Supramolecular chemistry#Template-directed synthesis

File:18-crown-6 was synthesized using potassium ion as the template cation.png can be synthesized from using potassium ion as the template cation]]

The existence of intermolecular forces was first postulated by Johannes Diderik van der Waals in 1873. However, Nobel laureate Hermann Emil Fischer developed supramolecular chemistry's philosophical roots. In 1894,{{Cite journal | doi = 10.1002/cber.18940270364| title = Einfluss der Configuration auf die Wirkung der Enzyme| journal = Berichte der Deutschen Chemischen Gesellschaft| volume = 27| issue = 3| pages = 2985–2993| year = 1894| last1 = Fischer | first1 = E.| url = https://zenodo.org/record/1425780}} Fischer suggested that enzyme–substrate interactions take the form of a "lock and key", the fundamental principles of molecular recognition and host–guest chemistry. In the early twentieth century non-covalent bonds were understood in gradually more detail, with the hydrogen bond being described by Latimer and Rodebush in 1920.

With the deeper understanding of the non-covalent interactions, for example, the clear elucidation of DNA structure, chemists started to emphasize the importance of non-covalent interactions.{{Citation |title=Supramolecular chemistry |date=2023-01-25 |url=https://en.wikipedia.org/w/index.php?title=Supramolecular_chemistry&oldid=1135615476 |work=Wikipedia |access-date=2023-02-15 |language=en}} In 1967, Charles J. Pedersen discovered crown ethers, which are ring-like structures capable of chelating certain metal ions. Then, in 1969, Jean-Marie Lehn discovered a class of molecules similar to crown ethers, called cryptands. After that, Donald J. Cram synthesized many variations to crown ethers, on top of separate molecules capable of selective interaction with certain chemicals. The three scientists were awarded the Nobel Prize in Chemistry in 1987 for "development and use of molecules with structure-specific interactions of high selectivity”.{{Cite web |title=The Nobel Prize in Chemistry 1987 |url=https://www.nobelprize.org/prizes/chemistry/1987/summary/ |access-date=2023-02-15 |website=NobelPrize.org |language=en-US}} In 2016, Bernard L. Feringa, Sir J. Fraser Stoddart, and Jean-Pierre Sauvage were awarded the Nobel Prize in Chemistry, "for the design and synthesis of molecular machines".{{Cite web |title=The Nobel Prize in Chemistry 2016 |url=https://www.nobelprize.org/prizes/chemistry/2016/summary/ |access-date=2023-02-15 |website=NobelPrize.org |language=en-US}}

File:Carboxylic acid dimers.png dimers]]

The term supermolecule (or supramolecule) was introduced by Karl Lothar Wolf et al. (Übermoleküle) in 1937 to describe hydrogen-bonded acetic acid dimers.{{cite journal | last1=Wolf | first1=Κ. L. | last2=Frahm | first2=H. | last3=Harms | first3=H. | title=Über den Ordnungszustand der Moleküle in Flüssigkeiten | journal=Zeitschrift für Physikalische Chemie | publisher=Walter de Gruyter GmbH | volume=36B | issue=1 | date=1937-01-01 | issn=2196-7156 | doi=10.1515/zpch-1937-3618 | page=237-287|trans-title=The State of Arrangement of Molecules in Liquids|language=de}}[https://media.wiley.com/product_data/excerpt/55/35273150/3527315055.pdf Historical Remarks on Supramolecular Chemistry] – PDF (16 pg. paper) The term supermolecule is also used in biochemistry to describe complexes of biomolecules, such as peptides and oligonucleotides composed of multiple strands.{{cite journal | last=Lehninger | first=Albert L. | title=Supramolecular organization of enzyme and membrane systems | journal=Die Naturwissenschaften | publisher=Springer Science and Business Media LLC | volume=53 | issue=3 | year=1966 | issn=0028-1042 | doi=10.1007/bf00594748 | pages=57–63| pmid=5983868 | bibcode=1966NW.....53...57L }}

Eventually, chemists applied these concepts to synthetic systems. One breakthrough came in the 1960s with the synthesis of the crown ethers by Charles J. Pedersen. Following this work, other researchers such as Donald J. Cram, Jean-Marie Lehn and Fritz Vögtle reported a variety of three-dimensional receptors, and throughout the 1980s research in the area gathered a rapid pace with concepts such as mechanically interlocked molecular architectures emerging.

The influence of supramolecular chemistry was established by the 1987 Nobel Prize for Chemistry which was awarded to Donald J. Cram, Jean-Marie Lehn, and Charles J. Pedersen in recognition of their work in this area.Schmeck, Harold M. Jr. (October 15, 1987) [https://query.nytimes.com/gst/fullpage.html?res=9B0DE0DB143DF936A25753C1A961948260&sec=&spon=&partner=permalink&exprod=permalink "Chemistry and Physics Nobels Hail Discoveries on Life and Superconductors; Three Share Prize for Synthesis of Vital Enzymes"]. New York Times The development of selective "host–guest" complexes in particular, in which a host molecule recognizes and selectively binds a certain guest, was cited as an important contribution.

Image:Protein translation.gif is a biological machine that uses protein dynamics on nanoscales]]

Molecular self-assembly is the construction of systems without guidance or management from an outside source (other than to provide a suitable environment). The molecules are directed to assemble through non-covalent interactions. Self-assembly may be subdivided into intermolecular self-assembly (to form a supramolecular assembly), and intramolecular self-assembly (or folding as demonstrated by foldamers and polypeptides). Molecular self-assembly also allows the construction of larger structures such as micelles, membranes, vesicles, liquid crystals, and is important to crystal engineering.{{Cite journal | doi = 10.1088/1468-6996/9/1/014109| title = Challenges and breakthroughs in recent research on self-assembly| journal = Science and Technology of Advanced Materials| volume = 9| issue = 1| pages = 014109| year = 2008| last1 = Ariga | first1 = K. | last2 = Hill | first2 = J. P. | last3 = Lee | first3 = M. V. | last4 = Vinu | first4 = A. | last5 = Charvet | first5 = R. | last6 = Acharya | first6 = S. | bibcode = 2008STAdM...9a4109A | pmid=27877935 | pmc=5099804}} {{open access}}

Molecular recognition is the specific binding of a guest molecule to a complementary host molecule to form a host–guest complex. Often, the definition of which species is the "host" and which is the "guest" is arbitrary. The molecules are able to identify each other using non-covalent interactions. Key applications of this field are the construction of molecular sensors and catalysis.{{Cite journal | doi = 10.1088/1468-6996/9/1/014103| pmid = 27877929| pmc = 5099798| title = Metallo-supramolecular modules as a paradigm for materials science| journal = Science and Technology of Advanced Materials| volume = 9| issue = 1| pages = 014103| year = 2008| last1 = Kurth | first1 = D. G.| bibcode = 2008STAdM...9a4103G}} {{Open access}}{{Cite journal | doi = 10.1039/C2SC20583A | title = Supramolecular hosts that recognize methyllysines and disrupt the interaction between a modified histone tail and its epigenetic reader protein |journal=Chemical Science| volume = 3| issue = 9 | pages = 2695| year = 2012| last1 = Daze | first1 = K.}}{{Cite journal | doi = 10.1088/1468-6996/9/1/014108| title = Chemistry and application of flexible porous coordination polymers| journal = Science and Technology of Advanced Materials| volume = 9| issue = 1| pages = 014108| year = 2008| last1 = Bureekaew | first1 = S. | last2 = Shimomura | first2 = S. | last3 = Kitagawa | first3 = S. | bibcode = 2008STAdM...9a4108B | pmid=27877934 | pmc=5099803}} {{Open access}}{{Cite journal | doi = 10.1002/anie.199013041| title = Perspectives in Supramolecular Chemistry—From Molecular Recognition towards Molecular Information Processing and Self-Organization| journal = Angewandte Chemie International Edition in English| volume = 29| issue = 11| pages = 1304–1319| year = 1990| last1 = Lehn | first1 = J. M.}}

Molecular recognition and self-assembly may be used with reactive species in order to pre-organize a system for a chemical reaction (to form one or more covalent bonds). It may be considered a special case of supramolecular catalysis. Non-covalent bonds between the reactants and a "template" hold the reactive sites of the reactants close together, facilitating the desired chemistry. This technique is particularly useful for situations where the desired reaction conformation is thermodynamically or kinetically unlikely, such as in the preparation of large macrocycles. This pre-organization also serves purposes such as minimizing side reactions, lowering the activation energy of the reaction, and producing desired stereochemistry. After the reaction has taken place, the template may remain in place, be forcibly removed, or may be "automatically" decomplexed on account of the different recognition properties of the reaction product. The template may be as simple as a single metal ion or may be extremely complex.{{citation needed|date=April 2019}}

Mechanically interlocked molecular architectures consist of molecules that are linked only as a consequence of their topology. Some non-covalent interactions may exist between the different components (often those that were used in the construction of the system), but covalent bonds do not. Supramolecular chemistry, and template-directed synthesis in particular, is key to the efficient synthesis of the compounds. Examples of mechanically interlocked molecular architectures include catenanes, rotaxanes, molecular knots, molecular Borromean rings{{Cite journal | doi = 10.1088/1468-6996/9/1/014104| pmid = 27877930| pmc = 5099799| title = Electrochromic materials using mechanically interlocked molecules| journal = Science and Technology of Advanced Materials| volume = 9| issue = 1| pages = 014104| year = 2008| last1 = Ikeda | first1 = T. | last2 = Stoddart | first2 = J. F. | bibcode = 2008STAdM...9a4104I}} {{Open access}}, 2D [c2]daisy chain polymer{{Cite journal | doi = 10.1038/s44160-025-00791-x| title = Synthesis of a crystalline two-dimensional [c2]daisy chain honeycomb network| journal = Nature Synthesis| volume = 4| pages = | year = 2025| last1 = Tang | first1 = Z.-B. | last2 = Bian | first2 = L. | last3 = Miao | first3 = X. | last4 = Gao | first4 = H. | last5 = Liu | first5 = L. | last6 = Jiang | first6 = Q. | last7 = Sheng | first7 = D. | last8 = Xu | first8 = L. | last9 = Sue | first9 = A. C.-H. | last10 = Zheng | first10 = X. | last11 = Liu | first11 = Z. C. }} and ravels.{{Cite journal | doi = 10.1038/ncomms1208| pmid = 21343923| title = Metallosupramolecular self-assembly of a universal 3-ravel| journal = Nature Communications| volume = 2| pages = 205| year = 2011| last1 = Li | first1 = F. | last2 = Clegg | first2 = J. K. | last3 = Lindoy | first3 = L. F. | last4 = MacQuart | first4 = R. B. | last5 = Meehan | first5 = G. V. | bibcode = 2011NatCo...2..205L| doi-access = free }}

In dynamic covalent chemistry covalent bonds are broken and formed in a reversible reaction under thermodynamic control. While covalent bonds are key to the process, the system is directed by non-covalent forces to form the lowest energy structures.{{Cite journal | doi = 10.1002/1521-3773(20020315)41:6<898::AID-ANIE898>3.0.CO;2-E| title = Dynamic Covalent Chemistry| journal = Angewandte Chemie International Edition| volume = 41| issue = 6| pages = 898–952| year = 2002|author1-link=Stuart Rowan|author4-link=Jeremy K. M. Sanders|author5-link=Fraser Stoddart| last1 = Rowan | first1 = S. J. | last2 = Cantrill | first2 = S. J. | last3 = Cousins | first3 = G. R. L. | last4 = Sanders | first4 = J. K. M. | last5 = Stoddart | first5 = J. F. | pmid = 12491278}}

Many synthetic supramolecular systems are designed to copy functions of biological systems. These biomimetic architectures can be used to learn about both the biological model and the synthetic implementation. Examples include photoelectrochemical systems, catalytic systems, protein design and self-replication.{{Cite journal | doi = 10.1038/nbt874|pmid=14520402| title = Fabrication of novel biomaterials through molecular self-assembly| journal = Nature Biotechnology| volume = 21| issue = 10| pages = 1171–8| year = 2003| last1 = Zhang | first1 = S.|s2cid=54485012}}

Molecular imprinting describes a process by which a host is constructed from small molecules using a suitable molecular species as a template. After construction, the template is removed leaving only the host. The template for host construction may be subtly different from the guest that the finished host binds to. In its simplest form, imprinting uses only steric interactions, but more complex systems also incorporate hydrogen bonding and other interactions to improve binding strength and specificity.{{Cite journal | doi = 10.1016/S0165-9936(98)00123-X| title = Molecular imprinting in chemical sensing| journal = TrAC Trends in Analytical Chemistry| volume = 18| issue = 3| pages = 192–199| year = 1999| last1 = Dickert | first1 = F.}}

Molecular machines are molecules or molecular assemblies that can perform functions such as linear or rotational movement, switching, and entrapment. These devices exist at the boundary between supramolecular chemistry and nanotechnology, and prototypes have been demonstrated using supramolecular concepts.{{Cite journal | doi = 10.1021/ar970340y| title = Molecular Machines| journal = Accounts of Chemical Research| volume = 31| issue = 7| pages = 405–414| year = 1998| last1 = Balzani | first1 = V. | last2 = Gómez-López | first2 = M. | last3 = Stoddart | first3 = J. F.}} Jean-Pierre Sauvage, Sir J. Fraser Stoddart and Bernard L. Feringa shared the 2016 Nobel Prize in Chemistry for the 'design and synthesis of molecular machines'.{{cite web |url=https://www.nobelprize.org/nobel_prizes/chemistry/laureates/2016/ |title=The Nobel Prize in Chemistry 2016 |author= |website=Nobelprize.org |publisher=Nobel Media AB 2014 |access-date=14 January 2017}}

Supramolecular systems are rarely designed from first principles. Rather, chemists have a range of well-studied structural and functional building blocks that they are able to use to build up larger functional architectures. Many of these exist as whole families of similar units, from which the analog with the exact desired properties can be chosen.

• The pi-pi charge-transfer interactions of bipyridinium with dioxyarenes or diaminoarenes have been used extensively for the construction of mechanically interlocked systems and in crystal engineering.
• The use of crown ether binding with metal or ammonium cations is ubiquitous in supramolecular chemistry.
• The formation of carboxylic acid dimers and other simple hydrogen bonding interactions.
• The complexation of bipyridines or terpyridines with ruthenium, silver or other metal ions is of great utility in the construction of complex architectures of many individual molecules.
• The complexation of porphyrins or phthalocyanines around metal ions gives access to catalytic, photochemical and electrochemical properties in addition to the complexation itself. These units are used a great deal by nature.

Macrocycles are very useful in supramolecular chemistry, as they provide whole cavities that can completely surround guest molecules and may be chemically modified to fine-tune their properties.

• Cyclodextrins, calixarenes, cucurbiturils and crown ethers are readily synthesized in large quantities, and are therefore convenient for use in supramolecular systems.
• More complex cyclophanes, and cryptands can be synthesised to provide more tailored recognition properties.
• Supramolecular metallocycles are macrocyclic aggregates with metal ions in the ring, often formed from angular and linear modules.Functional Metallosupramolecular Materials, Editors: John George Hardy, Felix H Schacher, Royal Society of Chemistry, Cambridge 2015, https://pubs.rsc.org/en/content/ebook/978-1-78262-267-3 Common metallocycle shapes in these types of applications include triangles, squares, and pentagons, each bearing functional groups that connect the pieces via "self-assembly."{{Cite journal | doi = 10.1021/ar700216n| pmid = 18271561| title = Chiral Metallocycles: Rational Synthesis and Novel Applications| journal = Accounts of Chemical Research| volume = 41| issue = 4| pages = 521–37| year = 2008| last1 = Lee | first1 = S. J. | last2 = Lin | first2 = W.}}
• Metallacrowns are metallomacrocycles generated via a similar self-assembly approach from fused chelate-rings.

Many supramolecular systems require their components to have suitable spacing and conformations relative to each other, and therefore easily employed structural units are required.{{Cite book|title=Comprehensive Supramolecular Chemistry II |last1=Atwood |first1=J. L. |last2=Gokel |first2=George W. |last3=Barbour |first3=Leonard J. |isbn=9780128031995 |location=Amsterdam, Netherlands |oclc=992802408 |page=46 |date=2017-06-22}}

• Commonly used spacers and connecting groups include polyether chains, biphenyls and triphenyls, and simple alkyl chains. The chemistry for creating and connecting these units is very well understood.
• nanoparticles, nanorods, fullerenes and dendrimers offer nanometer-sized structure and encapsulation units.
• Surfaces can be used as scaffolds for the construction of complex systems and also for interfacing electrochemical systems with electrodes. Regular surfaces can be used for the construction of self-assembled monolayers and multilayers.
• The understanding of intermolecular interactions in solids has undergone a major renaissance via inputs from different experimental and computational methods in the last decade. This includes high-pressure studies in solids and "in situ" crystallization of compounds which are liquids at room temperature along with the use of electron density analysis, crystal structure prediction and DFT calculations in solid state to enable a quantitative understanding of the nature, energetics and topological properties associated with such interactions in crystals.{{Cite book|last=Chopra|first=Deepak, Royal Society of Chemistry|url=https://www.worldcat.org/oclc/1103809341|title=Understanding intermolecular interactions in the solid state: approaches and techniques|date=2019|publisher=Royal Society of Chemistry|isbn=978-1-78801-079-5|location=London; Cambridge|language=English|oclc=1103809341}}

• Porphyrins, and phthalocyanines have highly tunable photochemical and electrochemical activity as well as the potential to form complexes.
• Photochromic and photoisomerizable groups can change their shapes and properties, including binding properties, upon exposure to light.
• Tetrathiafulvalene (TTF) and quinones have multiple stable oxidation states, and therefore can be used in redox reactions and electrochemistry.
• Other units, such as benzidine derivatives, viologens, and fullerenes, are useful in supramolecular electrochemical devices.

• The extremely strong complexation between avidin and biotin is instrumental in blood clotting, and has been used as the recognition motif to construct synthetic systems.
• The binding of enzymes with their cofactors has been used as a route to produce modified enzymes, electrically contacted enzymes, and even photoswitchable enzymes.
• DNA has been used both as a structural and as a functional unit in synthetic supramolecular systems.

Supramolecular chemistry has found many applications,Schneider, H.-J. ( Ed.) (2012) Applications of Supramolecular Chemistry, CRC Press Taylor & Francis Boca Raton etc, [https://www.crcpress.com/Applications-of-Supramolecular-Chemistry/Schneider/p/book/9781439840146] in particular molecular self-assembly processes have been applied to the development of new materials. Large structures can be readily accessed using bottom-up synthesis as they are composed of small molecules requiring fewer steps to synthesize. Thus most of the bottom-up approaches to nanotechnology are based on supramolecular chemistry.Gale, P.A. and Steed, J.W. (eds.) (2012) Supramolecular Chemistry: From Molecules to Nanomaterials. Wiley. {{ISBN|978-0-470-74640-0}} Many smart materialsSmart Materials Book Series, Royal Soc. Chem. Cambridge UK . http://pubs.rsc.org/bookshop/collections/series?issn=2046-0066 are based on molecular recognition.Chemoresponsive Materials /Stimulation by Chemical and Biological Signals, Schneider, H.-J. ; Ed:, (2015) The Royal Society of Chemistry, Cambridge https://dx.doi.org/10.1039/9781782622420

{{main|Supramolecular catalysis}}

A major application of supramolecular chemistry is the design and understanding of catalysts and catalysis. Non-covalent interactions influence the binding reactants.{{cite journal|author=Meeuwissen, J.; Reek, J. N. H.|title= Supramolecular catalysis beyond enzyme mimics |journal= Nat. Chem. |year=2010|volume= 2|issue= 8 |pages=615–21|pmid= 20651721 |doi= 10.1038/nchem.744 |bibcode=2010NatCh...2..615M}}

Design based on supramolecular chemistry has led to numerous applications in the creation of functional biomaterials and therapeutics.{{cite journal|last1=Webber|first1=Matthew J.|last2=Appel|first2=Eric A.|last3=Meijer|first3=E. W.|last4=Langer|first4=Robert|title=Supramolecular biomaterials|journal=Nature Materials|date=18 December 2015|volume=15|issue=1|pages=13–26|doi=10.1038/nmat4474|pmid=26681596|bibcode=2016NatMa..15...13W}} Supramolecular biomaterials afford a number of modular and generalizable platforms with tunable mechanical, chemical and biological properties. These include systems based on supramolecular assembly of peptides, host–guest macrocycles, high-affinity hydrogen bonding, and metal–ligand interactions.

A supramolecular approach has been used extensively to create artificial ion channels for the transport of sodium and potassium ions into and out of cells.{{cite book|first1= Nuria| last1= Rodríguez-Vázquez|first2= Alberto|last2= Fuertes|first3= Manuel|last3= Amorín|first4= Juan R.|last4= Granja |publisher= Springer|date= 2016|series= Metal Ions in Life Sciences|volume=16|title= The Alkali Metal Ions: Their Role in Life|editor1-first=Astrid|editor1-last= Sigel|editor2-first=Helmut|editor2-last=Sigel|editor3-first=Roland K.O.|editor3-last= Sigel|chapter= Chapter 14. Bioinspired Artificial Sodium and Potassium Ion Channels |pages= 485–556|doi=10.1007/978-3-319-21756-7_14| pmid= 26860310| isbn= 978-3-319-21755-0}}

Supramolecular chemistry is also important to the development of new pharmaceutical therapies by understanding the interactions at a drug binding site. The area of drug delivery has also made critical advances as a result of supramolecular chemistry providing encapsulation and targeted release mechanisms.Smart Materials for Drug Delivery: Complete Set (2013) Royal Soc. Chem. Cambridge UK http://pubs.rsc.org/en/content/ebook/9781849735520 In addition, supramolecular systems have been designed to disrupt protein–protein interactions that are important to cellular function.{{Cite journal | doi = 10.1016/j.jconrel.2011.04.027| pmid = 21571017| title = New pharmaceutical applications for macromolecular binders| journal = Journal of Controlled Release| volume = 155| issue = 2| pages = 200–10| year = 2011| last1 = Bertrand | first1 = N. | last2 = Gauthier | first2 = M. A. | last3 = Bouvet | first3 = C. L. | last4 = Moreau | first4 = P. | last5 = Petitjean | first5 = A. | last6 = Leroux | first6 = J. C. | last7 = Leblond | first7 = J.| s2cid = 41385952| url = https://hal.archives-ouvertes.fr/hal-02512499/file/1-s2.0-S0168365911002422-main.pdf}}

Supramolecular chemistry has been used to demonstrate computation functions on a molecular scale. In many cases, photonic or chemical signals have been used in these components, but electrical interfacing of these units has also been shown by supramolecular signal transduction devices. Data storage has been accomplished by the use of molecular switches with photochromic and photoisomerizable units, by electrochromic and redox-switchable units, and even by molecular motion. Synthetic molecular logic gates have been demonstrated on a conceptual level. Even full-scale computations have been achieved by semi-synthetic DNA computers.

• Organic chemistry
• Nanotechnology

• {{cite journal|author=Cook, T. R.; Zheng, Y.; Stang, P. J.|title= Metal-organic frameworks and self-assembled supramolecular coordination complexes: Comparing and contrasting the design, synthesis, and functionality of metal-organic materials|journal= Chem. Rev.|year= 2013|volume= 113|issue= 1|pages= 734–77|pmid= 23121121|pmc= 3764682|doi= 10.1021/cr3002824}}
• {{cite journal|author=Desiraju, G. R.|title= Crystal engineering: From molecule to crystal|journal= J. Am. Chem. Soc.|year= 2013|volume= 135|issue= 27|pages= 9952–67|pmid= 23750552|doi= 10.1021/ja403264c|bibcode= 2013JAChS.135.9952D}}
• {{cite journal|author=Seto, C. T.; Whitesides, G. M.|title= Molecular self-assembly through hydrogen bonding: Supramolecular aggregates based on the cyanuric acid-melamine lattice|journal= J. Am. Chem. Soc.|year= 1993|volume= 115|issue= 3|pages= 905–916|doi=10.1021/ja00056a014|bibcode= 1993JAChS.115..905S}}

{{Reflist|30em}}

{{commons|Supramolecular chemistry}}

• [https://web.archive.org/web/20110522025444/http://www.wikinfo.org/index.php/2D_and_3D_Models_of_Dodecahedrane_and_Cuneane_Assemblies 2D and 3D Models of Dodecahedrane and Cuneane Assemblies]
• [http://www.beilstein-journals.org/bjoc/browse/singleSeries.htm?sn=6 Supramolecular Chemistry] and [http://www.beilstein-journals.org/bjoc/browse/singleSeries.htm?sn=19 Supramolecular Chemistry II] – Thematic Series in the Open Access Beilstein Journal of Organic Chemistry

{{BranchesofChemistry}}

Category:Chemistry