2-Functional Groups.pdf

Functional Groups — A functional group is potentially reactive unit within a molecule. — Drugs typically are multi-functional molecules. — Sometimes functional groups are part of the basic framework of the molecule, while in other cases they are appendages to the structure. — Groups that are...

Functional Groups — A functional group is potentially reactive unit within a molecule. — Drugs typically are multi-functional molecules. — Sometimes functional groups are part of the basic framework of the molecule, while in other cases they are appendages to the structure. — Groups that are attached to the basic framework are called substituents. — Some substituents are also functional groups while others, such as methyl groups, are not. 2 Functional Groups — Knowing and being able to identify functional groups within drug molecules is important because functional groups affect: — how a drug is transported throughout the body — how it binds to its receptor — how it causes a biological response — how it undergoes metabolism — how it gets excreted from the body — the drug’s stability during storage 3 Functional Groups — You are responsible for knowing all of the functional groups listed in Figures 3.2-3.5 in the book, and understanding the difference between them. 4 Functional Groups — A functional group works together as a team. It cannot be dissected. — Electrons are shared throughout the functional group. An amide ONLY! Not an amine and a ketone A sulfonic acid ONLY! Not a sulfone and an alcohol 5 Functional Groups — Some common carbonyl-containing functional groups 6 Functional Groups — Some common nitrogen-containing functional groups 7 Functional Groups — Some common sulfur-containing functional groups 8 Functional Groups — Some miscellaneous functional groups 9 Tautomerization — Some functional groups are capable of existing in two distinct forms provided that a neighboring position has at least one attached hydrogen. — One example of this is seen with certain ketones. 10 Tautomerization — A hydrogen on an adjacent carbon can migrate to the carbonyl oxygen to form a O-H bond. — When the oxygen uses one of it’s lone-pairs to form a new bond to hydrogen, the electrons in the original C- H bond are released and flow towards the carbonyl group to form a new π-bond. — Electrons in the original C=O bond then are pushed onto oxygen to form a new lone pair. 11 Tautomerization Keto Enol — The resulting structure which has an OH attached to a double bond is called an enol. — The enol form and the keto (ketone) form are in equilibrium and the two structures, which differ only with respect to the point of attachment of the hydrogen and the location of the double bond, are called tautomers. 12 Tautomerization — The equilibrium constant depends on the relative stabilities of the two tautomers. — For ordinary ketones such as acetone the equilibrium greatly favors the keto form. Major (>99%) 13 Tautomerization — However for certain other ketones such as acetylacetone, the enol form is favored because an intramolecular hydrogen-bond between the enol OH group and the remaining carbonyl which stabilizes the structure. Major (>70%) 14 Tautomerization — While keto-enol is the best known form of tautomerization it is not the only one. — Another is imine-enamine tautomerization which strongly favors the imine form. Enamines are generally stable only if they lack hydrogen on the nitrogen. — One other is oxime-nitroso tautomerization which favors the oxime form. 15 Electronic Effects — A s-bond that is formed between atoms of different electronegativities will be polarized. — The electrons in such a bond will be attracted by the more electronegative atom which will then induce a small amount of positive charge on the other atom. — This in turn will attract electrons in the adjacent bond that will induce a smaller amount of positive charge, etc. — This sequential polarization due to electronegativity differences is called an inductive effect and decreases rapidly with distance. 16 Electronic Effects — When polarization is experienced through space rather than through bonds it is known as a field effect. — Two groups of different electronegativities need only be close to one another due to the geometry of the molecule for field effects to be observed. — Since it is often difficult to differentiate whether field effects or inductive effects are in operation the two together are often referred to as polar effects. — Polar effects decrease as the distance from the more electronegative element increases. 17 Electronic Effects — The third of the electronic effects is resonance. — Resonance refers to the conduction of electrons through a conjugated system. — A conjugated system is one in which there is alternating single and double bonds. — It is more favorable (lower in energy) to disperse electron density over several atoms rather than have it concentrated at one point. — Resonance does not significantly decrease with distance 18 Electron-Donating Groups — Functional groups can be divided into two groups: — Those that donate electron density to the molecule — Those that withdraw excess electron density from the molecule — Electron-donating groups transfer electron density into a molecule as needed — Usually this is in response to a developing positive charge — There are relatively few electron-donating functional groups: alcohols, ethers, amines, thiols, thioethers (sulfides), alkyl groups and aromatic rings 19 Electron-Donating Groups Alcohols and Ethers — These groups function by delocalizing the lone pair electrons on oxygen to a developing area of + charge. — This is another example of resonance, and helps to lower the energy of the compound. — The effect is to spread out any charge over several atoms, which lowers the energy relative to having the charge centered on a single atom. 20 Electron-Donating Groups Thiols and Thioethers (Sulfides) — These work in the same way as their oxygen analogs — Sulfur is much larger than carbon, and so p-orbital overlap to form a C=S bond is less efficient than for a C=O bond. — As a result these groups are less efficient as electron- donating groups than alcohols and ethers. 21 Electron-Donating Groups Amines — The mechanism of how amines donate electrons is the same as for alcohols — Nitrogen, because it is less electronegative than oxygen, can better tolerate a positive charge. — Therefore amines are excellent electron-donators 22 Electron-Donating Groups Alkyl Groups — Alkyl groups include such substituents as methyl, ethyl, propyl, etc. They are capable of delocalizing adjacent positive charge by a process known as hyperconjugation. — While there are no lone-pair electrons to delocalize, the electrons in an adjacent C-H bond are instead used for the same purpose. Vacant p- orbital 23 Electron-Donating Groups Alkyl Groups — While it costs energy to break a C-H bond it is compensated for by being able to disperse the charge by resonance. — Thus alkyl groups act as weak electron donors. — The greater the number of adjacent hydrogens, the better the electron-donating properties of the alkyl group (more resonance structures). Thus methyl>ethyl>i-propyl>t-butyl. 24 Electron-Donating Groups Aromatic Rings — Aromatic rings (also olefins and alkynes) can use some of the p-electron density to help stabilize adjacent charges, by delocalizing that charge. — In a benzene for example a positive charge can be delocalized onto both ortho-positions and the para- position. 25 Electron-Withdrawing Groups — These are groups which withdraw electron density from a system. They can act as sinks for excess electron density. They will stabilize existing or developing negative charge at or near the point of attachment. — Many of the electron withdrawing groups possess double or triple bonds. Thus all of the carbonyl-based functional groups, cyano, nitro, sulfonyl, sulfinyl, and imino-type functional groups are electron withdrawing. In addition the halides withdraw as do aromatic rings, olefins and alkynes. 26 Electron-Withdrawing Groups Carbonyls — Functional groups that contain a carbonyl at the position of attachment to a molecule withdraw electron density by two mechanisms. — Inductive effect — The electronegativity difference between carbon and oxygen polarizes the bond, with oxygen having a partial negative charge and carbon a partial positive charge — Resonance — Electron density can be delocalized by resonance through the C=O bond which spreads the charge over several atoms. 27 Electron-Withdrawing Groups Carbonyls — When one of the atoms directly connected to the carbonyl carbon is a heteroatom as in esters and amides a lone pair from the heteroatom can be pushed into the carbonyl group by resonance — This reduces the degree of positive charge that builds on the carbon of the carbonyl group. — Thus relative to ketones and aldehydes, esters and amides are slightly weaker electron-withdrawing groups. 28 Electron-Withdrawing Groups Carbonyls — One other thing about esters and amides to consider is that they are only electron-withdrawing when they are attached to the substrate at the carbonyl carbon. — If the position of attachment is the heteroatom, then they behave as weak electron-donating substituents. 29 Electron-Withdrawing Groups Nitriles — Nitriles have a carbon-nitrogen triple bond. — Nitrogen is more electronegative than carbon and so once again the bond is polarized. — Resonance is also important in helping to disperse excess electron density Electrostatic stabilization 30 Electron-Withdrawing Groups Nitro Groups — Nitro groups (-NO2) are among the strongest of electron- withdrawing groups — The nitrogen always carries a positive charge (4 bonds) and one of the oxygens a negative charge 31 Electron-Withdrawing Groups Sulfoxides — In a sulfoxide sulfur forms four bonds – two to the neighboring groups and a double bond to oxygen — As sulfur lies one row below oxygen on the Periodic Table it is larger than oxygen and p-bond formation between S and O is less efficient than C=O. Therefore a significant resonance form exists with a positive charge on S and single-bonded O having a negative charge Electrostatic stabilization of developing (-) charge Resonance stabilization 32 Electron-Withdrawing Groups Sulfones — In a sulfone sulfur forms six bonds – two to the neighboring groups and two double bonds to oxygen — As with sulfoxides a significant resonance form exists with a positive charge on S and a negative charge on one of the oxygen atoms — The presence of additional resonance structures makes a sulfonyl group a stronger electron withdrawer than a sulfinyl group Resonance stabilization 33 Electron-Withdrawing Groups Halides — Fluorine — Despite its very high electronegativity a single fluoro is only weakly electron withdrawing. — While the polar effects of fluorine are strongly withdrawing this is offset by back donation (resonance) into a vacant antibonding s* orbital. 34 Electron-Withdrawing Groups Halides — Chlorine, Bromine and Iodine — Note that since Cl, Br and I lie one, two and three rows below C in Periodic Table, the size difference makes back-donation by resonance inefficient. — Therefore Cl and Br withdraw electrons mainly by polar effects with Cl>Br>I Element Electro- negativity C 2.55 Cl 3.16 Br 2.96 I 2.66 35 Electron-Withdrawing Groups Trifluoromethyl — A very common functional group in medicinal chemistry is trifluoromethyl (CF3) which is a powerful electron- withdrawer — Having three fluorines attached to one carbon allows the polar effects of each one to attract electron density from the others which prevents their lone pairs from being back-donated. 36 Electron-Withdrawing Groups Aromatic Rings — The p-system of aromatic rings (and olefins and alkynes) can respond to both positive and negative charges on adjacent carbons. — The presence of other electron-withdrawing groups on an aromatic ring makes it an even stronger electron- withdrawing group since charge to be spread over even more atoms. 37