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DISCONNECTION.ppt.pptx

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DISCONNECTION.ppt.pptx

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An approach for designing organic synthesis which involves breaking down of target molecule into available starting material by imaginary breaking of bonds (disconnection) and/or by functional group interconversion is known as disconnection approach or retrosynthesis or synthesis backward.
The C-X disconnection approach is mainly applicable to a carbon chain attached to any of the heteroatoms like O, N, or S. Here, a bond joins the heteroatom (X) to the rest of the molecule like a C-O, C-N, or C-S group. This point is good point to initiate a disconnection. This is called a ‘One-group’ C-X disconnection as one would need to identify only one functional group like ester, ether, amide etc. to make the disconnection.
How to choose a disconnection?
These are the few general strategy which are important points introduced which apply to the whole of synthetic design rather than one particular area. The main choice is between the various disconnection, even such a simple disconnection as the following alcohol can be disconnected.




We want to get back to simple starting materials and we shall do if we disconnect the bond which are:
Towards the middle of the molecule thereby breaking into two reasonably equal halves rather than chopping off one or two carbon atoms from the end and,
At a branch as this is more likely to give straight chain fragments and these are more likely to be available.
Disconnections very often take place immediately adjacent to, or very close to functional groups in the target molecule. This is pretty much inevitable, given that functionality almost invariably arises from the forward reaction.
A simple example is the weedkiller propanil used on rice fields. Amide disconnection gives amine obviously made from o-dichlorobenzene by nitration and reduction. All positions around the ring in o-dichlorobenzene are about the same electronically but steric hindrance will lead to dichloronitrobenzene being the major product
This compound was needed for some research into the mechanisms of rearrangements. We can disconnect on either side of the ether oxygen atom, but (b) is much better because (a) does not correspond to a reliable reaction: it might be hard to control selective alkylation of the primary hydroxyl group in the presence of the secondary one.
The disconnections we have made so far have all been of C–O, C–N, or C–S bonds, but, of course, the most important reactions in organic synthesis are those that form C–C bonds. We can analyze C–C disconnections in much the same way as we’ve analyzed C–X disconnections.
The Zeneca drug propranolol is a beta-blocker that reduces blood pressure and is one of the top drugs worldwide. It has two 1,2-relationships in its structure but it is best to disconnect the more reactive amine group first.
Arildone is a drug that prevents polio and herpes simplex viruses from ‘unwrapping’ their DNA, and renders them harmless.

An approach for designing organic synthesis which involves breaking down of target molecule into available starting material by imaginary breaking of bonds (disconnection) and/or by functional group interconversion is known as disconnection approach or retrosynthesis or synthesis backward.
The C-X disconnection approach is mainly applicable to a carbon chain attached to any of the heteroatoms like O, N, or S. Here, a bond joins the heteroatom (X) to the rest of the molecule like a C-O, C-N, or C-S group. This point is good point to initiate a disconnection. This is called a ‘One-group’ C-X disconnection as one would need to identify only one functional group like ester, ether, amide etc. to make the disconnection.
How to choose a disconnection?
These are the few general strategy which are important points introduced which apply to the whole of synthetic design rather than one particular area. The main choice is between the various disconnection, even such a simple disconnection as the following alcohol can be disconnected.




We want to get back to simple starting materials and we shall do if we disconnect the bond which are:
Towards the middle of the molecule thereby breaking into two reasonably equal halves rather than chopping off one or two carbon atoms from the end and,
At a branch as this is more likely to give straight chain fragments and these are more likely to be available.
Disconnections very often take place immediately adjacent to, or very close to functional groups in the target molecule. This is pretty much inevitable, given that functionality almost invariably arises from the forward reaction.
A simple example is the weedkiller propanil used on rice fields. Amide disconnection gives amine obviously made from o-dichlorobenzene by nitration and reduction. All positions around the ring in o-dichlorobenzene are about the same electronically but steric hindrance will lead to dichloronitrobenzene being the major product
This compound was needed for some research into the mechanisms of rearrangements. We can disconnect on either side of the ether oxygen atom, but (b) is much better because (a) does not correspond to a reliable reaction: it might be hard to control selective alkylation of the primary hydroxyl group in the presence of the secondary one.
The disconnections we have made so far have all been of C–O, C–N, or C–S bonds, but, of course, the most important reactions in organic synthesis are those that form C–C bonds. We can analyze C–C disconnections in much the same way as we’ve analyzed C–X disconnections.
The Zeneca drug propranolol is a beta-blocker that reduces blood pressure and is one of the top drugs worldwide. It has two 1,2-relationships in its structure but it is best to disconnect the more reactive amine group first.
Arildone is a drug that prevents polio and herpes simplex viruses from ‘unwrapping’ their DNA, and renders them harmless.

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DISCONNECTION.ppt.pptx

  1. 1. C-X DISCONNECTION & C-C DICONNECTION
  2. 2. CONTENT • Introduction of disconnection approach • Retrosynthetic analysis FAQs • C-X disconnection a) One group disconnection b) Two group disconnection • C-C disconnection
  3. 3. DISCONNECTION APPROACH • An approach for designing organic synthesis which involves breaking down of target molecule into available starting material by imaginary breaking of bonds (disconnection) and/or by functional group interconversion is known as disconnection approach or retrosynthesis or synthesis backward. • This is the process of synthesis design which starts with product and works backward towards the starting material. • Retrosynthesis is indicated by using “=>” symbol.
  4. 4. DISCONNECTION APPROACH The aromatic amide amelfolide is a cardiac antiarrhythmic agent. Because we see that it is an amide, we know that it can be made quite simply from p- nitrobenzoyl chloride and 2,6-dimethyl-aniline again, we can represent this using a retrosynthetic arrow. Mentally breaking a molecule into its component parts like this is known as disconnection, and it’s helpful to indicate the site of the disconnection with a wiggly line as we have here.
  5. 5. • These are the few general strategy which are important points introduced which apply to the whole of synthetic design rather than one particular area. The main choice is between the various disconnection, even such a simple disconnection as the following alcohol can be disconnected. • We want to get back to simple starting materials and we shall do if we disconnect the bond which are: a) Towards the middle of the molecule thereby breaking into two reasonably equal halves rather than chopping off one or two carbon atoms from the end and, b) At a branch as this is more likely to give straight chain fragments and these are more likely to be available. • Disconnections very often take place immediately adjacent to, or very close to functional groups in the target molecule. This is pretty much inevitable, given that functionality almost invariably arises from the forward reaction. Retrosynthetic analysis FAQs How to choose a disconnection?
  6. 6. A good disconnection visibly simplifies the target molecule. Otherwise, the synthesis challenge doesn’t get any easier. A good trick here is to consider whether you can draw a resonance form of the synthon which looks more like a real reactive intermediate. If it does, you’ve clearly made a good choice of polarity, and you’ve most likely gone a long way to identifying the synthetic equivalent. How do I recognize a good disconnection? How do I decide which synthon carries which charge?
  7. 7. See immediately above, and consider also the inherent polarization of the key reactive bonds within your proposed synthetic equivalent; the synthon is often just an extreme, imaginary version of the real-life situation. • Recognize the functional group in the target molecule. • For compounds consisting of 2 parts joined by a heteroatom, disconnect next to the heteroatom. • Disconnection next to aromatic ring should not be a priority. • Consider alternative disconnections and choose routes that avoid chemo selectivity problems—often this means disconnecting reactive groups first • Disconnection must correspond to known, reliable reactions. How do I identify the synthetic equivalents of my synthons? Overall important points for choosing a disconnection
  8. 8. C-X DISCONNECTION • The C-X disconnection approach is mainly applicable to a carbon chain attached to any of the heteroatoms like O, N, or S. Here, a bond joins the heteroatom (X) to the rest of the molecule like a C-O, C-N, or C-S group. This point is good point to initiate a disconnection. This is called a ‘One-group’ C-X disconnection as one would need to identify only one functional group like ester, ether, amide etc. to make the disconnection. • The corresponding reactions are mainly ionic that involve nucleophilic displacement by SN1, SN2 or carbonyl substitution with amines, alcohols and thiols on carbon electrophiles.
  9. 9. C-N AMIDE DISCONNECTION • The synthesis is very simple. The only point worth noting is the use of catalytic hydrogenation for the reduction rather than the very messy tin and HCl, • Industry greatly prefers catalytic methods with no toxic by-products. A simple example is the weedkiller propanil used on rice fields. Amide disconnection gives amine obviously made from o-dichlorobenzene by nitration and reduction. All positions around the ring in o- dichlorobenzene are about the same electronically but steric hindrance will lead to dichloronitrobenzene being the major product.
  10. 10. C-O ETHER DISCONNECTION We can apply these ideas to the synthesis of the herbicide 2,4-D (2,4-dichlorophenoxyacetic acid).The most reasonable disconnection of an ether is the C-O bond because we know that ethers can be made from alkyl halides by substitution with an alkoxide anion. Once the retrosynthetic analysis is done, we can go back and use our knowledge of chemistry to think of reagents corresponding to these synthons. finish. It isn’t reasonable to try to predict exact conditions for a reaction: to do that you would need to conduct a thorough search of the chemical literature and do some experiments.
  11. 11. C-O ESTER DISCONNECTION A simple example to explain the disconnection approach: This compound is an insect repellent and as a solvent for perfumery. As it’s an ester, we know that it can be made from alcohol plus acyl chloride, and we can represent this using a retro synthetic arrow. The analysis reveals two available compounds: benzyl alcohol and benzyl chloride. Combining the two pyridine as solvent and catalyst gives the ester.
  12. 12. C-S SULFIDE DISCONNECTION Chlorbenside is used to kill ticks and mites. For compounds consisting of two parts joined by a heteroatom, disconnect next to the heteroatom, we can suggest a disconnection next to the sulfur atom. Chlorbenside synthesis:
  13. 13. TWO GROUP C-X DISCONNECTION This compound was needed for some research into the mechanisms of rearrangements. We can disconnect on either side of the ether oxygen atom, but (b) is much better because (a) does not correspond to a reliable reaction: it might be hard to control selective alkylation of the primary hydroxyl group in the presence of the secondary one.
  14. 14. TWO GROUP DISCONNECTION The Zeneca drug propranolol is a beta-blocker that reduces blood pressure and is one of the top drugs worldwide. It has two 1,2- relationships in its structure but it is best to disconnect the more reactive amine group first. The second disconnection can’t make use of an epoxide, but a simple ether disconnection takes us back to 1-naphthol and epichlorohydrin, a common starting material for this type of compound. (isoproplyamine)
  15. 15. C-C DISCONNECTION The only functional group is the triple bond, and we shall want to use the chemistry of alkynes to show us where to disconnect. You know that alkylation of alkynes is a reliable reaction, so a sensible disconnection is next to the triple bond. The disconnections we have made so far have all been of C–O, C–N, or C–S bonds, but, of course, the most important reactions in organic synthesis are those that form C–C bonds. We can analyze C–C disconnections in much the same way as we’ve analyzed C–X disconnections. Consider, for example, how you might make this simple compound, which is an intermediate in the synthesis of a carnation perfume.
  16. 16. C-C DISCONNECTION • In planning the synthesis of phenylacetic acid, two synthons are identified. A nucleophilic "- COOH" group, and an electrophilic "PhCH2+" group. • Of course, both synthons do not exist per se, synthetic equivalents corresponding to the synthons are reacted to produce the desired product. • In this case, the cyanide anion is the synthetic equivalent for the −COOH synthon, while benzyl bromide is the synthetic equivalent for the benzyl synthon. • The synthesis of phenylacetic acid determined by retrosynthetic analysis is thus: PhCH2Br + NaCN → PhCH2CN + NaBr PhCH2CN + 2 H2O → PhCH2COOH + NH3 In fact, phenylacetic acid has been synthesized from benzyl cyanide itself prepared by the analogous reaction of benzyl bromide with sodium An example of C-C disconnection will allow the concept of retrosynthetic analysis to be easily understood.
  17. 17. C-C DISCONNECTION With two carbonyl groups, the alkylation should be particularly straightforward since we can use a base like methoxide. The ether disconnection is then immediately obvious. In the synthesis of arildone the alkyl iodide was used for the alkylation. Arildone is a drug that prevents polio and herpes simplex viruses from ‘unwrapping’ their DNA, and renders them harmless. It has just the structural characteristic you should be looking for: a branch next to a carbonyl group. 2-chloro-5- methoxyphenol 1,6- dibromohexane
  18. 18. FEW OTHER EXAMPLES Paracetamol, for example, is an amide that can be disconnected either to amine + acyl chloride or to amine + anhydride. Retrosynthesis of propoxycaine
  19. 19. FEW OTHER EXAMPLES Benzocaine, we see an ester group and known that esters are reliably made from some derivative of an acid and an alcohol. We should disconnect the C-O ester bond. Retrosynthesis of ibuprofen
  20. 20. REFERENCE • ORGANIC. CHEMISTRY SECOND. EDITION. Jonathan Clayden Nick Greeves Stuart Warren. • Organic Synthesis: The Disconnection Approach, 2nd Edition Stuart Warren, Paul Wyatt.

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