I’ve written in schoolmarmish tones before about how pKa is one of the most important measures you can learn in organic chemistry, and not knowing some basic pKa values  before an exam is a lot like walking up to a poker table without knowing the values of the hands: you’re going to lose your shirt.

Today we’ll talk about what’s behind the trends in acidity for different molecules and discuss the most important factors that determine these values. Before we get started, however, let’s quickly review the basics of acidity and basicity. Here’s the condensed version:

  1. Bronsted acids are proton donors, Lewis acids are electron pair acceptors. Converse: Bronsted base = proton acceptor, Lewis base = electron pair donor.
  2. A conjugate base is what you obtain when you remove a proton (H+) from a compound. For instance, HO(-) is the conjugate base of water. O(2-) is the conjugate base of HO(-). Conversely, conjugate acids are what you obtain when you add a proton to a compound. The conjugate acid of water is H3O(+).
  3. Quick quiz: is pH 1 acidic or basic? pKa is similar to pH in that low (and even negative values) denote strong acids. That’s because pKa is based on the equilibrium:
  4. According to this, anything which stabilizes the conjugate base will increase the acidity. Therefore pKa is also a measure of how stable the conjugate base is. Put another way, strong acids have weak conjugate bases, and vice versa.

With that out of the way, let’s get started.

Factor #1 – Charge.

Removal of a proton, H+ , decreases the formal charge on an atom or molecule by one unit. This is, of course, easiest to do when an atom bears a charge of +1 in the first place, and becomes progressively more difficult as the overall charge becomes negative. The acidity trends reflect this:

Note that once a conjugate base (B-) is negative, a second deprotonation will make the dianion (B 2-). While far from impossible, forming the dianion can be difficult due to the buildup of negative charge and the corresponding electronic repulsions that result.

Factor #2 – The Role of the Atom

This point causes a lot of confusion due to the presence of two seemingly conflicting trends.

Here’s the first point: acidity increases as we go across a row in the periodic table. This makes sense, right? It makes sense that HF is more electronegative than H2O, NH3, and CH4 due to the greater electronegativity of fluorine versus oxygen, nitrogen, and carbon. A fluorine bearing a negative charge is a happy fluorine.

But here’s the seemingly strange thing. HF itself is not a “strong” acid, at least not in the sense that it ionizes completely in water. HF is a weaker acid than HCl, HBr, and HI. What’s going on here?

You could make two arguments for why this is.  The first reason has to do with the shorter (and stronger) H-F bond as compared to the larger hydrogen halides. The second has to do with the stability of the conjugate base. The fluoride anion, F(–) is a tiny and vicious little beast, with the smallest ionic radius of any other ion bearing a single negative charge. Its charge is therefore spread over a smaller volume than those of the larger halides, which is energetically unfavorable: for one thing, F(–) begs for solvation, which will lead to a lower entropy term in the ΔG.

Note that this trend also holds for H2O and H2S, with H2S being about 10 million times more acidic.

Factor #3 – Resonance.

A huge stabilizing factor for a conjugate base is if the negative charge can be delocalized through resonance. The classic examples are with phenol (C6H5OH) which is about a million times more acidic than water, and with acetic acid (pKa of ~5).

Watch out though – it isn’t enough for a π system to simply be adjacent to a proton – the electrons of the conjugate base have to be in an orbital which allows for effective overlap (for a dastardly trick question in this vein that routinely stymies Harvard premeds, look here.)

Factor #4 – Inductive effects. Electronegative atoms can draw negative charge toward themselves, which can lead to considerable stabilization of conjugate bases. Check out these examples:

Predictably, this effect is going to be related to two major factors: 1) the electronegativity of the element (the more electronegative, the more acidic) and the distance between the electronegative element and the negative charge.

Factor #5 – Orbitals. Again, the acidity relates nicely to the stability of the conjugate base. And the stability of the conjugate base depends on how well it can accomodate its newfound pair of electrons. In an effect akin to electronegativity, the more s character in the orbital, the closer the electrons will be to the nucleus, and the lower in energy (= stable! ) they will be.

Look at the difference between the pKa of acetylene and alkanes – 25! That’s 10 to the power of 25, as in, “100 times bigger than Avogadro’s number”.  Just to give you an idea of scale. That’s the amazing thing about chemistry – the sheer range in the power of different phenomena is awe-inspiring.

There’s actually a mnemonic I’ve found that can help you remember these effects. This is credited to Dr. Christine Pruis, Senior Lecturer at Arizona State University Tempe. 

Charge

Atom

Resonance

Dipole Induction

Orbitals

= CARDIO.

Tread carefully with mnemonics, but there you go.

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{ 40 comments… read them below or add one }

Heero Fong January 12, 2011 at 12:54 pm

I just wanted to say you are doing an absolutely fantastic job of teaching organic chemistry and making it comprehensible. I’ve been reading your posts for the last few days, and material which was alien to me before as finally started to make sense.

Thanks!

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James January 12, 2011 at 7:09 pm

Thanks!

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howaida jouni March 12, 2011 at 4:19 pm

thanks for making org chemistry easier but i have a question about resonance, you didnt mention electron donation or withdrawal by resonance

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James March 13, 2011 at 1:32 pm

That’s a thorny issue… it can be hard to separate the influence of inductive and resonance effects. Do you have a specific example that you’re thinking of?

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Ali October 19, 2011 at 2:36 am

I was the most confused person who could not understand the concept. I read your note. I received 100% on Acidity part on my Exam. Thank you!

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james October 19, 2011 at 3:10 am

This is the kind of comment that makes my day. Thanks!

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Pat November 5, 2011 at 12:03 am

I love this site… I hate reading organic chem txt books because most are boooooring but you make studying for O-chem the highlight of my friday evening… You are funny, and your delivery style is absolutely amazing!! I am in O-chem II, barely made it through the first but I am excelling in my second…. Thank you sir for doing this!! I appreciate it more than you know… Good day!

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Lara February 14, 2012 at 1:24 am

Thank you so much for this summary sheet, I was having so much trouble trying to figure out what made a molecule more acidic – and here it all is! Fully explained and easily understandable. Fantastic stuff.

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Laina March 12, 2012 at 7:06 pm

I just wanted to thank you for all the work you put into this site. I’m an undergraduate at Yale and for the past semester, I’ve been afraid I’ll fail Orgo. Thanks to your site, I no longer feel as stressed because you’ve done such a good job of explaining things. So, yes, thank you!!

Wishing you the best!

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james March 13, 2012 at 8:56 am

Thanks Laina. Glad you find it useful. Let me know if theres anything I can do to make the site more helpful for your needs.

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Ala March 22, 2012 at 6:03 pm

I have a problem where I have to determine the most stable conjugate base, which indicates the strongest acid. I just want to know, is it possible to have a strong acid according to its pKa value, but according to atom, resonance, etc. another acid is stronger?

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james March 23, 2012 at 5:31 pm

pKa represents an experimental measurement. Experimental measurements are primary – the concepts we pull out of them, such as the factors mentioned, are secondary. So what you’re mentioning isn’t possible, assuming all other variables are the same.

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Mariana April 24, 2012 at 7:27 pm

I just don’t seem to understand why does ionic radius increase acidity? I mean, Binding Energy decreases and it’s more easy to lose an electron, if acids are compounds that accept electrons how does acidity increase?

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james April 26, 2012 at 8:16 pm

Basicity is all about the stability of negative charge. With larger atoms, essentially the charge is more spread out over a greater volume. Lower charge densities are more stable. See also here: http://masterorganicchemistry.com/2012/04/25/walkthrough-of-acid-base-reactions-3-acidity-trends/

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Naomi Bowens June 2, 2012 at 3:44 am

I feel sooo much more confident about orgo bc of u =)

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Guvanthi July 29, 2012 at 5:03 pm

All these stuff were very useful to me. Got to know more things that I didn’t know before. Thanks a lot..! Similar article on basicity will be appreciated a lot..!

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Tom August 1, 2012 at 7:22 pm

On the figure describing inductive effects on pKa of carboxylic acids you have bromoacetic acid with pKa of 2.86 on one line and 2.97 on the next. Why the difference?

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james August 6, 2012 at 9:57 pm

Fixed. Thanks for the spot – Evans’ pKa table says 2.86. Not sure where I pulled the 2.97 from.

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Luis Sanchez September 7, 2012 at 12:05 am

This site is so helpful. It makes organic chemistry way easier. Thank you!

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james September 8, 2012 at 7:11 pm

Glad you find it helpful Luis.

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strea September 12, 2012 at 5:34 pm

Oh wow, this is amazing. I was starting to think there was no site/book that had exactly this information, this compactly (and brilliantly, might I add) presented. Thank you so much! You’ve got no idea how much this helped (and how much it reduced my study time, god knows we can all do with extra time on our hands :) ). Thanks again!

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Yash February 20, 2013 at 10:25 pm

This is awesome :D ! I never quite got a hold of this topic since the past 2-3 months and now after reading this page it’s all crystal clear to me ! And as for the mnemonic , when i told it to my chem teacher , he was impressed and asked me for the website :D ! Great job, keep it up :D

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james February 22, 2013 at 3:59 pm

Great, glad you found it useful!

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Annie March 1, 2013 at 7:41 pm

Can you please make these notes available as PDF?

Thanks.

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Akash Sharma April 16, 2013 at 2:38 am

you can use web2pdf for that……
google it…
it also has browser plugin..

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Akash Sharma April 16, 2013 at 2:34 am

Organic is my favourite part in chemistry. Your post and contents provided me a good quick revision before my exams and I did extremely well…..
Thanks to you….you have a good way of teaching organic chemistry..
I would definitely recommend this site to my friends who think organic is boaring subject….
Once again thanks…..

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Chris June 12, 2013 at 10:42 am

I am curious how you came up with this CARDIO acronym? And when? I have heard it from one other person a few years ago.

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james June 19, 2013 at 9:04 pm

I shamelessly stole it from a comment thread on SDN.

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Pegah Biparva June 12, 2013 at 6:53 pm

Did you get the CARDIO acronym from a Dr. Christine Pruis or Chad’s Reviews from Arizona State University? Dr. Pruis is our Organic Chemistry professor and came up with this acronym 7-8 years ago, so perhaps that is the ‘credit’ you speak of? If so, that is awesome!

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Emily September 23, 2013 at 3:26 pm

This was really clear and helpful Thank you so much!!

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James Ashenhurst September 24, 2013 at 10:30 pm

Awesome, glad to hear it.

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vicky October 28, 2013 at 10:18 am

i didnt get 5 point orbital as s character increases then t should be sp3<
sp2<sp

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Hamza January 16, 2014 at 8:09 pm

When trying to choose a compounds with the highest acidity, according to CARDIO, how do you determine which factor you should prioritize first?
For example:
Suppose you’re trying to determine which compound is more acidic, CHCH or benzene ring?
When you remove the proton the benzene ring is stabilized by resonance but the HCC- has a lot of s character in its orbital. How would you determine which compound is more acidic?

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nichole March 6, 2014 at 9:42 am

Just wanted to sincerely thankyou for transforming an extremely difficult subject into something comprehensible and futhermore enjoyable. There’s something to be said for that specific talent and it is greatly appreciated. Your use of acronyms and descriptive context have improved both my labs and test marks.
Thank you.

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Mariah March 12, 2014 at 8:56 pm

do lone pairs count when figuring out the hybridization of an orbital?

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Mariah March 12, 2014 at 9:08 pm

and for factor #5… do we look at the hybridization of the acid or the conjugate base?
ex// ch3 has a hybridization orbital of sp3 but its CB ch2 has a hybridization of sp2

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muhammad shahroz April 14, 2014 at 4:37 pm

Fantastic! What an explanation…. Truely helpful and admirable….

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Em May 5, 2014 at 6:49 pm

Thank you so much! Love reading through everything! You make it so understandable and interesting! I really appreciate the links to more topics too!

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mydoubts2 May 31, 2014 at 4:01 am

why is OH- more basic than SH-. “-” is minus sign

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Kiki June 3, 2014 at 4:17 pm

Thank you so much!! You have made my MCAT studying more a light jog ;)

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