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notably, Fumio Toda authored and co-authored numerous papers on the topic and developed many attractive protocols for previously tedious reactions . In fact, many air and moisture sensitive reactions and reagents can be used without the necessity of typical air and moisture techniques due to the greatly decreased diffusivity of vapors through nonporous solid mixtures as opposed to liquid mixtures. The lack of porosity in any given solid-phase organic reaction mixture is owed to the extremely low particle size obtained upon grinding with a mortar and pestle or ball mill, the former of which allows for much faster reaction times, while the latter facilitates the use of solid-state chemistry by untrained operators. In practice, the technique by which reactants are ground in a mortar and pestle is both simple and intuitive, and can be derived autonomously without instruction simply by finding the most ergonomically favorable grinding technique (which is individual to each operator) and observing the mixture's particle size to ensure that any macroscopic particles are ground until microscopic. Further grinding reduces particle sizes to clusters of a few hundred atoms each, and these clusters of particles react with clusters containing compatible molecules to form new product molecules, which themselves possess their own crystal structure and must displace the parent particles to conform to such a structure. This displacement then propels the parent particles towards other similarly low-volume/high-surface area particles, resulting in a cascading collisions that greatly enhance reaction times. Organic reactions in the solid phase often proceed 50-100 times more quickly than their counterparts, with some even progressing 1200 times more quickly. Solid-phase organic synthesis, while still discouraged by some chemists, boasts many advantages over solution phase reactions, most notably in its speed, selectivity, air and moisture tolerance, simplicity, environmental friendliness, safety, and accessibility. The source of the aversion to solid phase chemistry comes most likely from
Aristotle's famous quote "No Coopora nisi Fluida", meaning "No reaction occurs in the absence of solvent". This statement was a hypothesis on the basis that meat stew spoiled while salted meat did not, milk itself spoiled while powdered milk did not, and crushed grapes gave wine while dried grapes did not. This hypothesis, like many in the chemical community, was accepted as gospel until a pioneering chemist proved it wrong, and to this day is still accepted by the majority of chemists simply due to their lack of knowledge of this development. Even for decades following the discovery of solid phase peptide synthesis, it was not developed for organic synthesis until the late 1980s, and was developed out of a serendipitous discovery (i.e. not inspired by the success solid-phase peptide synthesis). Even now, it is frowned upon by numerous renowned synthetic chemists simply on the basis that they are unfamiliar with it.
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Seo, T.; Kubota, K.; Ito, H. Chem. Sci. 2022, 13 (2), 430–438. 11. Cao, Q.; Howard, J. L.; Wheatley, E.; Browne, D. L. Angewandte Chemie 2018, 130 (35), 11509–11513. 12. Rinaldi, L.; Martina, K.; Baricco, F.; Rotolo, L.; Cravotto, G. Molecules 2015, 20 (2), 2837–2849. 13. Tan, D.; Mottillo, C.; Katsenis, A. D.; Štrukil, V.; Friščić, T. Angew Chem Int Ed 2014, 53 (35), 9321–9324. 14. Turberg, M.; Ardila‐Fierro, K. J.; Bolm, C.; Hernández, J. G. Angew Chem Int Ed 2018, 57 (33), 10718–10722. 15. Jin, M.; Song, G.; Li, Z.; Zhou, F.; Fan, B.; Ouyang, P. Journal of
Heterocyclic Chem 2014, 51 (6), 1838–1843. 16.
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the solution of the protected building block and stirred. After the reaction between the bead and the protected building block is completed, the solution is removed and the bead is washed. Then the protecting group is removed and the above steps are repeated. After all steps are finished, the synthesised compound is chemically cleaved from the bead.
410:). A number of amino acids bear functional groups in the side chain which must be protected specifically from reacting with the incoming N-protected amino acids. In contrast to Boc and Fmoc groups, these have to be stable over the course of peptide synthesis although they are also removed during the final deprotection of peptides.
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If a compound containing more than two kinds of building blocks is synthesised, a step is added before the deprotection of the building block bound to the bead; a functional group which is on the bead and did not react with an added building block has to be protected by another protecting group which
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In the basic method of solid-phase synthesis, building blocks that have two functional groups are used. One of the functional groups of the building block is usually protected by a protective group. The starting material is a bead which binds to the building block. At first, this bead is added into
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7. Seo, T.; Ishiyama, T.; Kubota, K.; Ito, H. Chem. Sci. 2019, 10 (35), 8202–8210. 8. Yu, J.; Hong, Z.; Yang, X.; Jiang, Y.; Jiang, Z.; Su, W. Beilstein J. Org. Chem. 2018, 14, 786–795. 9. Yu, J.; Shou, H.; Yu, W.; Chen, H.; Su, W. Adv Synth Catal 2019, 361 (22), 5133–5139. 10. Gao, Y.; Feng, C.;
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Solid-phase synthesis techniques have historically been used primarily in biochemical settings with a strong focus on peptide couplings. However, developments in the late 1980s and early 1990s demonstrated the enhanced efficiency and selectivity of many reactions in the solid state. Perhaps most
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A chemist has edited the following article to add the solid-phase organic synthesis section. The chemist is unfamiliar with
Knowledge (XXG)'s formatting protocols but has provided references for this section. Any editing of the references section would be appreciated, as it could facilitate the
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bond. Then the amino group is deprotected and reacted with the carbonyl group of the next N-protected amino acid. The solid phase now bears a dipeptide. This cycle is repeated to form the desired peptide chain. After all reactions are complete, the synthesised peptide is cleaved from the bead.
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is not removed at the deprotective condition of the building block. Byproducts which lack the building block of this step only are prevented by this step. In addition, this step makes it easy to purify the synthesised compound after cleavage from the bead.
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chain in the SPPS method, although peptides are biologically synthesised in the opposite direction in cells. In peptide synthesis, an amino-protected amino acid is bound to a solid phase material or resin (most commonly, low cross-linked
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the article is essentially unsourced, and is unacceptably limited in scope for the preeminent article on this subject, omitting as it does nearly all aspects other than the solid phase synthesis of biological
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Guillier, Fabrice; Orain, David; Bradley, Mark (2000). "Linkers and
Cleavage Strategies in Solid-Phase Organic Synthesis and Combinatorial Chemistry".
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can be synthesised in a flask, they are almost always synthesised on solid phase using a DNA/RNA synthesizer. For a more comprehensive review, see
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The protecting groups for the amino groups mostly used in the peptide synthesis are 9-fluorenylmethyloxycarbonyl group (
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558:"Solid-phase peptide synthesis: an overview focused on the preparation of biologically relevant peptides"
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Merrifield, Bruce Arthur (1963). "Solid Phase
Peptide Synthesis. I. The Synthesis of a Tetrapeptide".
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and other synthetic applications. The process was originally developed in the 1950s and 1960s by
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6. Jiang, Z.-J.; Li, Z.-H.; Yu, J.-B.; Su, W.-K. J. Org. Chem. 2016, 81 (20), 10049–10055.
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Krchňák, Viktor; Holladay, Mark W. (2002). "Solid Phase
Heterocyclic Chemistry".
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in order to synthesise peptide chains, and which was the basis for his 1984
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N-(pyrimidin-2-yl)amino acid amides in drug research, see
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are also synthesised by the solid-phase method. Although
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support material and synthesised step-by-step in a single
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between the carbonyl group and the resin, most often an
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Merrifield, B. (1986-04-18). "Solid phase synthesis".
711:"The Nobel Prize in Chemistry 1984 - NobelPrize.org"
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313:The reaction can be driven to completion and high
365:Solid-phase synthesis is a common technique for
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369:. Usually, peptides are synthesised from the
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220:needs attention from an expert in Chemistry
75:needs attention from an expert in Chemistry
53:Learn how and when to remove these messages
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779:Solid-Phase Combinatorial Chemistry, see
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468:Noncovalent solid-phase organic synthesis
294:chemistry. Benefits compared with normal
254:Learn how and when to remove this message
193:Learn how and when to remove this message
16:Method of synthesizing complex molecules
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500:https://doi.org/10.1021/acs.joc.6b01938
517:https://doi.org/10.1002/anie.202217723
509:https://doi.org/10.1002/anie.201906755
231:may be able to help recruit an expert.
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414:Solid-phase synthesis of DNA and RNA
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131:adding citations to reliable sources
496:https://doi.org/10.1021/jo00013a055
484:https://doi.org/10.1021/jo00274a007
513:https://doi.org/10.1039/C3CS35526H
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225:autodidactic pursuits of readers.
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420:Oligonucleotide synthesis
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556:Palomo, Jose M. (2014).
347:Nobel Prize in Chemistry
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142:"Solid-phase synthesis"
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1021:Solid-phase synthesis
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272:solid-phase synthesis
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861:Convergent synthesis
841:Biomimetic synthesis
290:utilising selective
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571:(62): 32658–32672.
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276:molecules
268:chemistry
237:June 2024
183:June 2014
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