Organic Synthesis Notation Chemistry Advanced Higher

Organic molecule synthesis The construction of compounds via organic reactions. All chemical reactions involve the breaking and making of bonds. Curly arrows give an impression of bonds breaking and bonds being made. Curly arrows are specifically used to show the movement of electrons, both singly and in pairs. Curly arrows should not be used for any other purpose.

Curly arrows In order to represent the movement of an electron pair, this arrow is used: In order to represent the movement of a single electron, this arrow is used:

Curly arrows The arrow tail starts from where the electron pair/electron originates. The arrow head points to where the electron pair/electron finishes. The reaction between ethene and hydrogen bromide below illustrates this: C2H4 + HBr CH3CH2Br

Curly arrows H2C CH2 H Br H2C C+ H Br - Two electrons move from the double bond in ethene and a new bond forms with the hydrogen from the hydrogen bromide. At the same time the pair of electrons in the hydrogen bromide bond move to the bromine atom. Note that the head of the arrow points between the carbon and hydrogen, as that is where the new bond is formed. H2C C+ H Br -

Curly arrows H2C H The second stage of this reaction allows us to illustrate how to use curly arrows for a lone pair of electrons. The first stage of the reaction has left us with a positive charge on the carbon and a negative bromide ion. Notice the head of the arrow is pointing to a place between the carbon and the bromide ion since this is where the bond is formed. + H C Br - ..

Bond fission Homolytic Heterolytic Bond breaking is also known as bond fission. There are two ways in which bond fission can happen Homolytic Heterolytic

Homolytic bond fission The two shared electrons forming the bond separate equally, one going to each atom. In the case of hydrogen bromide: H : Br   Remember the single-headed arrow shows movement of only one electron. H• + •Br

Homolytic bond fission H : Br The dot (•) beside each atom represents the unpaired electron. The atoms are electrically neutral because each has equal numbers of protons and electrons. However, the atoms are highly reactive because the unpaired electron has a strong tendency to pair up with an electron from another atom or molecule. H• + •Br

Homolytic bond fission Highly reactive atoms or groups of atoms containing unpaired electrons are called free radicals. Because of their high reactivity free radicals only exist as reaction intermediates. Free radicals are most likely to be formed when the bond being broken is non-polar, ie has electrons that are more or less equally shared.

Free-radical chain reaction The reaction between methane and chlorine in which one of the hydrogen atoms in methane is replaced by one chlorine atom. This reaction is known as a free-radical chain reaction and has three distinct steps: initiation propagation termination.

Free-radical chain reaction Initiation UV light is required to split the chlorine molecules into two chlorine free radicals: UV Cl . Cl . Cl : Cl

Free-radical chain reaction Propagation (two steps) Firstly, a chlorine radical can collide with a methane molecule, resulting in removal of a hydrogen atom, forming a methyl radical: . Cl . . H

Free-radical chain reaction Propagation (two steps) In the second step, the methyl radical collides with another chlorine molecule, producing more chlorine radicals, which keeps the reaction repeating: .

Free-radical chain reaction Termination (three possible steps) Each of these steps removes the radicals from the process. i. Two chlorine radicals form a chlorine molecule. Cl . Cl . Cl Cl

Free-radical chain reaction Termination (three possible steps) Each of these steps removes the radicals from the process. ii. A methyl radical joins a chlorine radical to form chloromethane. . Cl .

Free-radical chain reaction Termination (three possible steps) Each of these steps removes the radicals from the process. iii. Two methyl radicals form ethane. .

Heterolytic bond fission If, when the bond breaks, one atom retains both of the electrons from the former covalent bond then an ion pair is formed. H : Br   Note the double-headed arrow showing movement of two electrons. H+ + Br -

Heterolytic bond fission Heterolytic fission is more likely when a bond is already polar. Bromomethane contains a polar carbon-to-bromine bond and under certain conditions this can break heterolytically. + Br -

Heterolytic bond fission It should be noted the CH3+ ion contains a positively charged carbon atom. The CH3+ ion is an example of a carbocation (also called a carbonium ion). Heterolytic fission can lead to the formation of ions containing a negatively charged carbon atom. These ions are called carbanions. Both these types of ions tend to be unstable and highly reactive. Consequently, they only exist as short-lived reaction intermediates.

Heterolytic bond fission In reactions involving heterolytic bond fission, attacking groups are classified as nucleophiles or electrophiles. Nucleophiles Electrophiles Nucleophile means ‘nucleus-loving’. Electron-rich species that seek out electron-deficient sites. Examples: OH− , Cl−, Br−, CN−, NH3, H2O. Atoms or groups of atoms that are attracted to atoms bearing a positive charge. Capable of donating and sharing electrons to form a new bond. May be uncharged molecules or negative ions, but must have at least one lone pair of electrons. Electrophile means ‘electron-loving’. Electron-deficient species that seek out electron-rich sites. Examples: H+, Cl+, Br+, I+, NO2+, CH3+, CH3CO+, SO3. Usually positive ions or uncharged molecules with one atom that has a slightly positive charge. Capable of accepting and sharing electrons to form a new bond.

Heterolytic bond fission The terms electrophile and nucleophile do not apply only to ions. Partial negative and positive charges can be found in polar compounds. These partial charges can also act as electrophilic or nucleophilic centres. Nucleophile Electrophile

Nucleophilic substitution reactions Nucleophilic substitution reactions involve an attacking nucleophile replacing a leaving group. Such substitution reactions fall into two categories: SN1 or SN2 (S = substitution, N = nucleophilic). In order to determine which mechanism applies to an organic compound we must look at the structure of the carbon skeleton.

Which mechanism, SN1 or SN2? If the compound can form a relatively stable positive ion (cation) then the more favoured reaction will be via the SN1 mechanism, while more unstable cations will react via the SN2 mechanism. The more heavily substituted the cations are, the more stable they will be. In the case of haloalkanes, tertiary and some secondary haloalkanes react via the SN1 mechanism because of the bulky groups surrounding the carbon atom.

SN1 mechanism The reaction of 2-bromo-2-methylpropane with hydroxide ions. The slow first step of this mechanism only involves one species (the haloalkane) reacting. This is why it is referred to as an SN1 reaction. The ‘1’ also means it is a first-order reaction (see the unit on physical chemistry). Br- HO-

SN1 mechanism This mechanism forms a true intermediate carbocation, as the cation itself is relatively stable. Once the carbocation is formed it will quickly react with the attacking nucleophile, as its electrons will be highly attracted to the carbocation itself. The carbocation is planar, which suggests that the substitution of the nucleophile could happen on either side, but there is some steric hindrance from the departing bromide ion so the hydroxide slightly favours the opposite side. Br- HO-

SN1 mechanism summary Br- Br- HO- HO-

SN2 mechanism In an SN2 mechanism there are two species involved in the rate-determining step. This type of mechanism is more likely to occur with a primary haloalkane such as bromoethane, as used here. The ‘2’ also means it is a second-order reaction (see the unit on physical chemistry).

SN2 mechanism The hydroxyl group approaches from the side away from the bromine. A five-centred transition state is formed. However, it is a one-step reaction to the product. HO-

SN2 mechanism summary HO-