# Synthon

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{{for|Dutch pharmaceutical company|Synthon (company)}}
{{short description|Hypothetical unit in retrosynthetic analysis}}
In [retrosynthetic analysis](/source/retrosynthetic_analysis), a '''synthon''' is a hypothetical unit within a target [molecule](/source/molecule) that represents a potential starting reagent in the retroactive synthesis of that target molecule. The term was coined in 1967 by [E. J. Corey](/source/E._J._Corey).<ref name="iupacCorey">{{cite journal| author= E. J. Corey | title = General methods for the construction of complex molecules |journal= Pure and Applied Chemistry |year=1967 | volume=14 | pages=30–37 | url=http://www.iupac.org/publications/pac/pdf/1967/pdf/1401x0019.pdf | doi=10.1351/pac196714010019| s2cid = 73595158 }}</ref> He noted in 1988 that the "word ''synthon'' has now come to be used to mean synthetic ''building block'' rather than retrosynthetic fragmentation structures".<ref>{{cite journal| title=Robert Robinson Lecture. Retrosynthetic thinking—essentials and examples | author= E. J. Corey | journal= Chem. Soc. Rev. |year= 1988 |volume= 17 |pages= 111–133 | doi= 10.1039/CS9881700111}}</ref>
It was noted in 1998<ref>{{cite book| title=Organic Synthesis, the science behind the art | author=W. A. Smit, A. F. Buchkov, R. Cople |publisher= Royal Society of Chemistry| isbn= 0-85404-544-9| year=1998}}</ref> that the phrase did not feature very prominently in Corey's 1981 book ''The Logic of Chemical Synthesis'',<ref>{{cite book |author1=Elias James Corey |author2=Xue-Min Cheng | title=The logic of chemical synthesis | publisher=Wiley-Interscience| year= 1995| isbn= 0-471-11594-0}}</ref> as it was not included in the index. Because synthons are [charged](/source/Ion), when placed into a synthesis an uncharged form is found commercially instead of forming and using the potentially very unstable charged synthons.

==Example==
:400px|Retrosynthetic analysis of phenylacetic acid

In planning the synthesis of [phenylacetic acid](/source/phenylacetic_acid), two synthons are identified: a [nucleophilic](/source/nucleophilic) "COOH<sup>−</sup>" group, and an [electrophilic](/source/electrophilic) "{{chem2|PhCH2+}}" group. Of course, both synthons do not exist by themselves; synthetic equivalents corresponding to the synthons are reacted to produce the desired [reactant](/source/reactant). In this case, the [cyanide anion](/source/cyanide_anion) is the synthetic equivalent for the COOH<sup>−</sup> synthon, while [benzyl bromide](/source/benzyl_bromide) is the synthetic equivalent for the [benzyl](/source/benzyl) synthon.

The synthesis of [phenylacetic acid](/source/phenylacetic_acid) determined by retrosynthetic analysis is thus:

:{{chem2|[Ph\sCH2\sBr](/source/Benzyl_bromide) + [[Sodium cyanide|Na+[C\tN]−]] → [Ph\sCH2\sC\tN](/source/Benzyl_cyanide) + [NaBr](/source/Sodium_bromide)}}
:{{chem2|Ph\sCH2\sC\tN + 2 [H2O](/source/Water) → [Ph\sCH2\sC(\dO)\sOH](/source/Phenylacetic_acid) + [NH3](/source/Ammonia)}}
where Ph stands for [phenyl](/source/phenyl).
:600 px

* C2 synthons - [acetylene](/source/acetylene), [acetaldehyde](/source/acetaldehyde)
* -C<sub>2</sub>H<sub>4</sub>OH synthon - [ethylene oxide](/source/ethylene_oxide)
* [carbocation](/source/carbocation) synthons - [alkyl halides](/source/alkyl_halides)
* [carbanion](/source/carbanion) synthons - [Grignard reagent](/source/Grignard_reagent)s, [organolithium](/source/organolithium)s, substituted acetylides

==Alternative use in synthetic oligonucleotides==
This term is also used in the field of gene synthesis—for example "40-base synthetic [oligonucleotides](/source/Oligonucleotide) are built into 500- to 800-bp synthons".<ref>{{cite journal| title=Total synthesis of long DNA sequences: Synthesis of a contiguous 32-kb polyketide synthase gene cluster|author1=Sarah J. Kodumal |author2=Kedar G. Patel |author3=Ralph Reid |author4=Hugo G. Menzella |author5=Mark Welch |author6=Daniel V. Santi |name-list-style=amp | journal = PNAS | date=November 2, 2004 | volume= 101 |issue=44|pages=15573–15578|bibcode = 2004PNAS..10115573K |doi = 10.1073/pnas.0406911101 | pmid=15496466 | pmc=524854|doi-access=free}}</ref>

==Carbocationic synthons==
thumb|Fig. 1: Strategic disconnection en route to the hops ether

Many retrosynthetic disconnections important for organic synthesis planning use carbocationic synthons. [Carbon-carbon bond](/source/Carbon-carbon_bond)s, for example, exist ubiquitously in [organic molecule](/source/organic_molecule)s, and are usually disconnected during a [retrosynthetic analysis](/source/retrosynthetic_analysis) to yield [carbocation](/source/carbocation)ic and [carbanion](/source/carbanion)ic synthons. Carbon-[heteroatom](/source/heteroatom) bonds, such as those found in [alkyl halide](/source/alkyl_halide)s, [alcohol](/source/alcohol_(chemistry))s, and [amide](/source/amide)s, can also be traced backwards retrosynthetically to polar C-X bond disconnections yielding a carbocation on [carbon](/source/carbon). [oxonium](/source/Oxonium_ion) and [acylium](/source/acylium) ions are carbocationic synthons for [carbonyl compound](/source/carbonyl_compound)s such as [ketone](/source/ketone)s, [aldehyde](/source/aldehyde)s and [carboxylic acid](/source/carboxylic_acid) derivatives. An oxonium-type synthon was used in a disconnection en route{{cln|reason=What on this Earth is "en route"??? Clear this jargon for an average mortal human being!|date=June 2023}} to the hops ether{{cln|reason=What on this Earth is "hops ether"??? Clear this jargon for an average mortal human being!|date=June 2023}},<ref>{{cite journal|last1=Linderman|first1=Russell J.|last2=Godfrey|first2=Alex.|title=Novel synthesis of tetrahydrofurans via a synthetic equivalent to a carbonyl ylide|journal=Journal of the American Chemical Society|date=August 1988|volume=110|issue=18|pages=6249–6251|doi=10.1021/ja00226a052|pmid=22148812}}</ref> a key component of [beer](/source/beer) (see fig.1). In the forward direction, the researchers used an [intramolecular](/source/intramolecular_reaction) [aldol reaction](/source/aldol_reaction) catalyzed by [titanium tetrachloride](/source/titanium_tetrachloride) to form the [tetrahydrofuran](/source/tetrahydrofuran) ring of hops ether.

Another common disconnection that features carbocationic synthons is the [Pictet-Spengler reaction](/source/Pictet-Spengler_reaction). The mechanism of the reaction involves C-C pi-bond attack onto an iminium ion, usually formed in situ from the condensation of an amine and an aldehyde. The Pictet-Spengler reaction has been used extensively for the synthesis of numerous [indole](/source/indole) and [isoquinoline](/source/isoquinoline) alkaloids.<ref>{{cite book|author1=Whaley, W. M. |author2=Govindachari, T. R. |chapter=The Pictet-Spengler Synthesis of Tetrahydroisoquinolines and Related Compounds|title=Organic Reactions|editor=Adams, R.|publisher=John Wiley and Sons|location=New York|year=1951|volume= VI|page=151|doi=10.1002/0471264180.or006.03|isbn=0471264180}}</ref>
:The Pictet-Spengler disconnection

[Carbanion](/source/Carbanion) alkylation is a common strategy used to create carbon-carbon bonds. The alkylating agent is usually an alkyl halide or an equivalent compound with a good leaving group on carbon. Allyl halides are particularly attractive for [S<sub>N</sub>2](/source/SN2_reaction)-type reactions due to the increased reactivity added by the allyl system. [Celestolide](/source/Celestolide) (4-acetyl-6-t-butyl-1,1-dimethylindane, a component of [musk](/source/musk) perfume) can be synthesized using a benzyl anion alkylation with [3-chloro-2-methylprop-1-ene](/source/3-chloro-2-methylprop-1-ene) as an intermediate step.<ref>{{cite journal|last1=Kagabu|first1=Shinzo|last2=Kojima|first2=Yuka|title=A synthesis of indane musk Celestolide|journal=Journal of Chemical Education|date=May 1992|volume=69|issue=5|pages=420|doi=10.1021/ed069p420|bibcode=1992JChEd..69..420K}}</ref> The synthesis is fairly straightforward, and has been adapted for teaching purposes in an undergraduate laboratory.

==References==
{{reflist}}

Category:Organic synthesis

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Adapted from the Wikipedia article [Synthon](https://en.wikipedia.org/wiki/Synthon) by Wikipedia contributors ([contributor history](https://en.wikipedia.org/wiki/Synthon?action=history)). Available under [Creative Commons Attribution-ShareAlike 4.0 International](https://creativecommons.org/licenses/by-sa/4.0/). Changes may have been made.