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What are aryl chlorides currently used for?
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Mary Clayton
What are aryl chlorides currently used for?
Synthetic handles: for organometallic couplings (Sonogashira, Suzuki...), there is a selectivity ($\ce{aryl-I} > \ce{aryl-OTf} >\ce{aryl-Br} >\ce{aryl-Cl}$) that can be crucial in the total synthesis. You can make the other position ($\ce{aryl-I}$ or whatever) react first, then use modified conditions suitable for aryl chloride couplings (plenty of examples on this website). Or make an halogen exchange before coupling your chloro- position.
Common functionalities: halogen bonds can change binding affinities. Even if they are weaker than hydrogen bonds, they are specific (see C. Bissantz et al., J. Med. Chem., 2010, 53 (14), 5061–5084.). They can make interactions with electrophiles, nucleophiles, or with themselves (ex: $\ce{C-X...O}$ $\ce{sp^2}$ or $\ce{X...X}$). One example of molecule designed with chloroaryl moieties is
represented here (see Furet et al., Bioorg. Med. Chem. Lett.
2012, 22 (10), 3498–3502, which shows the docking model). This is an inhibitor which blocks the binding pocket of the
regulator protein MDM2. The 6-chloroindolyl moiety enables to fill a
subpocket (TRP 23), while the p-chlorophenyl fills another one (Leu 26). The chlorine-chlorine interactions between the 6-chloroindolyl moiety and the triptophan residue in the protein was a key point in the design of this inhibitor, strongly enhancing the binding affinities.
Synthetic handles: for organometallic couplings (Sonogashira, Suzuki...), there is a selectivity ($\ce{aryl-I} > \ce{aryl-OTf} >\ce{aryl-Br} >\ce{aryl-Cl}$) that can be crucial in the total synthesis. You can make the other position ($\ce{aryl-I}$ or whatever) react first, then use modified conditions suitable for aryl chloride couplings (plenty of examples on this website). Or make an halogen exchange before coupling your chloro- position.
Common functionalities: halogen bonds can change binding affinities. Even if they are weaker than hydrogen bonds, they are specific (see C. Bissantz et al., J. Med. Chem., 2010, 53 (14), 5061–5084.). They can make interactions with electrophiles, nucleophiles, or with themselves (ex: $\ce{C-X...O}$ $\ce{sp^2}$ or $\ce{X...X}$). One example of molecule designed with chloroaryl moieties isrepresented here (see Furet et al., Bioorg. Med. Chem. Lett.2012, 22 (10), 3498–3502, which shows the docking model). This is an inhibitor which blocks the binding pocket of theregulator protein MDM2. The 6-chloroindolyl moiety enables to fill asubpocket (TRP 23), while the p-chlorophenyl fills another one (Leu 26). The chlorine-chlorine interactions between the 6-chloroindolyl moiety and the triptophan residue in the protein was a key point in the design of this inhibitor, strongly enhancing the binding affinities.
Synthetic handles: for organometallic couplings (Sonogashira, Suzuki...), there is a selectivity ($\ce{aryl-I} > \ce{aryl-OTf} >\ce{aryl-Br} >\ce{aryl-Cl}$) that can be crucial in the total synthesis. You can make the other position ($\ce{aryl-I}$ or whatever) react first, then use modified conditions suitable for aryl chloride couplings (plenty of examples on this website). Or make an halogen exchange before coupling your chloro- position.
Common functionalities: halogen bonds can change binding affinities. Even if they are weaker than hydrogen bonds, they are specific (see C. Bissantz et al., J. Med. Chem., 2010, 53 (14), 5061–5084.). They can make interactions with electrophiles, nucleophiles, or with themselves (ex: $\ce{C-X...O}$ $\ce{sp^2}$ or $\ce{X...X}$). One example of molecule designed with chloroaryl moieties is represented here (see Furet et al., Bioorg. Med. Chem. Lett. 2012, 22 (10), 3498–3502, which shows the docking model). This is an inhibitor which blocks the binding pocket of the regulator protein MDM2. The 6-chloroindolyl moiety enables to fill a subpocket (TRP 23), while the p-chlorophenyl fills another one (Leu 26). The chlorine-chlorine interactions between the 6-chloroindolyl moiety and the triptophan residue in the protein was a key point in the design of this inhibitor, strongly enhancing the binding affinities.
Synthetic handles: for organometallic couplings (Sonogashira, Suzuki...), there is a selectivity ($\ce{aryl-I} > \ce{aryl-OTf} >\ce{aryl-Br} >\ce{aryl-Cl}$) that can be crucial in the total synthesis. You can make the other position ($\ce{aryl-I}$ or whatever) react first, then use modified conditions suitable for aryl chloride couplings (plenty of examples on this website). Or make an halogen exchange before coupling your chloro- position.
Common functionalities: halogen bonds can change binding affinities. Even if they are weaker than hydrogen bonds, they are specific (see C. Bissantz et al., J. Med. Chem., 2010, 53 (14), 5061–5084.). They can make interactions with electrophiles, nucleophiles, or with themselves (ex: $\ce{C-X...O}$ $\ce{sp^2}$ or $\ce{X...X}$). One example of molecule designed with chloroaryl moieties isrepresented here (see Furet et al., Bioorg. Med. Chem. Lett.2012, 22 (10), 3498–3502, which shows the docking model). This is an inhibitor which blocks the binding pocket of theregulator protein MDM2. The 6-chloroindolyl moiety enables to fill asubpocket (TRP 23), while the p-chlorophenyl fills another one (Leu 26). The chlorine-chlorine interactions between the 6-chloroindolyl moiety and the triptophan residue in the protein was a key point in the design of this inhibitor, strongly enhancing the binding affinities.
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