STRENGTH OF NUCLEOPHILES (NUCLEOPHILICITY)

The relative rate at which a nucleophile (Nu:-) reacts to displace (substitute for) a leaving group is
called nucleophilicity. Consider the following nucleophilic substitution reactions:
CH3OH + HI CH3I + HOH
CH3OH + HCl CH3Cl + HOH
The first reaction is much faster than the second because I- is a much better Nu:- than Cl-. The
leaving group (HOH) was the same in both cases. The nucleophilicity (relative reactivity) of various
Nu:-s is listed in the following table ...
Reactivity

Nu:-

Relative Reactivity

very weak

HSO4-, H2PO4-, RCOOH

< 0.01

weak

ROH

HOH, NO3-

100

F-

500

Cl-, RCOO-

20 103

NH3, CH3SCH3

~ 300 103

N3-, Br-

~ 600 103

OH-, CH3O-

2 106

CN-, HS-, RS-, (CH3)3P: , I-, H-

> 100 106

fair

good
very good

Note that Nu:-s are electron donors as are Lewis bases and reducing agents. Nu:-s are either
uncharged (with nonbonded electrons) or they are anions, but they are never cations. Nu:-s are
basic, neutral, or sometimes weakly acidic, but not strongly acidic. Strong acids (HCl, H2SO4) and
Lewis acids (AlCl3, SnCl2) are electrophiles (E+s), i.e., electron acceptors as are oxidizing agents.
1. Within any given row of the periodic table, nucleophilicity decreases from left to right as
polarizability decreases (because electronegativity of the central atom is increasing) ...
CH3-

>

NH2-

>

OH-

>

F-

>

NH3

>

OH2

>

HF

PH2-

>

SH

>

Cl-

PH3

>

SH2

>

HCl

2. For nucleophiles with the same attacking atom, the anion is more nucleophilic than the neutral
compound.
Cl- > HCl
OH- > HOH
RO- > ROH
NH2- > NH3
CH3CO2- > CH3CO2 H CN- > HCN
3. Nucleophilicity increases down any column of the periodic table; as the polarizability of atoms
increases ...
NH2-

OH-

F-

increasing nucleophilicity
increasing polarizability

H2P-

HS-

Cl-

H2As-

HSe-

Br-

H2Sb-

HTe-

I-

Note the similarities and differences of nucleophiles and bases ...

Nu:-s and bases are both electron donors
Basicity deals with equilibrium position (Keq). At equilibrium, a stronger base holds a greater
proportion of H+. Nucleophilicity deals with kinetics. A stronger Nu:- attacks faster than a
weaker one.
Basicity deals with interaction with H+ while nucleophilicity is broader and also deals with
interaction with other atoms, especially, but not only C atom.
Polarizability of Nucleophiles:
A polarizable nucleophile, e.g., I-, is large and soft (teddy bear-like) because its valence
(donor) electrons are far from the nucleus (in the 5th period). The electron cloud is readily
distorted during bond making and breaking which reduces the energy maximum in the
transition state and thus speeds up reactions.
A non-polarizable nucleophile, e.g., F- is small and hard (golf ball-like). Its outer valence
electrons are close to the nucleus (in the 2nd period) and tightly held. F- forms strong bonds
but its electron cloud is not easily distorted during bond formation and breaking so its
transition states are high energy (slow reaction).
It is generally true that good nucleophiles are also good leaving groups for the same reasons,
i.e., they are polarizable and stabilize a negative charge (which leaving groups often have).
Efficiency of Leaving Groups:
Groups which best stabilize a '-' charge are the best leaving groups, i.e., the weakest bases
are most stable as anions and are the best leaving groups. These are salts of strong acids
(conjugate bases of strong acids), e.g., HI + H2O I- + H3O+
In the following table, the relative rate at which various groups will leave in a substitution
reaction are listed. Note that the weakest bases (which are least reactive most stable) are
the best leaving groups.
pKb = 23

pKb = 22

pKb = 21

pKb = 11

pKb = -1.7

pKb = -2

pKb = -21

TosO-

I-

Br -

Cl-

F-

HO-

RO-

H2N-

60,000

30,000

10,000

200

Note: F-, OH-, RO-, & NH2- are not displaced by nucleophiles, i.e., they are lousy leaving
groups.

Elimination Often Competes with Substitution:

Strong dehydrating acids (H2SO4, H3PO4) favor elimination (dehydration) in alcohols. Because they are
strong acids, they readily protonate the alcohol thereby converting a poor leaving group (OH-) into a
good leaving group (HOH), however, the anions produced after protonation of the alcohol (HSO4- or
H2PO4-) are very poor nucleophiles and cant replace the leaving group.
CH3CH2-OH

(CH3)2CH-OH +

H2SO4 (catalyst) CH3CH=CH2 + H2O

(CH3)3C-OH

H2SO4 (catalyst)

H 2O

(elimination)
(elimination)

(CH3)2C=CH2 + H2O

(elimination)

Strong non-dehydrating acids (like HI, HBr and HCl) also readily protonate an alcohol creating a good
leaving group (HOH) but with the difference that the resulting Nu:-s (like I-, Br-, and Cl-), are very good
Nu:-s and readily replace the leaving group which results in substitution.
+

HBr

CH3CH2-Br

+ H2O

(substitution)

(CH3)2CH-OH +

HBr

(CH3)2CH-Br + H2O

(substitution)

CH3CH2-OH

(CH3)3C-OH

CH2=CH2

H2SO4 (catalyst)

(CH3)3C-Br

HBr

+ H2O

(substitution)

Very strong bases can cause elimination reactions with alkyl halides because strong hydrohalic acids (HX)
produced by elimination react rapidly and completely with the excess strong base in a neutralization
reaction, as per Le Chatalier. This is especially true with 2 and 3 alkyl halides which are bulky
(hindered) and the Nu:- has difficulty contacting the reactive C atom.
CH3CH2-Cl

CH3O Na+

[CH3CH2-OCH3 + NaCl] & [CH2=CH2 + CH3O-H + NaCl]

(v. strong base)

(CH3)2CH-Cl +

CH3O Na+

~ 20 % sub.
+

~3 % sub.
+

~80% elim.

CH3O Na+ [(CH3)3C-OCH3 + NaCl] & [(CH3)2C=CH2+ CH3OH + NaCl]

3
(CH3)3C-Cl

<10% elim.

[(CH3)2CH-OCH3 + NaCl] & [CH3CH=CH2 + CH3OH + NaCl]

2
(CH3)3C-Cl

> 90 % sub.

Na+CN

~ 97% elim.

(CH3)3C-CN + NaCl

(v. good Nu:-)

(almost all sub.)

What Makes A Good Nucleophile?

by James
in Organic Chemistry 1, Understanding Electron Flow, Where Electrons Are

If you read the last post, youll recall that a nucleophile is a species that donates a pair of electrons
to form a new covalent bond. Nucleophilicity is measured by comparing reaction rates; the faster
the reaction, the better (or, stronger) the nucleophile.
When discussing nucleophilicity were specifically talking about donating a pair of electrons to an
atom other than hydrogen (usually carbon). When a species is donating a pair of electrons to a
hydrogen (more specifically, a proton, H+) we call it a base.
This post attempts to address one of the most vexing question to students of organic chemistry.
What are the factors that make a good nucleophile?
For our purposes, there are at least four key factors contributing to nucleophilicity.
1.
2.
3.
4.

Charge
Electronegativity
Solvent
Steric hindrance

The first two should hopefully be familiar from the discussion of what makes something a strong
base. After all, basicity and nucleophilicity essentially describe the same phenomenon, except
basicity concerns donation of lone pairs to hydrogen, and nucleophilicity concerns donations of lone
pairs to all other atoms. Its the third and fourth points where extra factors come into play.
1. The Role of Charge
Since a nucleophile is a species that is donating a pair of electrons, its reasonable to expect that its
ability to donate electrons will increase as it becomes more electron rich, and decrease as it
becomes more electron poor, right? So as electron density increases, so does nucleophilicity.
A handy rule to remember for this purpose is the following: the conjugate base is always a better
nucleophile.

2. Electronegativity
Assuming an atom has a pair of electrons to donate, the ability of a species to donate that pair
should be inversely proportional to how tightly held it is. The key factor for determining
determi
how
tightly held an electron pair is bound is the familiar concept of electronegativity.
electronegativity Bottom line: as
electronegativity increases, nucleophilicity decreases
decreases.. Note: Its important to restrict application of
this trend to atoms in the same row of the periodic table; for instance, C N O F, or Si P S Cl. Going
down the periodic table, another factor comes into play (next)
3. Solvent
Nucleophilicity is not a property inherent to a given species; it can be affected by the medium its in
(otherwise known
n as the solvent). [For an introduction to the different classes of solvents, click
here]
A polar protic solvent can participate in hydrogen bonding with a nucleophile, creating a shell of
solvent molecules around it like mobs of screaming teenage fans swarming the Beatles in 1962. In
so doing, the nucleophile is considerably less re
reactive;
active; everywhere it goes, its lone pairs of electrons
are interacting with the electron-poor
poor hydrogen atoms of the solvent.

The ability of nucleophiles to participate in hydrogen bonding decreases as we go down the periodic
table. Hence fluoride is the strongest
trongest hydrogen bond acceptor, and iodide is the weakest. This
means that the lone pairs of iodide ion will be considerably more free than those of fluoride,
resulting in higher rates (and greater nucleophilicity).

A polar aprotic solvent does not hydrogen bond to nucleophiles to a significant extent, meaning that
the nucleophiles have greater freedom in solution. Under these conditions, nucleophilicity
correlates well with basicity and fluoride ion, being the most unstable of the halide ions, reacts
re
fastest with electrophiles.

[Often asked: why dont we care about non polar solvents here? Remember like dissolves like?
If we want a reaction to take place, we need to use solvents that will actually dissolve our
nucleophile. Many nucleophiless are charged species (ions) they dont dissolve in non-polar
non
solvents.]
4. Steric hindrance
Since, when discussing nucleophilicity, were often discussing reactions at carbon, we have to take
into account that orbitals at carbon that participate in re
reactions are generally less accessible than
protons are. An effect called steric hindrance comes into play.
The bottom line here is that the bulkier a given nucleophile is, the slower the rate of its reactions
[and therefore the lower its nucleophilicity]
nucleophilicity].
So comparing several deprotonated alcohols, in the sequence methanol ethanol isopropanol tbutanol, deprotonated methanol (methoxide) is the strongest nucleophile, and deprotonated tt
butanol (t-butoxide)
butoxide) is the poorest (or weakest) nucleophil
nucleophile.

Miss anything? Any further questions? Leave a comment below!

Next Post: What Makes A Good Leaving Group?
Note: Are there other factors? Yes. This list of four covers the basics, but several other factors are
worth noting. 1) the identity of the electrophile 2) atoms with lone pairs adjacent to the nucleophile
3) in the case of ions, the identity of the counter-ion [i.e. positively charged species] can be
significant.

Related Posts:

Comparing the SN1 and SN2 Reactions

Nucleophiles and Electrophiles
Steric Hindrance is Like a Fat Goalie
Carbonyl Chemistry: 10 Key Concepts (Part 1)

Tagged as: base, charge, electron rich, electronegativity, leaving groups, lewis bases, nucleophiles,
nucleophilicity, solvent, steric hindrance
{ 41 comments read them below or add one }

Doug Borgman June 28, 2012 at 1:49 am

My understanding with I>F in polar protic solvents wasnt because F has MORE hydrogen
bonding but rather that it is more affected by the hydrogen bonding due to being smaller in
size. Roughly, the larger I ion has the same hydrogen bonds but can still wiggle the
electron pair through them since it is a looser coat of hydrogen bonds
is this correct?
Reply

james June 29, 2012 at 9:23 am

Its correct in that fluoride, being smaller, has a larger charge density, and the interactions
with the partial positive charges on the hydrogen of water will be stronger. Iodide, being
larger, will have a lower charge density and interactions with hydrogen will be weaker. Does
that make sense to you?
Reply

Joseph December 17, 2012 at 8:04 am

Its actually the opposite. Since flourine is smaller, its charge is confined to a smaller space
and it therefore has a higher electron density. Florine is effected by hydrogen bonding more
than Iodine (in polar protic solvents) but the reason is because Florines smaller size makes it
more easily solvated (surrounded by solvent molecules) than iodine so it cant react as well.
Remember that nucleophilicuty is a measure of how well/fast something reacts, while
basicity is a measure of how willing an atom is to give up a lone pair. They are correlated
most of the time but not always.
Reply

Morgan October 24, 2012 at 10:47 am

With the bulkiness, does that have to do with Beta-branching?
Reply

james November 5, 2012 at 2:15 pm

Yes it does.
Reply

Garrett December 15, 2012 at 11:15 pm

How is polarizability related to nucleophilic strength? Would it fit into any of these
categories?
Reply

Joseph December 17, 2012 at 7:59 am

Polarizability plays a role when you take the solvent into account. In polar protic solvents,
hydrogen bonding occurs between the partial positive hydrogen (H attached to N or O
usually) and the nucleophile. Smaller nucleophiles become more solvated than larger

nucleophiles, which means that smaller nucleophiles in polar protic solvents will not be able
to react as well and thus are poorer nucleophiles.
For example, Florine anions become so heavily solvated in polar protic solvents that they
wont even react, but Iodine, being much larger, is much less solvated and can still react.
In aprotic solvents, hydrogen bonding does not occur to any significant extent and the
stronger base is usually the stronger nucleophile.
Reply

mike April 11, 2013 at 2:03 am

THANK YOU!
Reply

PaladinQ March 31, 2013 at 10:34 pm

Excellent post, but
If this list does not take into account all the factors that make a good nucleophile, where is a
more detailed treatment of the ones that are remaining?
Also, in the case of polar aprotic solvents, one may mention the idea of the cation being
solvated, while the anion (nucleophile) less so, and so it is more reactive.
Once again, excellent post.
Reply

james April 1, 2013 at 3:05 pm

Whats missing is hard-soft acid base (HSAB) theory which involves discussion of molecular
orbitals. Ive chosen to defer that discussion for now. One example is the differing selectivity
of enolates for C vs. O alkylation; depending on the nature of the solvent, counter-ion, and
electrophile, either dominant O vs. C alkylation can be achieved. For a discussion Id refer to
Carey and Sundberg but there are many other online sources which discuss HSAB.

Reply

PaladinQ March 31, 2013 at 10:37 pm

Also, I think Polarizability was a factor that may have been missed, or perhaps stated in a
more subtle manner
Reply

Jessica April 2, 2013 at 12:51 am

Hi, I was wondering why (CH3)2N- is better nucleophile than CH3NH- which is better than
H2N-, when (CH3)2N- and CH3NH- has more steric hindrance? I understand that the
presence of electron donating groups (eg. methyl groups) would increase the nucleophilicity,
but how do I know which factor is more important?
Thanks!
Reply

james April 3, 2013 at 12:02 pm

Great question. These types of tradeoffs are what can make organic chemistry difficult. In
advance, its hard to know exactly which factor is most important until you actually see the
results from experiment.
Good discussion here:
http://wavefunction.fieldofscience.com/2010/11/why-are-secondary-amines-mostbasic.html
Reply

Rashika April 8, 2013 at 9:00 am

How do we decide that from anisole, nitrobenzene and benzene, what will be the correct
order of rate of electrophillic substitution? And can you possibly link me to an article related

to it?
PS AMAZING site! You are soon gonna get a lot of Indian visitors. :D
Reply

Jim2013 July 31, 2013 at 7:47 pm

Hello,
Is it accurate to say that primary amines are more strongly nucleophilic than carboxylic
acids? I presume this is so given the charge delocalization in COO- and the steric hindrance in
COOH. Do you happen to know of a reference in the literature that compares these two
species nucleophilicity?
Many thanks for your help and time.
Jim
Reply

Matheus October 10, 2013 at 11:41 am

Bottom line: as electronegativity increases, nucleophilicity decreases
Under these conditions, nucleophilicity correlates well with basicity and fluoride ion,
being the most unstable of the halide ions, reacts fastest with electrophiles.
Which one is it? It seems to me that you are contradicting yourself and making me more
confused than I was previous to visiting this page
Reply

James Ashenhurst November 14, 2013 at 10:20 am

Maybe I should have made this clearer. Its consistent if you consider that nucleophilicity
increases with basicity EXCEPT in the case of polar protic solvent, in which nucleophilicity
increases with polarizability.
Basicity: CH3(-) > NH2(-) > HO(-) > F(-) and F(-) > Cl(-) > Br (-) > I(-) [in polar aprotic solvents].
Reply

Anna Moravec May 21, 2014 at 5:33 pm

I dont understand why F(-)>Cl(-)>Br(-)>I(-)
Electronegativity decreases down a group, so shouldnt nucleophilicity increase down the
group?
SO CONFUSED!
Reply

Frances August 28, 2014 at 5:29 am

The electronegativity decreases, nucleophilicity increases rule applies only to atoms within
the SAME ROW in the periodic table. Also, that rule only applies for polar protic solvents. F(-)
tends to H-bond with the solvent more, making it less reactive as a nucleophile, as compared
to a nucleophile containing carbon.
The reverse of the rule is what actually applies in polar aprotic solvents. Since the solvent
does not H-bond to the halide nucleophiles, fluorine basically becomes the most reactive
among the halides.
It took me way too long before I finally understood this whole nucleophile thing, but I hope
my answer helped.
Reply

Abhishek November 14, 2013 at 7:19 am

is boron quadfluoride a nucleophile
Reply

James Ashenhurst November 14, 2013 at 10:14 am

What do you think? What atom(s) on BF4(-) could donate a pair of electrons?

Reply

sarah December 23, 2013 at 6:33 am

Hi,
This was very helpful, but Im still confused about 1 thing, how is fluorine a better base than
iodine but a worse nucleophile?
Reply

James Ashenhurst December 27, 2013 at 12:55 am

In polar protic solvents (and only in polar ptotic solvents) fluorines strong Lewis basicity
helps it form very strong hydrogen bonds with the solvent. The resulting shell of solvent
molecules around fluorine acts to hinder fluorine and therefore makes it a poorer
nucleophile. Iodine does not form strong hydrogen bonds and therefore is not accompanied
by a large solvent shell, so it is less hindered in polar protic solvents and thus a better
nucleophile.
Reply

Katie January 19, 2014 at 10:33 am

Does good nucleophilies have anything to do with hard/soft base?
Reply

Bk February 19, 2014 at 10:14 am

Hi, I came across a question asking Which is the stronger base? Pyridine or Morpholine? Is
it the same as asking which is the stronger nucleophile? Anyway, I think the answer is
morpholine but I do not know how to explain it. Could anyone please help me on this?
Reply

Hamada Abulkhair November 14, 2014 at 11:11 am

I expect that, in pyridine nitrogen atom surrounded by three bons all of them with carbon
atoms while in morpholine there are three bonds two of them with crbon and the thired one
with hydrogen which is lower electronegative than carbon so the availability of unshered
electron pair in morpholine more than that in pyridine.
Reply

Hawers March 9, 2014 at 12:28 pm

in sn2 reaction know why we use polar aprotic solvent, but under which conditon the
reaction may retard? I mean which polar aprotic solvent may retard reaction ?
Reply

Mannat May 26, 2014 at 2:36 am

Can u explain finkelsteins reaction on the basis of the effect of polar Aprotic solvents on Nu
?
Reply

James May 26, 2014 at 3:41 pm

No, Finkelsteins reaction goes forward because NaI is soluble in acetone, whereas NaCl
precipitates out. That drives the equilibrium forward.
Reply

liangyy July 17, 2014 at 12:55 am

You mean only hindrance effect make basicity and nucleophilicity different?
Reply

James July 22, 2014 at 10:00 pm

Not quite. Acidity/basicity is measured by equilibrium constant, whereas nucleophilicity is
measured by reaction rate (since the vast majority of substitution reactions are not
reversible). But steric hindrance (due to the fact that a sigma star orbital is being attacked on
carbon, versus an S orbital on hydrogen) is the key difference.
Reply

Lauren September 20, 2014 at 4:19 pm

Hello!
My question is why flouride ion behaves as a strong nucleophile in aprotic polar solvent
when nucleophilisity is related to polarizability. any specie that is more polarizable tends to
be a good nucleophile. Then why not iodide is a strong nucleophile in aprotic polar solvent
and also iodide is less electronegative than fluoride so it should easily donate its lone pair of
elctron
Reply

Mariam Sanah November 21, 2014 at 1:03 pm

Because Iodine has a VERY big electron cloud. It does not prefer to accommodate any other
atom with it. Therefore fluoride is a better nucleophile than iodide.
Reply

symara October 11, 2014 at 10:25 am

Hi! It says in my textbook that in methanol, RS- is a better nucleophile than iodide. This is
something I didnt get it. I mean, sulfur is smaller and the R group is probably making it more
basic by electron-donating effect, thus making it a stronger base. This means that RS- should
be the most solvated one and therefore less nucleophilic. But according to Ms. Paula Bruice,
no, RS- is the better one.
By the pka table, HI is a stronger acid than RSH. So, RS- would still have the stronger base,
that would still be more solvated. I really dont get it. When I think I got it, I didnt. I used to

like Ochem a lot, but now I think I will never undestand it and it bums me out.
Another thing, in a SN2 reaction, ammonia is the nucleophile and it is asked which solvent
will make the reaction faster: ether or ethanol. I would say ethanol, because it would
stabitize the transition state by solvation, right? But, no, according to my professor, ether
would be the best one because it would not make hydrogen bonds to ammonia. Now I dont
know if I must consider transition states, and solvents stabilizing carbocations or just the
nucleophile and hydrogen bonding.
Please, help.
Reply

James October 12, 2014 at 1:53 pm

Hi Symara there are many factors involved in nucleophilicity. Its not a simple, one-variable
equation.
Hydrogen bonding is most important for atoms O, N, and F (because of the large difference
in electronegativity between these atoms and H). When you compare that to S
(electronegativity 2.6) there just isnt much hydrogen bonding going on so it shouldnt affect
nucleophilicity. So the above answer (RS- beats I-) and ether being a better solvent than
ethanol probably makes the most sense.
As an aside, when talking about different variables like basicity or polarizability it is much
clearer if you are going across a row or up and down a column of the periodic table. For
example, compare polarizability going down (F- Cl- Br- I- ) or basicity going across (H3C- H2NHO- F- ). Comparing both at once (e.g. Cl- and H2N- ) really requires looking at experimental
evidence.
Reply

Seung October 11, 2014 at 6:16 pm

Being challenged, need reasons why H2O instead of Br- became nucleophiles. Textbooks
with huge price tags just presents drawings of kind of skeletons, H2O and arrows.
Here I get it.
Thank you James.
Reply

Victor B. November 21, 2014 at 12:39 pm

Great article! But I still have a question. I understand now how one nucleophile can be
stronger or weaker than another, but what would you consider to be (absolutely) strong?
Just because one nucleophile is stronger than another does not mean they both cannot be
weak nucleophiles, I think. What are the cuttoff points for strong nucleophiles that would be
able to partake in SN2 reactions?
Reply

James December 2, 2014 at 7:53 am

We can come up with a good general scale for acidity, which can be measured by equilibria.
Nucleophilicity is a bit trickier because the reactions are irreversible and were measuring
rates. The rate of the reaction is a combination of orbital overlap and charge density and by
changing conditions (like solvent, reagent, etc) we can also affect nucleophilicity.
The classic example is the reaction of enolates. Under different conditions either the O or
the C of the enolate can be the best nucleophile.
Later on in organic chemistry the topic of hard soft acid base theory is covered which helps
to explain some of these mysteries.
Reply

Stephano December 1, 2014 at 11:34 am

Hi every one
I know -OH has more electronegativity than -NH2 , also increasing electronegativity
decreases the lone pair availability; I think the lone pair on the nitrogen atom is more
available to resonance with phenyl ring (because the above reason), so if lone pair of the NH2 is shared in the resonance, the lone pair of -OH is free to play a nucleophilic role.
But in many reactions -NH2 is the nucleophile (sometimes -OH is nucleophile and sometimes
both of them play this role). (http://www.chemsink.com/list_reactions/7/403/1/1/)
Is there any convincing reason? please explain with details.
Reply

Cat December 2, 2014 at 12:45 am

This saves my life! Very clear and helpful, thanks a lot!
Reply

waqar baig January 28, 2015 at 11:16 am

How can we differentiate between a nucleophile and a base? e.g KOH in aquous and in
alcoholic medium has two opposite effect one as a nucleuphile and other as a base why? I
have heard that alcoholic medium increases its basic strength but how ???
Reply
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Four Factors to Consider in Determining the Relative Ease at which SN2 Displacement
Occurs

1.
2.
3.
4.

The nature of the leaving group (SN2 Reactions-The Leaving Group)

The reactivity of the nucleophile (SN2 Reactions-The Nucleophile)
The solvent (SN2 Reactions-The Nucleophile)
The structure of the alkyl portion of the substrate (SN2 Reactions-The Substrate)

The Reactivity of the Nucleophile

Now that we have determined what will make a good leaving group, we will now consider
nucleophilicity. That is, the relative strength of the nucleophile. Nucleophilicity depends on many
factors, including charge, basicity, solvent, polarizability, and the nature of the substituents.

Increasing the Negative Charge Increases Nucleophilicity

Nucleophiles can be neutral or negatively charged. In either case, it is important that the
nucleophile be a good Lewis base, meaning it has electrons it wants to share. The following diagram
is just a reminder of some of the nucleophiles that were presented in the section covering
nucleophilic substitution. In looking at these two types of nucleophiles, you should notice that a
reactive atom, such as oxygen, in a neutral species can also be a reactive atom in a negatively
charged species. For example, the O in OH- is negatively charged, but the O in H2O is neutral.

It has been experimentally shown that a nucleophile containing a negatively charged reactive atom
is better than a nucleophile containing a reactive atom that is neutral. The next diagram illustrates
this concept. Notice that when oxygen is part of the hydroxide ion, it bears a negative charge, and
when it is part of a water molecule, it is neutral. The O of -OH is a better nucleophile than the O of
H2O, and results in a faster reaction rate. Similarly, when nitrogen is part of NH2, it bears a negative
charge, and when it is part of NH3, it is neutral. The N of NH2 is a better nucleophile than the N of
NH3, and results in a faster reaction rate.

When Moving Across a Row, Nucleophilicity Follows basicity

To say that nucleophilicity follows basicity across a row means that, as basicity increases from right
to left on the periodic table, nucleophilicity also increases. As basicity decreases from left to right on
the periodic table, nucleophilicity also decreases. When it comes to nucleophilicity, do not assign
this same rule when making comparisons between the halogens located in a column. In this case of
moving up and down a column, nucleophilicity does not always follow basicity. It depends on the
type of solvent you are using.

In the section Nucleophilic Substitution, we assigned a relationship to leaving groups containing C,

N, O, and F, showing that the strength of the leaving group follows electronegativity. This is based
on the fact that the best leaving groups are those that are weak bases that do not want to share
their electrons. The best nucleophiles however, are good bases that want to share their electrons
with the electrophilic carbon. The relationship shown below, therefore, is the exact opposite of that
shown for the strength of a leaving group.

Solvents and Nucleophilicity

In general chemistry, we classified solvents as being either polar or nonpolar. Polar solvents can be
further subdivided into protic and and aprotic solvents.

Protic Solvents
A protic solvent is a solvent that has a hydrogen atom bound to an oxygen or nitrogen. A few
examples of protic solvents include H2O, ROH, RNH2, and R2NH, where water is an example of an
inorganic protic solvent, and alcohols and amides are examples of organic solvents. The diagram
below shows a few examples of protic solvents we will see.

Since oxygen and nitrogen are highly electronegative atoms, the O-H and N-H bonds that are
present in protic solvents result in a hydrogen that is positively polarized. When protic solvents are
used in nucleophilic substitution reactions, the positively polarized hydrogen of the solvent
molecule can interact with the negatively charged nucleophile. In solution, molecules or ions that
are surrounded by these solvent molecules are said to be solvated. Solvation is the process of
attraction and association of solvent molecules with ions of a solute. The solute, in this case, is a
negatively charged nucleophile.
The following diagram depicts the interaction that can occur between a protic solvent and a
negatively charged nucleophile. The interactions are called hydrogen bonds. A hydrogen bond
results from a from a dipole-dipole force between between an electronegative atom, such as a
halogen, and a hydrogen atom bonded to nitrogen, oxygen or fluorine. In the case below, we are
using an alcohol (ROH) as an example of a protic solvent, but be aware that this interaction can
occur with other solvents containing a positively polarized hydrogen atom, such as a molecule of
water, or amides of the form RNH2 and R2NH.

Why is this important? Solvation weakens the nucleophile; that is, solvation decreases
nucleophilicity. This is because the solvent forms a "shell" around the nucleophile, impeding the
nucleophile's ability to attack an electrophilic carbon. Furthermore, because the charge on smaller
anions is more concentrated, small anions are more tightly solvated than large anions.
The picture below illustrates this concept. Notice how the smaller fluoride anion is represented as
being more heavily solvated than the larger iodide anion. This means that the fluoride anion will be
a weaker nucleophile than the iodide anion. In fact, it is important to note that fluoride will not
function as a nucleophile at all in protic solvents. It is so small that solvation creates a situation
whereby fluoride's lone pair of electrons are no longer accessible, meaning it is unable to participate
in a nucleophilic substitution reaction.

Previously we learned how nucleophilicity follows basicity when moving across a row. In our
discussion on the effect of protic solvents on nucleophilicity, we learned that solvation weakens the

nucleophile, having the greatest effect on smaller anions. In effect, when using protic solvents,
nucleophilicity does not follow basicity when moving up and down a column. In fact, it's the exact
opposite: when basicity decreases, nucleophilicity increases and when basicity increases,
nucleophilicity decreases.

Aprotic Solvents
An aprotic solvent is a solvent that lacks a positively polarized hydrogen. The next diagram
illustrates several polar aprotic solvents that you should become familiar with.

Aprotic solvents, like protic solvents, are polar but, because they lack a positively polarized
hydrogen, they do not form hydrogen bonds with the anionic nucleophile. The result, with respect
to solvation, is a relatively weak interaction between the aprotic solvent and the nucleophile.
The consequence of this weakened interaction is two-fold. First, by using an aprotic solvent we can
raise the reactivity of the nucleophile. This can sometimes have dramatic effects on the rate at

which a nucleophilic substitution reaction can occur. For example, if we consider the reaction
between bromoethane and potassium iodide, the reaction occurs 500 times faster in acetone than
in methanol.

A second consequence that results from the weak interaction that occurs between aprotic solvents
and nucleophiles is that, under some conditions, there can be an inversion of the reactivity order.
An inversion would result in nucleophilicity following basicity up and down a column, as shown in
the following diagram. When we considered the effects of protic solvents, remember that the
iodide anion was the strongest nucleophile. Now, in considering aprotic solvents under some
conditions, the fluoride anion is the strongest nucelophile.

Increasing Atomic Size Increases Nucleophilicity

Thus far, our discussion on nucleophilicity and solvent choice has been limited to negatively charged
nucleophiles, such as F-, Cl-, Br-, and I-. With respect to these anions we learned that, when using
protic solvents, nucleophilicity does not follow basicity, and when using aprotic solvents, the same
relationship can occur, or there could be an inversion in the order of reactivity.

What happens as we move up and down a column when considering uncharged nucleophiles? It
turns out that, in the case of uncharged nucleophiles, size dictates nucleophilicity. This is because
larger elements have bigger, more diffuse, and more polarizable electron clouds. This cloud
facilitates the formation of a more effective orbital overlap in the transition state of bimolecular
nucleophilic substitution (SN2) reactions, resulting in a transition state that is lower in energy and a
nucleophilic substitution that occurs at a faster rate.

Sterically Hindered Nucleophiles React More Slowly

In the section Kinetics of Nucleophilic Substitution Reactions, we learned that the SN2 transition
state is very crowded. Recall that there are a total of 5 groups around the electrophilic center.

For this reason, sterically hindered nucleophiles react more slowly than those lacking steric bulk.

Next section: SN2 Reactions-The

The Substrate

Contributors

Rachael Curtis (UCD)

ntroduction:
The most important variable in dec
deciding
iding between SN1, SN2, E1, and E2 mechanisms is the
structure of the alkyl halide (R
(R-X). However, the second deciding variable is the strength of
the nucleophile/base. For this class, I have tried to simplify this decision by putting all the
nuc/bases into
nto one of four categories. I have also ignored solvent effects which can change
and complicate these reactivity trends.

How to:
1) Nuc/Base Strengths. The easiest categories to recognize are the strong/strong and
weak/weak categories. These follow the general correlation between basicity and
nucleophilicity. The more difficult categories are the weak/strong and strong/weak because
they deviate from this correlation.
2) Descriptions and explanations of the four categories.

examples of weak bulkyy nucleophiles that are strong bases (weak/strong)

(i) Strong/strong. In general, good bases are also good nucleophiles. Therefore, strong bases
such as negatively charged oxygens and nitrogens will also be strong nucleophiles.
Note, not all negatively charged oxygen and nitrogen nuc/bases fall into the strong/strong
category. These exceptions populate the weak/strong and strong/weak categories.

(ii) Weak/weak. In general, weak bases are also weak nucleophiles. Therefore, weak bases
such as neutral oxygens with a proton will also be weak nucleophiles.
Weak/weak nuc/bases are usually also the solvent for their reactions. This makes sense as
they are so weak that you need a lot of the nuc/base to facilite the substitution or
elimination reaction.
(iii) Weak/strong. One exception to strong bases also being strong nucleophiles is for very
bulky nuc/bases. SN2 reactions are particularly sensitive to the size of the nuc/base because
they proceed via a crowded transition state. Elimination reactions are
re less sensitive to the
size of the nuc/base since the beta
beta-hydrogen
hydrogen is sticking out and is easy to access.
Therefore, a very bulky (large) nuc/base can be a weak nucleophile while still being a
strong base. We will only learn two nuc/bases that fa
fallll into this category. They are
potassium tert-butoxide
butoxide (KOt
(KOt-Bu) and lithium diisopropyl amide (LDA). The structures of
these two weak/strong nuc/bases are shown below.
(iv) Strong/weak. These nuc/bases fall into two general categories that will reduce their
basicity:

i) Neutral nuc/bases that have lone pairs on less electronegative atoms such as nitrogen,
sulfur, and phosphorous. These include amines, thiols and phosphines.
(ii) Negatively charged nuc/bases that are stabilized by resonance or have a negative charge
on a large atom such as sulfur or iodine.
) Descriptions and explanations of the four categories.

examples of weak bulky nucleophiles that are strong bases (weak/strong)

(i) Strong/strong. In general, good bases are also good nucleoph
nucleophiles. Therefore, strong bases
such as negatively charged oxygens and nitrogens will also be strong nucleophiles.