D6 were
L. Isaacs, R. Glaser, K. Mlinaric-Majerski et al.FULL PAPERTable 2. Crystallographic data collection and structure refinement details of Diam-1,6-di(NH3Cl) dihydrate 2·2HCl·2H2O, Diam-1,6-di(NHMe2I) dihydrate 3·2HI·2H2O, Diam-4,9-di(NH3Cl) anhydrate/Diam-4,9-di(NH3Cl) dihydrate 4(A)·2HCl/4(B)·2HCl·2H2O; andDiam-4,9-di(NMe3I) 5.
2·2HCl·2H2O 3·2HI·2H2O 4(A)·2HCl/4(B)·2HCl·2H2O 5
Empirical formula C14H28Cl2N2O2 C18H36I2N2O2 C14H26Cl2N2O C20H36I2N2
Goodness of fit 1.125 1.177 0.984 1.079H atom treatment mixed mixed mixed mixedLargest diff. peak/hole /eÅ–3 0.699/–0.771 2.089/–1.592 0.356/–0.543 3.536/–2.382
referenced to tetramethylsilane as an internal standard. The spec-tral reference for spectra measured in D2O was one drop of [D8]-dioxane added after recording the original spectrum. Chemicalshift assignments of the final N-methylated products 3 and 5 weremade based on the results of spectra acquired by COSY, HSQC,HMBC, and NOESY 2D pulse sequences. IR spectra were re-corded with a FT-IR ABB Bomem MB 102 spectrophotometer.MALDI-TOF MS spectra were obtained in “reflectron” mode withan Applied Biosystems Voyager DE STR instrument (Foster City,CA). Melting points were obtained by using an Original KoflerMikroheitztisch apparatus (Reichert, Wien). All of the solventswere obtained from commercial sources and used without furtherpurification.
N,N,N�,N�-Tetramethyl-1,6-diaminodiamantane Dihydroiodide(3·2HI): A mixture of diamine 2[14] (109 mg, 0.5 mmol), excessCH3I (0.47 mL, 7.5 mmol) and NaHCO3 (420 mg, 5.0 mmol) inmethanol (15 mL) was heated to reflux for 48 h.[9b] The mixturewas cooled, the solvent evaporated and the crude product washedwith hot acetone (20 mL) to afford white solid compound 3·2HI(227 mg, 86%), m.p. � 300 °C. IR (KBr): ν = 3462 (br.), 2947 (m),2922 (s), 2768 (w), 1462 (m), 1404 (s), 1360 (s), 1074 (m), 1028 (w),
N,N,N,N�,N�,N�-Hexamethyldiamantane-4,9-diaminium Diiodide(5): A mixture of diamine 4[14] (87 mg, 0.4 mmol), excess CH3I(0.37 mL, 6.0 mmol) and NaHCO3 (336 mg, 4.0 mmol) in meth-anol (15 mL) was heated to reflux for 48 h.[9b] The mixture wascooled, the solvent evaporated and the crude product washed withhot acetone (20 mL) to afford white solid compound 5 (172 mg,77%), m.p. � 300 °C. IR (KBr): ν = 3446 (br.), 3024 (w), 2947 (m),2895 (s), 1637 (m), 1489 (m), 1363 (w), 1084 (w), 947 (w), 866(m) cm–1. 1H NMR (300 MHz, D2O, 25 °C): δ = 2.22 (br. s, 12 H,H(3,5,8,10,12,14)), 2.27 (br. s, 6 H, H(1,2,6,7,11,13)), 3.11 (s, 18 H, N-CH3) ppm. 13C NMR (150 MHz, D2O, 25 °C): δ = 33.9 (6 C,C(3,5,8,10,12,14)), 37.1 (6 C, C(1,2,6,7,11,13)), 48.83 (2 C, CH3), 48.86 (2
Diamantane Diammonium Salts
C, CH3), 48.88 (2 C, CH3), 71.2 (2 C, C(4,9)) ppm. HRMS(MALDI): calcd. for [C20H36N2I]+ 431.1918; found 431.1928.
1,6-Dichlorodiamantane (12): Diacetamide 11[13] (60 mg, 0.2 mmol)was added to concentrated HCl (10 mL) and the reaction mixtureheated to reflux for 72 h. Evaporation of the solvent gave a crudeproduct that was then sublimed (20 Torr, 60 °C) to yield 40 mg(78%) of pure white solid compound 12, m.p. 162–164 °C. IR(KBr): ν = 3435 (br.), 2928 (s), 2854 (m), 1460 (w), 1439 (w), 983(m), 822 (m), 692 (w) cm–1. 1H NMR (600 MHz, C6D6, 25 °C): δ= 1.19 (d, J = –13.3 Hz, 4 H), 1.62–1.66 (m, 2 H), 1.86 (br. s, 4 H),1.97–2.00 (m, 4 H), 2.30 (d, J = –13.3 Hz, 4 H) ppm. 13C NMR(150 MHz, C6D6, 25 °C): δ = 30.0, 32.7, 47.6, 49.8, 73.9 ppm.
N,N�-Bis(4-hydroxybutyl)-N,N�-dimethyl-1,6-diaminodiamantaneDihydroiodide (18). Procedure A: Diazide 13[14] (54 mg, 0.2 mmol)and excess Pd/C (10%, 100 mg) were added to unstabilized THF(20 mL) in a Paar shaker. After 24 h under a hydrogen atmosphere(60 psi) the catalyst was filtered off, and the solvent was removedunder reduced pressure to afford compound 17 as a crude product.Without further purification, diamine 17 was methylated to affordtitle salt 18 as a white solid (described in Procedure B). ProcedureB: A mixture of diamine 17, excess CH3I (0.19 mL, 3.0 mmol) andNaHCO3 (168 mg, 2.0 mmol) in methanol (15 mL) was heated toreflux for 48 h.[9b] The mixture was cooled, the solvent evaporatedand the crude product washed with hot acetone (20 mL) to afford18 as a white solid (85 mg, 66%), m.p. 293–295 °C. IR (KBr): ν =3414 (br.), 2995 (m), 2920 (m), 2868 (w), 1655 (m), 1458 (m), 1363(w), 1028 (m), 991 (w) cm–1. 1H NMR (300 MHz, D2O, 25 °C): δ= 1.66–2.13 (m, 20 H), 2.40 (br. s, 2 H), 2.63 (br. s, 2 H), 2.76 (br.s, 2 H), 2.92 (s, 6 H), 3.03–3.15 (m, 2 H), 3.40–3.52 (m, 2 H), 3.65–3.80 (m, 4 H) ppm. 13C NMR (75 MHz, D2O, 25 °C): δ = 22.5,26.7, 28.9, 29.1, 29.3, 29.4, 29.5, 32.5, 33.4, 38.1, 38.3, 38.8, 38.9,50.9, 51.0, 61.5, 68.1 ppm. HRMS (MALDI): calcd. for[C24H42N2O2 + H]+ 391.3319; found 391.3318.
N,N�-Bis(4-hydroxybutyl)-N,N,N�,N�-tetramethyldiamantane-4,9-di-aminium Diiodide (20): Procedure A: Diazide 16[14] (81 mg,0.3 mmol) and excess Pd/C (10%, 150 mg) were added to unstabi-lized THF (20 mL) in a Paar shaker. After 24 h under a hydrogenatmosphere (60 psi) the catalyst was filtered off, and the solventwas removed under reduced pressure to afford compound 19 as acrude product. Without further purification, diamine 19 was meth-ylated to afford title salt 20 as a white solid (described in ProcedureB). Procedure B: A mixture of diamine 19, excess CH3I (0.28 mL,4.5 mmol) and NaHCO3 (252 mg, 3.0 mmol) in methanol (15 mL)was heated to for 48 h.[9b] The mixture was cooled, the solventevaporated and the crude product washed with boiling acetone(20 mL) to afford 20 as a white solid (120 mg, 65%), m.p. 277–278 °C. IR (KBr): ν = 3419 (br.), 3369 (s), 2926 (m), 2889 (m), 1635(m), 1473 (s), 1369 (w), 1086 (m), 849 (w) cm–1. 1H NMR(600 MHz, D2O, 25 °C): δ = 1.68–1.74 (m, 4 H), 1.93–2.00 (m, 4H), 2.28 (br. s, 12 H), 2.32 (br. s, 6 H), 3.03 (s, 12 H), 3.38–3.43(m, 4 H), 3.75–3.79 (m, 4 H) ppm. 13C NMR (150 MHz, D2O,25 °C): δ = 20.0, 28.9, 33.9, 37.3, 44.1, 58.4, 61.4, 73.7 ppm. HRMS(MALDI): calcd. for [C26H48N2O2I]+ 547.2755; found 547.2748.
Calculations: The AM1 semiempirical Diam-1,6-di(NMe3) dicationof 14 geometry-optimized model was calculated with the Gaussian
09W program.[22]
X-ray Crystallography General Methods: Crystallizations were per-formed by slow evaporation of the solvent or a mixture of solventsused [2·2HCl·2H2O from deuterated methanol, 3 free base frommethanol, 3·2HI·2H2O from deuterated water, 4(A,B)·2HCl·H2Ofrom methanol, 5 crystallized from acetonitrile/water, 10 from hex-ane, 12 from [D6]benzene, 13 from methanol/dichloromethane,
16(A,B) from acetone, and 20·2H2O from acetonitrile/water]. Crys-tals were mounted on a glass fiber, and then fixed to the goniome-ter head of the X-ray diffractometer. Crystallographic measure-ments for 2·2HCl·2H2O, 3 free base, 3·2HI·2H2O, 4(A,B)·2HCl·H2O, 5, 10, 12, 13, 16(A,B), and 20·2H2O crystals were madeat ambient temperature 293(2) K with an Oxford Diffraction Xcali-bur Nova R with graphite monochromated Cu-Kα (λ = 1.54184 Å)radiation. The ω scans measurement method was utilized for allcrystals. Data were reduced by the CrysAlis PRO[23] software pack-age. Analysis of the data showed negligible decay during data col-lection, the intensities were corrected for Lorentz and polarizationfactors, and an empirical absorption coefficient was applied byusing the program CrysAlis PRO. A “multi-scan” absorption cor-rection was used. The structures were solved by application of di-rect methods and refined by full-matrix least-squares on F2 byusing the SHELXS97[24] software package and refined withSHELXL97.[25] Hydrogen atoms in these structures were intro-duced at calculated positions and treated with appropriate ridingmodels, except hydrogen atoms attached to the O-atom, which wererefined isotropically and restrained. All non-hydrogen atoms wererefined anisotropically.
Crystal structures reported herein were deposited and allocated thefollowing CCDC disposition numbers: CCDC-972220 (for2·2HCl·2H2O), -972223 (for 3), -972224 (for 3·2HI·2H2O), -972226[for 4(A,B)·2HCl·H2O], -972227 (for 5), -974945 (for 10), -972221(for 12), -972222 (for 13), -972225 [for 16(A,B)], and -972228 (for20·2H2O). These data can be obtained free of charge from TheCambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
Supporting Information (see footnote on the first page of this arti-cle): 22 pages; 10 CIF files; Table S1 containing crystallographicdata collection and structure refinement details of 3, 10, 12, 13,16(A,B), and 20·2H2O; Figures S1–S12 illustrate ORTEP3[26] plotsfor crystal structures noted in this report; Figures S13–S25 illus-trate packing diagrams and intermolecular interactions for thesecrystal structures; Figures S26–S30 show 1H and 13C NMR spectraof new compounds; Table S2 gives the Cartesian coordinates ofAM1 geometry optimized model of Diam-1,6-di(NMe3) diaminiumcation.
Acknowledgments
The authors thank the Croatian Ministry of Science, Educationand Sports (grant numbers 098-0982933-2911, to K. M.-M. and098-1191344-2943), the US National Science Foundation (NSF)(grant CHE-1110911, to L. I.) and the Ben-Gurion University Re-search Fund for Scientific Relations (grant to R. G.) for financialsupport of this study.
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Received: December 11, 2013Published Online: February 19, 2014
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