Hydrolysis of Phosphate Esters - Online Tutor, Practice Problems & Exam Prep

Phosphate esters are classified as monoesters, diesters, or triesters based on the number of alkyl groups attached to the phosphate ion (PO₄^3-). Their reactivity towards hydrolysis increases as the charge decreases, with triesters being the most reactive. Saponification of phosphate triesters can occur via two mechanisms: phosphorus-oxygen bond cleavage (nucleophilic acyl substitution) and carbon-oxygen bond cleavage (SN2 substitution). The former involves a penta coordinated complex formation, while the latter is favored with small primary alkyl groups, yielding dialkyl phosphates and alcohols.

Hydrolysis of Phosphate Esters Concept 1

Hey everyone. So let's take a look at phosphate esters. We're going to say depending on the number of alkyl groups, phosphate esters can be of 3 types. Now, first of all, we have just a phosphate ion. Remember, that is just PO₄³⁻.

If we were to draw its Lewis dot structure, we'd have a phosphorus in the center double-bonded to oxygen, single-bonded to three oxygens. It has resonance structures, but this is the general form that we have. When we're talking about our phosphate esters, we're talking about the addition of alkyl groups to these negatively charged oxygens. If there's one R group attached, then it's called a monoester. Now, if there's 2, we're going to say that is a diester.

And then if it's 3, we're going to say that they are triesters. These R groups could be different, or they could be the same. Now here, we're going to say the reactivity of phosphate esters towards hydrolysis increases as the charge on the molecule decreases. That's because you have more R groups present where you can do some type of cleavage. We're going to say when we're talking about reactivity, monoesters will be the least reactive, then we'd have diesters, and triesters will be the most reactive because they have the lowest overall charge.

Right. So just remember, we have our phosphate ion. When we're talking about our phosphate esters, we're attaching R groups to these negatively charged oxygens of the original phosphate ion. We're basically creating more substitution on those oxygens. Alright.

So, we can have monoesters, diesters, and triesters as a result.

Hydrolysis of Phosphate Esters Example 1

Here in this example question, it says, arrange the following compounds from least reactive to most reactive in a saponification reaction. Remember, we said that hydrolysis of a phosphate ester increases as the charge of the molecule decreases. If we take a look here, we have one charge here, we have no charges here, and we have 2 charges here. So reactivity increases as our overall charge decreases. This would mean that if we're taking a look here, that 2 should be the most reactive.

And, actually, we're going from least reactive to most reactive. So 3 would be the least reactive because it has the most charge followed by 1. And then 2 would be the most reactive because it has the lowest overall charge. If we look at our choices, the only one that matches this order would be d. So 3 is the least reactive because it has the most charge, then 1 is more reactive, and 2 is the most reactive because it has the least amount of charge on the molecule.

Hydrolysis of Phosphate Esters Concept 2

Hey everyone. So, in our discussion of the hydrolysis of phosphate esters, we're going to take a look at phosphate triester saponification. Here we're going to say, saponification, again, remember, is basic hydrolysis. We're going to say basic hydrolysis of phosphate triesters can proceed through 2 possible mechanisms. Mechanism 1 deals with a Phosphorus Oxygen Bond Cleavage, and this is just a nucleophilic acyl substitution at the Phosphorus atom.

And then 2, we have a Carbon Oxygen Bond Cleavage. This is an S_N2 substitution at the Carbon atom. Right. So, when we're talking about phosphate trimester saponification, we’re going to be referring to these two possible mechanisms when we're dealing with different types of questions.

Hydrolysis of Phosphate Esters Concept 3

So let's take a look at the first possible mechanism where we are dealing with a Phosphorus oxygen bond cleavage. Here we are going to say similar to the attack on the carbonyl carbon, a nucleophile attacks the phosphorus atom in the Phosphorus oxygen bond cleavage mechanism. Now, the key parts of this type of mechanism involve Step 1: nucleophilic attack, Step 2: loss of leaving group, and then Step 3: proton transfer.

So if we take a look here, we're going to say in step 1, the hydroxide ion (OH^-) attacks the phosphorus atom forming a trigonal bipyramidal intermediate, what we call a penta-coordinated complex, pentamer having 5. So here we have this coming in, hitting this phosphorus and breaking the bond up to the oxygen. So now, here we'd have our phosphorus in the center. It'd be connected to this negative oxygen. We'd have the OH being opposite the negative O.

And then on the same plane, we'd have these three OR groups. So this will represent our penta-coordinated complex or our trigonal bipyramidal intermediate. Now, next step 2, the intermediate collapses and an alkoxide (OR^-) is kicked out. This comes down to make a double bond which kicks out one of these OR groups. So then what we have is our phosphorus double bonded again to oxygen.

We'd have an OR here. We'd have another OR here, and we'd have an OH plus the alkoxide ion that got kicked out. Now the alkoxide ion then deprotonates the protonated Dialkyl Phosphate. So, this oxygen with one of its lone pairs deprotonates this OH group. Oxygen holds on to the electrons making this oxygen negatively charged.

So at the end, we would have this structure, O^- plus an alcohol. So this would be the general mechanism for our phosphorus oxygen bond cleavage.

Hydrolysis of Phosphate Esters Example 2

Everyone, so here it says, what products are formed when the following ester undergoes complete saponification? Complete saponification here just means that we're going to get cleavage happening multiple times. So, in essence, what's going to occur is that all of these OR groups eventually can get kicked out to become alcohol groups. So we would make three types of alcohols.

We'd have, let's see, we'd have a methyl, methanol, another methanol, and then here, this larger alcohol, which is an isopropyl alcohol. So those will be our three alcohols, plus we'd have a phosphate ion. The key to this question, it said complete saponification. We've seen just one of these OR groups being jettisoned to create an alcohol.

But here it says complete saponification, so all three of the OR groups have to be kicked out, jettisoned, removed to become three different alcohols. And then remember what's left behind is a negatively charged oxygen. Doing this gives us a PO4 3- ion at the end and these three alcohol molecules.

Hydrolysis of Phosphate Esters Concept 4

Hey, everyone. So now let's take a look at the Carbon Oxygen Bond mechanism. Here we're going to say the hydroxide ion can also attack our alpha carbon of an alkyl group to give products via the SN2 mechanism. Now, we're going to say a dialkyl phosphate and an alcohol are formed in a single step. So here, we just have step 1 which is nucleophilic attack.

This is our alpha carbon, and next to it is our beta. The hydroxide ion attacks this alpha carbon, and as a result, this bond breaks and oxygen holds onto the electrons. So, we wind up making our Dialkyl Phosphate, which is this structure here with the negative oxygen plus our alcohol. So here we'd have CH₃CH₂OH as the other product. Now, here we're going to say phosphate esters with small primary alkyl halides or unalkyl halides alkyl groups prefer the carbon-oxygen bond cleavage mechanism.

Alright. So we typically see this mechanism coming to the forefront when we're dealing with small primary alkyl groups. Alright. So keep that in mind. That's when we typically see this type of mechanism with our phosphate esters.

Hydrolysis of Phosphate Esters Example 3

If we take a look at the example question, it says, "Write a mechanism for the basic hydrolysis of trimethylphosphate, here for one alkyl group only." Alright. So here we are going to do the carbon-oxygen bond cleavage mechanism. Remember, under this mechanism, the hydroxide ion attacks an alpha carbon.

All of these are methyl groups, so they're all the same. So we can attack any of them. The hydroxide ion comes in, hits one of them, and it causes this bond to break and oxygen to hold onto the electrons. What we end up making is a dialkyl phosphate. We would have methyl connected to oxygen, connected to phosphorus double bonded here.

Same here. We'd have a negative oxygen plus our alcohol that we just created. There would be a methyl group connected to OH. Remember, this type of mechanism is pretty common when we're dealing with a phosphate ester that possesses small, typically primary alkyl groups. What's even smaller than primary alkyl groups?

Methyl groups. Right. So here the hydroxide ion again attacks the alpha carbon causing a break in the bond or doing it via an SN₂ mechanism. So all that's really going on is a nucleophilic attack and the group leaves, creating at the end a dialkyl phosphate plus an alcohol.

Draw the mechanism for the hydrolysis of the benzyl group in benzyl dimethyl phosphate.

In this practice question, it says draw the mechanism for the hydrolysis of the benzyl group and Benzyl Dimethyl Phosphate. Alright. So if we look, the OR groups are not the same for this phosphate ester. But they're telling us specifically which one to target. They're telling us we're gonna have the hydrolysis of the benzyl group. So right here, in this reaction, our hydroxide ion is going to hit this alpha carbon that's part of the benzyl group. So it comes in, hits this carbon, the bond breaks, and the oxygen holds on to the electrons. At the end, we create a dialkyl phosphate. So here goes our dialkyl phosphate, plus an alcohol. So C6H5, that's just benzene. Here, I'm just gonna draw it. And then we have CH2 connected to an OH. So, we created a Benzoyl Alcohol. So, again, the OR groups here are all different. Well, these two are the same, but they're different from this Benzoyl group. I'm specifically telling you we're gonna do hydrolysis of the Benzoyl group. That is the OR group that needs to be kicked out in terms of this phosphate ester. And once we know the right group to kick out, it's just a simple nucleophilic attack via an SN2 mechanism to get to our final product, which again would be a dialkyl phosphate plus an alcohol.

Here’s what students ask on this topic:

What are phosphate esters and how are they classified?

Phosphate esters are organic compounds derived from phosphoric acid (PO₄^3-) by replacing one or more of its hydroxyl groups with alkyl or aryl groups. They are classified based on the number of alkyl groups attached to the phosphate ion. If one alkyl group is attached, it is called a monoester. If two alkyl groups are attached, it is a diester. If three alkyl groups are attached, it is a triester. The reactivity of these esters towards hydrolysis increases as the number of alkyl groups increases, with triesters being the most reactive.

What is the mechanism of phosphorus-oxygen bond cleavage in phosphate triester hydrolysis?

The mechanism of phosphorus-oxygen bond cleavage in phosphate triester hydrolysis involves three main steps. First, a nucleophile, such as a hydroxide ion, attacks the phosphorus atom, forming a trigonal bipyramidal intermediate known as a penta-coordinated complex. Second, the intermediate collapses, and an alkoxide group is expelled. Finally, the expelled alkoxide deprotonates the protonated dialkyl phosphate, resulting in a negatively charged oxygen and an alcohol. This mechanism is similar to nucleophilic acyl substitution at the phosphorus atom.

How does the reactivity of phosphate esters towards hydrolysis change with the number of alkyl groups?

The reactivity of phosphate esters towards hydrolysis increases as the number of alkyl groups attached to the phosphate ion increases. Monoesters, with one alkyl group, are the least reactive. Diesters, with two alkyl groups, have moderate reactivity. Triesters, with three alkyl groups, are the most reactive. This trend is due to the decreasing overall charge on the molecule as more alkyl groups are added, making it easier for nucleophiles to attack and cleave the bonds.

What is the difference between phosphorus-oxygen bond cleavage and carbon-oxygen bond cleavage in phosphate triester hydrolysis?

In phosphate triester hydrolysis, phosphorus-oxygen bond cleavage involves nucleophilic attack on the phosphorus atom, forming a penta-coordinated complex, followed by the expulsion of an alkoxide group. This mechanism is similar to nucleophilic acyl substitution. In contrast, carbon-oxygen bond cleavage involves nucleophilic attack on the alpha carbon of an alkyl group, leading to an SN2 substitution reaction. This mechanism is favored with small primary alkyl groups and results in the formation of dialkyl phosphates and alcohols.

What factors influence the choice of mechanism in phosphate triester saponification?

The choice of mechanism in phosphate triester saponification is influenced by the size and type of the alkyl groups attached to the phosphate ion. Phosphorus-oxygen bond cleavage is more common with larger or more complex alkyl groups, while carbon-oxygen bond cleavage is favored with small primary alkyl groups. The nature of the nucleophile and the reaction conditions, such as the presence of a base, also play a role in determining the preferred mechanism.