CSUMB
ESSP 311 Organic Chemistry I
Ronald W. Rinehart, Ph.D.

Chapter 8 Nucleophilic Substitution

Substitution and Elimination Reactions of alkyl halides
by Paul R. Young at the University of Illinois, Chicago
http://www.chem.uic.edu/web1/OCOL-II/WIN/CH11/F2.HTM webtext
http://www.chem.uic.edu/web1/PDF/CH6.PDF PowerPoint-type slides

http://www.bluffton.edu/~bergerd/classes/CEM221/sn-e/home.html
Animations of SN1 and SN2 mechanisms by Daniel A. Berger of Bluffton College are at
http://www.bluffton.edu/~bergerd/classes/CEM221/sn-e/SN1-1.html
http://www.bluffton.edu/~bergerd/classes/CEM221/sn-e/SN2-1.html
Animations of SN1 and SN2 mechanisms by Jennifer Muzyka at Centre College
http://web.centre.edu/muzyka/organic/organic.htm > Substitution and Elimination
http://web.centre.edu/~muzyka/organic/sn1/main.htm
http://web.centre.edu/~muzyka/organic/sn2/main.htm
Nucleophilic Substitution by Gary Trammell and Srinivas Vuppuluri at the University of Illinois at Springfield
http://people.uis.edu/gtram1/organic/alkylHalides/nucleophilicsubstitution.htm 
http://people.uis.edu/gtram1/organic/alkylHalides/sn1.htm
http://people.uis.edu/gtram1/organic/alkylHalides/sn2.htm 
http://people.uis.edu/gtram1/organic/alkylHalides/substitutionAndElimination.htm 
Nucleophilic Substitution Mechanisms Menu by Jim Clark, Cornwall UK
http://www.chemguide.co.uk/mechanisms/nucsubmenu.html#top
Mechanisms of Nucleophilic Substitution Reactions by William Reusch at Michigan State University
http://www.cem.msu.edu/~reusch/VirtualText/alhalrx2.htm#hal4
From Brent Iverson at the University of Texas, Austin:
SN2 QuickTimemovie with written commentary
http://www.cm.utexas.edu/academic/courses/Fall2001/CH610A/Iverson/reaction%20movies/IVERSON/SN2HOME2.HTM
Table of Nucleophiles
http://www.cm.utexas.edu/academic/courses/Fall2001/CH610A/Iverson/potd/potdGIFS/toNUC.gif
Substitution vs Elimination "decision map"
http://www.cm.utexas.edu/academic/courses/Fall2001/CH610A/Iverson/potd/potdGIFS/SubElim.gif
SN1 and SN2 reaction mechanisms by Arthur Winter at Frostburg State U, MD
http://www.chemhelper.com/sn1.html
http://www.chemhelper.com/sn2.html
really nice SN1 and SN2 Chime tutorials from Mol4D, U Nijmegen, Netherlands
http://www.cmbi.kun.nl/wetche/organic/sn1/
http://www.cmbi.kun.nl/wetche/organic/sn2/
SN1 vs SN2 Shockwave tutorial from Colby College
http://www.colby.edu/chemistry/OChem/DEMOS/Substitution.html
Electrophiles and Nucleophiles by Steven Hardinger at UCLA
http://web.chem.ucla.edu/~harding/tutorials/elec_nuc/elec_nuc.html
SN2 Reaction Mechanism by Abby L. Parrill and Jacquelyn Gervay at the University of Arizona
http://www.cem.msu.edu/~parrill/sn2.html
Nucleophilic Substitution by Roberta W. Kleinman at Lock Haven University of PA
http://www.lhup.edu/~rkleinma/Chem220/  > CH 7
Carey PowerPoint slides for chapter 8 from Columbia University
intro
   http://www.columbia.edu/itc/chemistry/c3045/client_edit/ppt/08_01_02.html 
SN2   http://www.columbia.edu/itc/chemistry/c3045/client_edit/ppt/08_03_06.html
nucleophiles  http://www.columbia.edu/itc/chemistry/c3045/client_edit/ppt/08_07.html 
SN http://www.columbia.edu/itc/chemistry/c3045/client_edit/ppt/08_08_12.html 
subst vs elim   http://www.columbia.edu/itc/chemistry/c3045/client_edit/ppt/08_13.html
tosylates, ROH  http://www.columbia.edu/itc/chemistry/c3045/client_edit/ppt/08_14_15.html 
 
 
 

Chapter 8:  Nucleophilic Substitution Reactions 

I.  Review of SN1 and SN2

            A. SN1
                        1.   Substitution Nucleophilic Unimolecular
                                    a)  First-order kinetics are observed. 
                                    b)  Carbocation intermediates are involved.
                                    c)  Rearrangements can occur.
                                    d)  Racemic mixtures result from the reaction of optically active reactants. 

            B. SN2    
                        1.  Substitution Nucleophilic Bimolecular
                                    a)         Second-order kinetics are observed.
                                    b)         Inversion of configuration is observed. 

II. Reactions of Alkyl Halides (X = F, Cl, Br, I)  
            A.  Functional Group Transformations
                        1.  Alkyl halides can be converted to various types of compounds:
                                    a)  Ethers  R-O-R'
                                    b)  Thiols  R-S-H
                                    c)  Nitriles (Alkyl cyanides)  R-CN
                                    d)  Alkyl Azides   R-N3
                                    e)  Other alkyl halides (RF, RI)
                                    f)  Alcohols 

            B.  Reactions With:
                        1.  Metal Alkoxides:
                                    a)  Alkoxide Ion RO 
à  ETHERS 
                                    R'O  +  R-X 
à    R'-O-R  +  X    The Williamson ether synthesis
                                                                  ether 

                                    b) Example

                         2.  Metal Hydrosulfide: 
                                    a)  Hydrosulfide Ion HS  
à  THIOLS 
                                                HS
  +  R-X  à  RSH  +  X 
                                                                          Thiol

                                     b)  Example:

                        3.   Metal Cyanides: 
                                    a)   Cyanide Ion CN  
à  Alkyl Cyanide    (Nitriles)
                                    :N≡C:  +  R-X 
à     RC≡N:       +  X
                                                                alkyl cyanide

                                     b)   Example

                         4. Metal Azides: 

                                    a)  Azide Ion N3      à   Alkyl Azides      
                                                RX   +   N3
   à                       RN3
                                                            Azide Ion                   Alkyl Azide    

                                    b)  Example

             C.  Solvents.

                        1.  Solvents used in the above reactions must dissolve both the nonpolar alkyl halide and the ionic
                                     nucleophile.
                        2. Two solvent systems which work are:
                                    a)   alcohol/water
                                    b)  DMSO 

            D. Substitution of One Halogen By Another:  Halide-Halide Exchange

                        1.  We already have methods for making R-Cl and R-Br, but we are limited in making R-F and R-I. 
                        2.  We will make use of Le Chatelier's Principle to make these types of compounds.
                        3.  Synthesis of R-F. 

                                    a)   Example 1.


                                    b)  Example 2.

                                    c)  The synthesis of alkyl fluorides takes advantage of the fact that alkyl fluorides
                                        have a lower boiling point than the corresponding alkyl chloride, bromide, or iodide.
                                                i)  Distillation of the product  fluoride drives the reaction toward products. 

                        4.  Synthesis of R-I

                                    a) The production of an alkyl iodide takes advantage of the fact that NaI is soluble in acetone,
                                        whereas the corresponding chloride and bromide are not.
                                    b)  Formation of the insoluble NaCl or NaBr drives the reaction towards the formation of product.

 III.  Mechanisms 

            A.  SN2:  Substitution Nucleophilic Bimolecular
                        1.  Example. 

                                    HO  +  CH3-Br  à  [HO...CH3...Br] à  HOCH3 + Br  [slow, one step]

                        2. Evidence for the SN2 Mechanism:
                                    a.  2nd order kinetics.
                                    b.  Inversion at the chiral center.

                                     c.  Example.

                         2.  Steric Effects on SN2 Reactions.
                                    a) Steric Effects of Alkyl Halide:  The ease of approach by the nucleophile depends upon steric
                                                hindrance:

 

Alkyl Halide

Type

Relative Rate of Reaction

CH3-X

Methyl

3,000,000

CH3CH2-X

1o

100,000

CH3CH2CH2-X

1o

40,000

(CH3)2CH-X

2o

2,500

(CH3)3C-CH2-X

1o (neopentyl)

1

(CH3)3C-X       

3o

~0

                                 b) Order of Reactivity of RX:   CH3 > 1o > 2o >> neopentyl > 3o 

                        3.  Steric Effects of Nucleophile
                                    a) In general, the stronger the base the better the nucleophile.

                                                i)   t-Butoxide is a stronger base than ethoxide, but the BULKY t-butoxide ion is a weaker
                                                            nucleophile.

                                                ii)  Steric hindrance has little effect on basicity since basicity involves attack on an unhindered                                                                    proton.

                                                iii) This is not the case with a  nucleophilic attack on the carbon atom.                                                                                                                       

                                    b) The general rule of increasing basicity corresponding to increasing nucleophilicity is observed
                                                with bases on the same period:

                                                              NH2   >  OH  >     F

                                                    most basic                    least basic
                                                best nucleophile            worst nucleophile 

                                                i)  This is not observed going down a group: 

                                                                I     >             Br      >    Cl        >               F

                                                            least basic                                                         most basic
                                                      best nucleophile                                                    worst nucleophile

                                     c)  The azide ion, N3, is an example of a very good nucleophile which is not a strong base. 

                        4.   Solvent Effects on SN2 Reactions.
                                    a)  MeOH and EtOH are often used as solvents since they are:
                                                i)  inexpensive.
                                                ii)  easily removed after reaction.  
                                    b)   BUT: many SN2 reactions are slowest in  PROTIC solvents since H-bonds stabilize and decrease
                                                the reactivity of the nucleophile since the solvent molecules form a cage around the nucleophile.
                                    c) Solution:  use POLAR APROTIC solvents. Valuable polar aprotic solvents include:


acetonitrile

 


MeCN

 




 

dimethylformamide

DMF

dimethyl sulfoxide

DMSO

hexamethylphosphoramide

HMPA

                                                 i)   Since these solvents are aprotic, they do not form hydrogen bonds.

                                     d)  The data below shows the effect of solvents on an SN2 reaction:   

CH3CH2CH2CH2Br +  N3  à  CH3CH2CH2CH2N3  +  Br 

Solvent

Relative Reaction Rate

MeOH

1

H2O

6.6

DMSO

1,300

DMF

2,800

MeCN

5,000

HMPA

200,000

                        5.  The identity of the attacking nucleophiles is very important in SN2 reactions.

                                   a)  Any Lewis base, neutral or anionic, can be a nucleophile. 

                        6.  As mentioned earlier, when comparing nucleophiles with the same attacking atom,
                                     nucleophilicity (roughly) parallels basicity
                                    a)  Table 8-1 illustrates this trend. 

            Table 8-1:  Nucleophilicity and Basicity

Nucleophile

Rel. Nucleophilicity
Towards CH3Br

Conjugate Acid

pKa

EtO

25,000

EtOH

16

OH

16,000

H2O

15.7

PhO

8,000

PhOH

10

CH3CO2

500

CH3CO2H

4.8

H2O

1

H3O+

-1.7

                                         b)  Looking at the above table one can see that as you go down the table, basicity DECREASES and
                                                 nucleophilicity DECREASES.

 

                        7. Nucleophilicity increases down a column on the periodic table.
                                    a)  Among the halide ions, I is the most nucleophilic.   I  >  Br  >  Cl  >  F
                                    b)  The same trend is observed in Group VI:   HS  >  HO
                                    c)  This is the reverse of the first trend (comparing base strength with  nucleophilicity) and is
                                                probably due to a solvation phenomena.
                                                i)  Smaller anions are more highly solvated, which inhibits them from acting as a nucleophile.

                Table 8-2: Nucleophilicity of Common Nucleophiles

Reactivity Class

Nucleophile

Very good

I,  HS, RS

Good

Br,  OH, RO,  CN,  N3

Fair

NH3, Cl, F,  RCO2

Weak

H2O, ROH

Very Weak

RCO2H

                           8.   Leaving groups are important for both SN1 and SN2 reactions.
                                    a)   The best leaving groups should be the most stable.
                                                i)  For anions this is the anion best able to stabilize the negative charge.
                                                ii)  Anion stability is related to basicity:  the best leaving groups are the least basic.
                                                iii)  Recall that weak bases are the conjugate bases of strong acids.
                                    b)   Table 8-3 shows the relationship between the leaving group's ability to leave and its basicity  

            Table 8-3.  Leaving Groups and Relative Reactivities.

Leaving group

Relative Reactivity

pKa of Conjugate Acid

TsO

60,000

-6.5

I

30,000

-9.5

Br      

10,000

-9

Cl

200      

-7

F

1

3.2

CH3CO2

0

4.8

OH

0

15.7

EtO

0

16

H2N

0

35

                                     c)  Table 8-3 suggests that under "normal" circumstances alkyl fluorides, acetates, alcohols, ethers,
                                                and amines tend not to undergo displacement reactions. 

            B.   SN1:  Substitution Nucleophilic Unimolecular

                        1.  Example.

                         2.   Evidence for the SN1 mechanism:
                                    a)  1st order kinetics is observed;     Rate  =  k[RX].
                                    b)  Rearrangements often occur (evidence of a carbocation intermediate.)
                                    c)  Racemization is observed.

          

                                    d)   Why is the observed product ratio not 50:50?  

                                    ION PAIRS:  The carbocation formed is not completely free of the leaving group (Cl-)
                                                             before the nucleophile attacks.  The Cl- blocks the nucleophile. 

                        2.   Solvent Effects on SN1 Reactions.
                                    a)   SN1 reactions are subject to large solvent effects. 
                                    b)   They are favored by POLAR, PROTIC solvents since the energy of the transition state leading to
                                                 the formation of the carbocation intermediate is lowered by solvation more than the ground-state
                                                 reactant (alkyl halide in the following reaction).
                                    c)  Relative reaction rate for the solvolysis of 2-chloro-2-methylpropane: 

Dielectric Constant

Solvent

Relative Rate

24.3

EtOH

1

6.2

HOAc

2

 

80% EtOH (aq)

100

 

40% EtOH (aq)

14,000

80.4

H20

~105

                         3.  SN1 and SN2 reactions show solvent effects for different reasons.  Consider the reaction: 
                                                R-X  +  Nu:
à  R-Nu  +  X

                                    a)    SN1
                                                R-X       
à          [R....X]            à                 R+  +  X                                                                         TS leading to                 carbocation intermediate

                                                i)  The transition state leading to the formation of the carbocation intermediate is more polar
                                                            than RX and therefore more stabilized by polar solvents. 

                                    b)   SN
                                                 R-X + Nu:  
à [Nu-R--X]  à Nu-R + X 

                                                i)          Solvent polarity is not as important since both starting materials (RX + Nu:) and the
                                                            transition state (Nu...R...X) are both negatively charged. 

                        4.  Nucleophiles in SN1 Reactions 
                                    a)  Are nucleophiles important to the reaction rate?  Explain.

                                                Not important to reaction rate since nucleophiles are not in the rate-limiting step.

                                    b)   Solvent molecules can compete as nucleophiles (solvolysis).                       

                        5.  Leaving Groups:  Same order as for SN2 reactions.

                        6.  Conclusions

                                    a)  From the above observations we may conclude that SN1 reactions are favored by:
                                                i)   3o RX
                                                ii)  Nonbasic nucleophiles
                                                iii) Polar, protic solvents
                                    b)  Why nonbasic nucleophiles?  Answer:   To avoid competing  Elimination.

                                     c)  Exercise:  Write the mechanisms for  the above reactions. 

                                    d)   We may also conclude that SN2 reactions are favored by:
                                                i)    CH3X and 1o RX
                                                ii)   Nonbasic nucleophiles
                                                iii)  Polar aprotic solvents                                        

 IV.  Substitution vs Elimination Reactions 

            A.  Order of Reactivities of Alkyl Halides  

                        1.     E1:     3o RX  >  2o RX  >  1o RX 

                        2.     E2:          3o RX  >  2o RX  >  1o RX 

                        3.    SN1:   3o RX  >  2o RX  >  1o RX  >  CH3

                        4.    SN2:   CH3X   >  1o RX  >  2o RX  >  3o RX 

            B.   Primary Alkyl Halides

                        1.   1o alkyl halides react via the SN2 or E2 mechanisms since:
                                    a)    They are relatively unhindered.
                                    b)    They avoid the formation of unstable primary carbocations, although rearrangements to more
                                                stable carbocations can occur.
                        2.   When good nucleophiles are used (for example, N3−, I−, Br−, CN−, RS−) nucleophilic substitution
                                    occurs without competing elimination.  
                                    a)  Even the use of strong bases (such as OH− and EtO−) results in significant amounts of
                                                substitution products in   addition to elimination products.
                        3.  The E2 mechanism can be made to be the main reaction when strong, bulky bases are used.
                                    a)   t-Butoxide is the typical example of this kind of bulky base.
                        4.  Example

 

 

 

            C.  Secondary Alkyl Halides
                        1.  2o alkyl halides react by any of the four  mechanisms.
                        2.  E2 reactions are favored by the use of strong bases (EtO, OH, NH2).
                        3.  SN2 reactions are favored by the use of polar aprotic solvents (eg HMPA) with a good nonbasic
                                    (or weakly basic) nucleophile.

          

                        4.   SN1 and E1 reactions occur under solvolysis conditions when weakly basic nucleophiles are used in
                                    polar protic solvents.
                                    a)   Since these conditions favor both pathways, a mixture of products is formed.
                                    b)  SN1 and E1 reactions with secondary alkyl halides are therefore generally useless for the
                                                synthesis of organic compounds.

            D.   Tertiary Alkyl Halides
                        1.  Reactions can occur via SN1, E1, and E2 pathways.
                        2.    3o alkyl halides are too sterically  hindered for SN2 reactions
                                     (but not for E2 reactions which are also bimolecular.  Why? 

                        3.   Strong bases favor E2 reactions.
                        4.   SN1 reactions are favored by nonbasic nucleophiles in polar protic solvents.
                        5.   E1 reactions occur under solvolysis conditions (polar solvents) and weak base.

   

            E.   Practice Problems.  Complete the following reactions showing the preferred product(s) and then
                        classify the reactions as E1, E2, SN1, or SN2.

 

V.   Sulfonate Esters as Substrates in Nucleophilic Substitution Reactions.  (Alkyl esters of sulfonic acids.)
            A.   Sulfonic Acids
                        1.    Sulfonic acids are strong acids, on the order of sulfuric acid.
                        2.   Two examples of sulfonic acids are shown below:

methanesulfonic acid

p-toluenesulfonic acid
(“tosylic acid”)

                           3.  Some esters of sulfonic acids are useful in synthesis as they make excellent leaving groups.

            B.   Reaction of Sulfonic Acids and Alcohols
                        1.  Overall reaction

 

                        2.  The sulfonate esters used most often in nucleophilic substitutions are p-toluene-sulfonates known as
                                     TOSYLATES (ROTs):   
                                    a)     These are excellent leaving groups.

 

                                    b)   The limitations in the use of sulfonate esters are the same as with alkyl halides: 
                                                Competition from elimination exists.
                                    c)   Advantage of sulfonate esters over alkyl halides:  Their preparation from alcohols do not involve
                                                 bonds to C       (the alcohol oxygen becomes the O that connects the alkyl groupto the sulfonyl
                                                group. 

                                                i)   In the formation of alkyl halides from alcohols the C-O bond breaks and the C-X bond may
                                                             or may not be stereospecific.) 

                                                ii)  As a result the configuration of the sulfonate ester is the same as that of the alcohol: 
                                                            An optically active tosylate ester can be prepared from an optically active alcohol.

 

 

VI.   Review of the Reaction Between Alcohols and Hydrogen   Halides.  (From Chapter 4). 

            A.   General Reaction :                 ROH  +  HX  à  RX  +  H2

            B.   Observations and Conclusions 

                        1.  Reactivity of ROH:   3o >  2o  >  1o  <  CH3OH
                        2.   3o and most 2o ROH undergo SN1 mechanism.
                        3.   Methyl and 1o usually undergo SN2 mechanism.
                        4.  Branching adjacent to the reaction site often results in rearrangements.
                        5.   Unbranched 1o ROH and 3o ROH usually react with HX without rearrangement.
                        6.   To keep 2o ROH from rearrangment upon  treatment with HX first convert the alcohol to the tosylate
                                    and then treat the tosylate ester with NaX. (X = Cl, Br, I).

 

Many thanks to Rod Oka of MPC for generously sharing his "Lecture Companion" outline,
reproduced here in extensively modified form by permission, with web references and other goodies added by me.
Structures drawn using  MDL IsisDraw™, CS ChemOffice ChemDraw™, and ACDLabs ChemSketch™  .