Approaching Mechanism
Knowing the basics of electronegativity, bond strengths, acids & bases, pKa values, pH, stereochemistry, and regiochemistry will help to break complex problems down to manageable ideas and processes.
Complexity
If you’ve ever driven into a big city such as New York (or seen Manhattan from the Staten Island ferry like in this image) what you see is a collection of structures of different heights, shapes, and sizes. This is a 2-dimensional view of a very complex entity (part of NYC) that does not give any idea of what’s behind the front buildings and how everything in the city is connected.
This is how students often see mechanism; a bunch of unrelated structures and pathways that they have to memorize in order to pass the Organic sequence. This task is made more manageable with a little organization of the ideas that are picked up in the Organic 1 course. We want to see the aerial “helicopter view” of the city/subject (below) and see how streets connect blocks and individual neighbourhoods in surprisingly simple ways.
The Basics
We need to know about basic topics such as Electronegativity and Bonding, which then leads to an appreciation of Bond Strength and how to spot weak bonds that are likely to be broken in a mechanism.
Understanding Acids and Bases and the pH of the reaction medium will be key. This dictates what is allowed and present in a reaction and what is not.
Being comfortable with where charge prefers to be (negative in anions, positive in carbocations) will help to explain a lot about intermediate structures and product outcomes.
If we are solid on these basics, and know that only a limited number of things can happen as bonds form and break, the bigger mechanisms such as the Claisen condensation shown here become much more manageable.
Know Some Electronegativity values
Periodic table trends are helpful, but actual Electro-negativity values are even more so. What about the Mg to C bond? The trend says that C is more electronegative but by how much? Knowing Mg is 1.2 and C is 2.5 (on the Pauling scale) says this is a very polar covalent bond in which the C is electron-rich and thus reactive. When we get into the weeds, e.g. B and Al in reducing reagents, knowing these numbers will explain the very different reactivities of compounds like NaBH4 and LiAlH4.
Know Some BOND strengths
There is a general relationship between the strength of a bond and the relative atom size and electronegativity of the elements involved. Bonds between atoms of quite different sizes tend to be weak. An example would be C-O (350 kj/mol) and C-S (260 kj/mol) single bonds. Oxygen is directly above sulfur in the periodic table so O is smaller (and closer in size to C) and more electronegative (O = 3.5 vs S = 2.5). The C-S bond is weaker and easier to break. A C-N single bond (290 kj/mol) should be favoured over a C-Br bond (275 kj/mol), which contains a larger bromine. This will be impiortant, for example in SN2 reactions, in which nitrogen nucleophiles can displace Br on alkyl bromide substrates.
In reactions involving double bonds, sigma bonds are generally stronger than pi bonds so addition to pi bonds to produce new single bonds is usually favoured. Many addition reactions are essentially irreversible at room temperature (e.g. hydroboration), partly because of the swapping of a weaker C=C pi bond (270 kj/mol) for (cumulatively) stronger C-H (413 kj/mol) and C-B (372 kj/mol) single bonds. Expect pi bonds to be reactive in many situations.
Bonds formed between atoms that each have at least one lone pair are always going to be weak. Bonds in peroxides (RO-OR) are easily broken (O-O single bond = 146 kj/mol), which correlates with electron repulsion between lone pairs on adjacent O atoms that are close in space. Likewise, the Br-Br bond (193 kj/mol) and Cl-Cl bond (239 kj/mol) will break easily, for example in the initiation step of a radical-based process.
See here for a general discussion of bond strengths.
Know About Acids & Bases
Acid-Base chemistry is where the discussion of mechanism begins in most Organic 1 courses. While this topic is covered in General Chemistry, its application in Organic seems to cause problems as the structures of the acids and bases involved are generally more complicated than the simple examples seen in the first year. The ideas, however, are the same.
Initially we are looking at protic acids in which the H will be bonded to a more electronegative element (e.g. OH in water and alcohols) or a bigger element (e.g. Br in HBr). HBr is a stronger acid than water because the H-Br bond is weaker and easier to break (363 kj/mol, with very different sized atoms) than the O-H bond (467 kj/mol, atoms closer in size), but also because of the relative conjugate base stabilities. Br is much better at dealing with a negative charge (extra electrons) than O because it is bigger and the charge (lone pair) has more volume to occupy. The Br anion is thus much easier to form and is much more stable than hydroxide (and later alkoxide) so this reaction favours the right-hand side completely.
Knowing actual pKa values (examples in the video below) will help in solving acid-base problems quickly. Again, trends are helpful but actual numbers will help us quantify equilibrium constants in individual steps to see if a reaction pathway (mechanism) stands a chance of actually happening. While pKa values are explained by a combination of factors (polarity, anion stability), it is convenient to have a set of numbers that include all of this background for use as a quick tool in problem solving. A more exhaustive list of pKa values will be needed later when we contemplate deprotonating weaker acids such as alkynes and amines.
Be ready for arrow pushing
Knowing what the products are in the reaction between hydroxide and HBr, we can make our first attempt at using curved arrows to show a mechanism that takes account of which bonds are formed and broken. This general idea will be used extensively throughout the Organic sequence. The electron-rich hydroxide base is attracted to the electron-poor proton on H-Br (H EN = 2.1; Br = 2.8) so they interact to begin forming a bond. Since we know only one bond needs to form and one needs to break, we can be sure this won’t be a complicated mechanism. In fact, everything can happen at once in a concerted process, which is confirmed by kinetic data, that shows the reaction to be bimolecular. Two curved arrows only will be needed here to give the following mechanism.
Application in Acid-Base Reactions
So, what have we learned from the NaOH/HBr reaction? Hydroxide is reactive because the extra lone pair (i.e. the negative charge) is on a fairly small atom (O). In the presence of HBr, the hydroxide has a potential vehicle for becoming more stable through reaction. The electron-rich O is attracted to the electron-poor H and an O-H bond starts forming. As the introduction of more electrons breaks the “octet” rule at H, the H-Br bond must begin breaking, which makes sense as it’s weak. The H-Br bond pair of electrons becomes a lone pair on Br, which is able to handle that extra lone pair (i.e. the negative charge) because Br is reasonably electronegative but moreso because Br is large and can handle the four lone pairs. Overall, a weak H-Br bond is sacrificed for a stronger O-H bond and the negative charge ends up in a better place on Br.
This prompts an important question; where does charge (in this case negative charge) want to be? Generally, electronegative atoms prefer holding a negative charge and larger atoms are stable with that extra lone pair. Additionally, electron delocalization (resonance) greatly stabilizes negative charges and contributes to the favourability of certain species in reactions. In acid-base situations, if the charge in one of the bases is able to delocalize, that species will generally form and be favoured. In the example below, hydroxide reacts with the carboxylic acid to give products that are heavily favoured because the negative charge in the conjugate base is able to delocalize.
understand pH
Outside of students just not studying and thus making a hash of mechanisms, more points are lost on mechanistic questions through a lack of understanding of pH than any other topic. This idea is introduced in high school and first year college chemistry classes, yet it becomes obvious at the second year level how little students actually understand about what species will, and will not, be present in a reaction flask at a certain pH level. This doesn’t need to be complicated, and we won’t be doing any calculations, but knowing what is present in base versus acid, and how that dictates mechanism, will clear up a lot of confusion.
For “neutral” read inert or unreactive first in that the substrate itself is unlikely to be attacked as there are no strong acids or bases present. The substrate will have time to “do its own thing” for example by breaking apart in carbocation-based reactions. Consider the SN1 reaction between a tertiary alkyl halide in an alcohol solvent. The pH of the mixture will be neutral when the chemicals are first introduced so there is no strong acid to be attacked or strong base to do the attacking. The alkyl halide is able to collapse to a carbocation, which then attracts the electron-rich O of the alcohol and an ether is formed. In the example below, the stable carboxylic acid does not react with water (or alcohols) at neutral pH as there is nothing that reactive present.
If we can identify the conditions in a reaction as being acidic (sulfuric acid, HBr, generic H3O+, etc.) we already know what is going to happen first; the organic substrate is going to attack the acid and the substrate will become activated. This is of major importance in acid-catalyzed reactions where neutral conditions are not sufficient for reactivity but adding an acid gets things going by activating the organic substrate. This shows up in dozens of mechanisms in Organic 1 and 2 and gives an element of predictability to how pathways unfold. Since we are dealing with a “positive” environment, any intermediates formed during these pathways will be positively charged (oxonium ions, carbocations, etc.).
See the reaction bottom left for an example where the substrate attacks the acid to yield a cationic oxonium ion intermediate, which may react further depending on what else is present. The environment in the bottom right example has changed to strongly basic so the “attacker” and “attackee” change. Now the negative (electron-rich) base can attack the (electron-poor) carboxylic acid proton as a way to become stable through deprotonation. Notice how the mechanism arrows have changed direction in going from acidic to basic conditions. In general, organic substrates attack acids while bases attack organic substrates. This is a reliable indicator of what will happen in other mechanisms in the different pH environments.
A note. In strong acid there cannot be any strong bases and in strong bases there cannot be any strong acids. For example, it is impossible to have hydroxide anion in sulfuric acid, and it is impossible to have H3O+ in hydroxide solution (they would be neutralized immediately). In neutral conditions there are no strong acids or strong bases. Carbocations will not form under basic conditions because the base is likely to attack the substrate quickly before a carbocation can form (e.g. in the E2 process).