Self-Assembly

DOI: 10.1002/ange.200504447

Choices of Iron and Copper: CooperativeSelection during Self-Assembly**

David Schultz and Jonathan R. Nitschke*

The technique of subcomponent self-assembly is emerging atthe intersection of dynamic covalent[1] and metallo-supra-molecular[2] chemistry. In subcomponent self-assembly twohierarchical self-assembly reactions[3] occur as parts of thesame overall process: Intraligand (generally C=N) bondsform at the same time as metal–ligand bonds, thus bringingmolecular and supramolecular structures into being at thesame time.[4]

The use of subcomponents rather than presynthesizedligands in programmed self-assembly presents a particularchallenge to the “programmer/chemist”: for a given level ofstructural complexity, one must employ subcomponents that

contain more self-assembly information than presynthesizedligands, since “assembly instructions” for both the ligands andsupramolecular structure must be included. This problembecomes acute when sets of “non-orthogonal” subcompo-nents are employed, for example, two amines that couldcondense with two different aldehydes to give a dynamiclibrary[5] of four imines, with the size of this library growingfor larger collections or multivalent starting materials.

We have previously described a system consisting of a setof ligand components that combine together in all possibleways in the absence of copper(i) ions, but which undergo athermodynamic self-sorting process in the presence of themetal ion, thereby eliminating all mixed ligands from thesystem [Eq. (1)].[6]

Herein, we describe a more-complex self-organizingsystem,[7] in which a larger dynamic library collapses duringthe simultaneous formation of iron(ii) and copper(i) com-plexes [Eq. (2)]. Each one of the six initially present chemical

species was directed to its place in one of the two productcomplexes by the dynamic interplay of steric and electronicfactors on both covalent and coordinative levels. We are notaware of another example of a clean sorting of chemicallynon-orthogonal components into two well-separated “bas-kets”. The driving forces behind this selectivity were exam-ined individually, and it was found that selection preferencesexpressed by the two metals acted in concert to deconvolutethe initial library of ligands. Although these preferences donot lead to quantitative selection in the absence of one of themetals, they reinforce each other in the full mixture to selectthe observed products from all the possible products.Although this model system consists of only two mononuclearcomplexes, the methodology demonstrated here may thusprove useful in the development of hierarchically self-assembled systems of greater complexity and function.

Mixing pyridine-2-carbaldehyde (A, 3 equiv), 6-methyl-pyridine-2-carbaldehyde (B, 3 equiv), tris(2-aminoethyl)-amine (C, 1 equiv), and ethanolamine (D, 3 equiv) in aqueoussolution affords a dynamic library of imines (Scheme 1) inequilibrium with the starting materials, as observed by ESI-MS and NMR spectroscopy. The addition of copper(i)tetrafluoroborate (1.5 equiv) and iron(ii) sulfate (1 equiv)resulted in the dynamic library of imines collapsing within12 h at 323 K to leave 1 and 2 as the sole products. This sortingprocess is thermodynamic in nature. NMR spectra of thereaction mixture during the hours following the addition ofthe metals revealed the presence of kinetic products, whichdisappeared during equilibration.

Certain factors play a clear role in winnowing down thenumber of observed product structures: The template effect[8]

[*] D. Schultz, Dr. J. R. NitschkeDepartment of Organic ChemistryUniversity of Geneva30 Quai Ernest Ansermet, 1211 Gen0ve 4 (Switzerland)Fax: (+41)22-379-3215E-mail: jonathan.nitschke@chiorg.unige.ch

[**] This work was supported by the Swiss National Science Foundation.We thank Profs. A. Hauser, J. Lacour, and C. Piguet for criticalcomments on the manuscript, and P. Perrottet for mass spectro-metric analyses.

Supporting information for this article (the syntheses of 1, 2, and 3,as well experimental details for the reactions shown) is available onthe WWW under http://www.angewandte.org or from the author.

AngewandteChemie

2513Angew. Chem. 2006, 118, 2513 –2516 � 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

should eliminate all partially formed ligands and ligandsubcomponents from the mixture, the chelate effect[9] shouldfavor structures containing ligands that bear the highestnumber of bound donor atoms possible, and the iron(ii) andcopper(i) ions should be bound to six and four donor atoms,respectively. Within these limits, a variety of different productstructures might nonetheless be envisaged. We discuss hereinour investigations of three distinct preferences exhibited bycopper(i) and iron(ii) ions. These preferences act in concert toselect 1 and 2 alone as the products of the reaction shown inScheme 1.

Firstly, copper(i) ions formed complexes that incorporatedmethylated aldehyde B in preference to A. ESI-MS analysisof the reaction mixture following the addition of copper(i)tetrafluoroborate (1 equiv) to an aqueous mixture of alde-hydes A and B as well as amine D (2 equiv each) showed thepresence of all the three possible products shown in Scheme 2.We were not able to quantify them by NMR spectroscopicanalysis because of overlapping signals, however the concen-trations of the free aldehydes A and B could be quantified.Aldehydes A and B were incorporated into the productmixture in a ratio of 30:70, which indicates a slight (ca. 6.3 kJ

mol�1) thermodynamic preference (assuming an equilibriumof the type [Cu(B)2]+ 2AÐ[Cu(A)2]+ 2B) for the incorpo-ration of B. This preference may be attributed to the presenceof an electron-donating methyl group on B, which allows theligands to better stabilize the cationic copper(i) center.

Secondly, iron(ii) ions were observed to form pseudo-octahedral complexes that incorporate triamine C in prefer-ence to monoamine D. Complex 1 and amine D were the onlyproducts observed by NMR spectroscopy and ESI-MS whencomplex 3, prepared as a mixture of fac and mer isomers, wasmixed with an equimolar amount of triamine C in aqueoussolution (Scheme 3). On the basis of the sensitivity of the

NMR spectrometer at the concentration studied (63 mm), weconcluded that C and 3 were present at concentrations of lessthan 1%. We estimate therefore that the energetic drivingforce for this reaction is greater than 22 kJ mol�1 (assuming anequilibrium of the type [Fe(D)3]+CÐ[Fe(C)]+ 3D). Thechelate effect[9] may be understood to drive this substitution:The incorporation of one equivalent of amine C results in theliberation of three equivalents of amine D, which provides theentropic driving force for this reaction.

A third driving force for the observed selectivity, com-plementing and amplifying the choice of the copper center forB over A, is the preference of iron(ii) ions to incorporatealdehyde A instead of B into complexes of type 1. As shown

Scheme 1. The formation of a dynamic combinatorial library of ligands, and the collapse of this library following addition of CuI and FeII ions.

Scheme 2. The choice of copper: aldehyde B was incorporated inpreference to A during the formation of 2 in aqueous solution.

Scheme 3. The choice of iron: the entropically driven displacement ofmonoamine D by triamine C.

Zuschriften

2514 www.angewandte.de � 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Angew. Chem. 2006, 118, 2513 –2516

in Scheme 4, the addition of iron(ii) ions (1 equiv) to amixture of triamine C (1 equiv) and aldehydes A and B(3 equiv of each) gave a product mixture in which free A andB were present in a 3:97 ratio following equilibration at 323 K

over 4 days. This ratio suggests that the incorporation ofaldehyde A over B was favored by about 14.1 kJmol�1

(assuming an equilibrium of the type [Fe(A)3]+BÐ[Fe(A)2(B)]+A). The broad NMR and the ESI-MSspectra of the product mixture were assigned to a mixtureof 1, incorporating uniquely aldehyde A, and 4, incorporatingtwo equivalents of A and one equivalent of B. The reactionshown in Scheme 4 deviates substantially from a statisticalmixture of products; indeed, only two of the expected fourproducts are observed to form. No evidence was found ofcomplexes incorporating two or three equivalents of B.

Mixtures of products were obtained when either cobalt(ii)or zinc(ii) sulfate was used in place of the iron(ii) salt in thereactions shown in Schemes 1 or 4. The crystal structuresshow that the iron(ii) ion is bound more tightly in 1 (meanrFe-N = 1.95 A)[10] than is the cobalt(ii) ion (mean rCo-N =

2.15 A)[10] or zinc(ii) ion (mean rZn-N = 2.18 A)[10] in complexeswith the same ligand. This observation correlates with thefinding that the FeII ion is the only divalent first-row transitionmetal to have a low-spin ground state with this ligand.[10] Theresearch groups of Drago,[11] Hendrickson,[12] and Hauser[13]

have investigated the magnetic behavior of 1 and 4 as well asthe other two congeners incorporating two and three equiv-alents of B, respectively. They determined that although 1remains in the low-spin 1A1 state over the temperature range30–450 K,[12,13] the complexes containing B subcomponentsundergo spin crossover to the high-spin 5T2 state as thetemperature increases. The more B subcomponents a com-plex contains, the lower the temperature at which it under-goes spin crossover. A steric clash between the methyl groupsand the facing pyridyl rings, as shown in Scheme 4, appears todestabilize the low-spin state relative to the high-spin state byelongating the Fe�N bonds.

The strong thermodynamic preference of iron(ii) ions toincorporate aldehyde A in preference to B during theformation of 1 might thus be attributed to the high energy

penalty paid for a steric clash in iron(ii) complexes of thistype. Since the presence of high-spin iron(ii) centers may beinferred in complexes incorporating one or more B subcom-ponent, one might also invoke the possibility of a “spin-selection” phenomenon, whereby the formation of short,strong bonds between low-spin iron(ii) centers and sp2

nitrogen atoms serves as a thermodynamic driving force forthe preferential incorporation of sterically unhindered A.

In summary, we have examined individually the factorsleading to the observed high degree of selectivity in thissimple model system. The preference for iron(ii) complexes toincorporate triamine C in preference to monoamine D may beconsidered as “strong”—in excess of 22 kJ mol�1. The prefer-ences of copper for subcomponent B (ca. 6.3 kJmol�1) andiron for subcomponent A (ca. 14.1 kJ mol�1) were bothweaker, but these preferences complemented each otherand reduced the concentrations of mixed products toundetectable levels (estimated to be < 1 %, based on ESI-MS and NMR spectroscopic measurements).

This deconvolution methodology may prove useful indetermining the thermodynamic preferences of other systemsincorporating mixed sets of subcomponents, particularly incases where selective self-assembly is desired. The concurrentformation of complexes 1 and 2 might also be harnessed todrive the self-assembly of larger, more complex structures:the covalent attachment of other self-assembling groups to A,B, C, or D could allow the self-assembly “program” thatgenerates 1 and 2 to be used as a “subroutine” within theassembly of a superstructure incorporating 1 and 2 assubunits.

Received: December 14, 2005Published online: March 9, 2006

.Keywords: coordination modes · copper ·dynamic combinatorial chemistry · iron · self-assembly

[1] a) S. J. Rowan, S. J. Cantrill, G. R. L. Cousins, J. K. M. Sanders,J. F. Stoddart, Angew. Chem. 2002, 114, 938 – 993; Angew. Chem.Int. Ed. 2002, 41, 898 – 952; b) S. Otto, J. Mater. Chem. 2005, 15,3357 – 3361; c) R. Cacciapaglia, S. Di Stefano, L. Mandolini, J.Am. Chem. Soc. 2005, 127, 13666 – 13 671; d) F. Arico, T. Chang,S. J. Cantrill, S. I. Khan, J. F. Stoddart, Chem. Eur. J. 2005, 11,4655 – 4666; e) T. Ono, T. Nobori, J.-M. Lehn, Chem. Commun.2005, 1522 – 1524.

[2] a) C. J. Baylies, T. Riis-Johannessen, L. P. Harding, J. C. Jeffery,R. Moon, C. R. Rice, M. Whitehead, Angew. Chem. 2005, 117,7069 – 7072; Angew. Chem. Int. Ed. 2005, 44, 6909 – 6912; b) B. J.Holliday, C. A. Mirkin, Angew. Chem. 2001, 113, 2076 – 2097;Angew. Chem. Int. Ed. 2001, 40, 2022 – 2043; c) C. Piguet, G.Bernardinelli, G. Hopfgartner, Chem. Rev. 1997, 97, 2005 – 2062;d) W.-Y. Sun, M. Yoshizawa, T. Kusukawa, M. Fujita, Curr. Opin.Chem. Biol. 2002, 6, 757 – 764; e) D. L. Caulder, K. N. Raymond,Acc. Chem. Res. 1999, 32, 975 – 982; f) F. A. Cotton, C. Lin, C. A.Murillo, Acc. Chem. Res. 2001, 34, 759 – 771; g) M. Albrecht, J.Inclusion Phenom. Macrocyclic Chem. 2000, 36, 127 – 151;h) S. R. Seidel, P. J. Stang, Acc. Chem. Res. 2002, 35, 972 – 983;i) B. Linton, A. D. Hamilton, Chem. Rev. 1997, 97, 1669 – 1680;j) M. Albrecht, Chem. Rev. 2001, 101, 3457 – 3497; k) J. C. G.Bunzli, C. Piguet, Chem. Rev. 2002, 102, 1897 – 1928.

Scheme 4. The choice of iron: the preferential incorporation of theless-hindered aldehyde A into 1 and 4. The steric clash between methylgroup and ring is shown for 4.

AngewandteChemie

2515Angew. Chem. 2006, 118, 2513 –2516 � 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim www.angewandte.de

[3] a) M. Albrecht, S. Mirtschin, M. de Groot, I. Janser, J. Runsink,G. Raabe, M. Kogej, C. A. Schalley, R. Froehlich, J. Am. Chem.Soc. 2005, 127, 10371 – 10 387; b) V. Berl, M. J. Krische, I. Huc, J.-M. Lehn, M. Schmutz, Chem. Eur. J. 2000, 6, 1938 – 1946.

[4] a) L. Hogg, D. A. Leigh, P. J. Lusby, A. Morelli, S. Parsons,J. K. Y. Wong, Angew. Chem. 2004, 116, 1238 – 1241; Angew.Chem. Int. Ed. 2004, 43, 1218 – 1221; b) D. A. Leigh, P. J. Lusby,S. J. Teat, A. J. Wilson, J. K. Y. Wong, Angew. Chem. 2001, 113,1586 – 1591; Angew. Chem. Int. Ed. 2001, 40, 1538 – 1543; c) H.Houjou, A. Iwasaki, T. Ogihara, M. Kanesato, S. Akabori, K.Hiratani, New J. Chem. 2003, 27, 886 – 889; d) L. J. Childs, N. W.Alcock, M. J. Hannon, Angew. Chem. 2002, 114, 4418 – 4421;Angew. Chem. Int. Ed. 2002, 41, 4244 – 4247; e) J. Hamblin, L. J.Childs, N. W. Alcock, M. J. Hannon, J. Chem. Soc. Dalton Trans.2002, 164 – 169; f) J. R. Nitschke, D. Schultz, G. Bernardinelli, D.GLrard, J. Am. Chem. Soc. 2004, 126, 16538 – 16543; g) J. R.Nitschke, J.-M. Lehn, Proc. Natl. Acad. Sci. USA 2003, 100,11970 – 11 974; h) J. R. Nitschke, M. Hutin, G. Bernardinelli,Angew. Chem. 2004, 116, 6892 – 6895; Angew. Chem. Int. Ed.2004, 43, 6724 – 6727; i) S. Brooker, S. J. Hay, P. G. Plieger,Angew. Chem. 2000, 112, 2044 – 2046; Angew. Chem. Int. Ed.2000, 39, 1968 – 1970; j) K. S. Chichak, S. J. Cantrill, A. R. Pease,S.-H. Chiu, G. W. V. Cave, J. L. Atwood, J. F. Stoddart, Science2004, 304, 1308 – 1312.

[5] a) S. G. Telfer, X. J. Yang, A. F. Williams, Dalton Trans. 2004,699 – 705; b) K. Severin, Chem. Eur. J. 2004, 10, 2565 – 2580; c) S.Otto, R. L. E. Furlan, J. K. M. Sanders, Science 2002, 297, 590 –593; d) R. Nguyen, I. Huc, Chem. Commun. 2003, 942 – 943;e) J.-M. Lehn, A. V. Eliseev, Science 2001, 291, 2331 – 2332; f) F.Hof, C. Nuckolls, J. Rebek, Jr., J. Am. Chem. Soc. 2000, 122,4251 – 4252; g) M. Albrecht, I. Janser, J. Runsink, G. Raabe, P.Weis, R. Froehlich, Angew. Chem. 2004, 116, 6832 – 6836; Angew.Chem. Int. Ed. 2004, 43, 6662 – 6666.

[6] D. Schultz, J. R. Nitschke, Proc. Natl. Acad. Sci. USA 2005, 102,11191 – 11 195.

[7] a) A. X. Wu, L. Isaacs, J. Am. Chem. Soc. 2003, 125, 4831 – 4835;b) M. Schmittel, V. Kalsani, R. S. K. Kishore, H. Colfen, J. W.Bats, J. Am. Chem. Soc. 2005, 127, 11 544 – 11545.

[8] T. J. Hubin, D. H. Busch, Coord. Chem. Rev. 2000, 200, 5 – 52.[9] G. Schwarzenbach, Helv. Chim. Acta 1952, 35, 2344 – 2363.

[10] R. M. Kirchner, C. Mealli, M. Bailey, N. Howe, L. P. Torre, L. J.Wilson, L. C. Andrews, N. J. Rose, E. C. Lingafelter, Coord.Chem. Rev. 1987, 77, 89 – 163.

[11] M. A. Hoselton, L. J. Wilson, R. S. Drago, J. Am. Chem. Soc.1975, 97, 1722 – 1729.

[12] A. J. Conti, C. L. Xie, D. N. Hendrickson, J. Am. Chem. Soc.1989, 111, 1171 – 1180.

[13] S. Schenker, A. Hauser, W. Wang, I. Y. Chan, J. Chem. Phys.1998, 109, 9870 – 9878.

Zuschriften

2516 www.angewandte.de � 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Angew. Chem. 2006, 118, 2513 –2516