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Unformatted text preview: EXAM 1 Average
Stnd. Dev. 79.5 / 100
16.9 2 Grignard Reagents are BASES • A Grignard reagent is a powerful base that reacts with very weak acids.
• Water, alcohols, terminal alkynes and even amines react with a Grignard
reagent to form the corresponding alkane (the conjugate acid) and the
conjugate base of each of the weak acids mentioned.
• Methylmagnesium bromide (22) is formed by reaction of iodomethane and
magnesium, and will react with water to form methane (the conjugate acid)
and hydroxide ion (BrMgOH, the conjugate base).
• This reaction effectively destroys the Grignard reagent (breaks the C-Mg
bond to form C-H).
• Similarly, 22 reacts with ethanol or acetic acid to give methane and ethoxide
or the acetate anion, respectively. BrMg !+ Br Mg
22 !" + H O H H CH3 + O H Grignard Reagents are Poor Nucleophiles with RX
• In general, a simple Grignard reagent derived from an alkyl halide does not
react with an alkyl halide to give a coupling product.
• a Grignard reagent from simple aliphatic alkyl halides is a poor
nucleophile in an SN2 reaction with a simple aliphatic halide.
• An exception to this statement occurs when the Grignard reagent is
unusually reactive and/or the alkyl halide is particularly reactive.
• Benzyl bromide or allyl bromide are examples of such reactive alkyl halides.
23 ether Br 25 MgBr No Coupling 24
Mg MgBr ether
Br 3 Kharasch Reaction
• A Grignard reagent reacts with an alkyl halide if a transition metal salt
is added to the reaction.
• This variation is called the Kharasch reaction, and the important thing to
remember is that a transition metal is needed in order for common
Grignard reagents to react with common alkyl halides.
• With no transition metal additive, assume that simple aliphatic Grignard
reagents do not react with alkyl halides, but that aliphatic Grignard reagents
with CuBr or FeBr3 and alkyl halides do give the coupling product. Br
CuBr or FeBr3 4 5 Oganolithium Reagents • Reaction of an alkyl halide with the Group 1 metal lithium (Li)
gives an organometallic called an organolithium reagent
• The reaction of 1-bromobutane (23) and lithium metal (which
exits primarily as dilithium, Li2) forms 28, where lithium has
• This organolithium reagent is known as n-butyllithium or 1lithiobutane, and it is characterized by a C-Li bond.
• The C-Li bond is polarized with a !– carbon and a !+ lithium
(see 28) because carbon is more electronegative than lithium. Br
23 !+ Li-Li Li
28 !" + L iB r 6 Oganolithium Reagents
• Formation of an organolithium reagent (RLi) is thought to proceed via a
radical intermediate (see CH3 in 32), those radicals may react to form other
• If two radicals come together, they react to form a new molecule. Each
radical donates one electron to form a new "-bond (composed of two
electrons) in what is known as radical coupling.
• Once the CH3 radical is formed it may couple to another methyl radical to
generate ethane (CH3CH3), shown in violet using single-headed arrows.
• Radical coupling of two alkyl radicals to form an alkane, in the presence of
the metal, is called Wurtz coupling. H3C CH3 H3C • I Li I Li •
Li H3C Li 32 33 7 Oganolithium Reagents • A tertiary organolithium is much more reactive than the secondary organolithium,
which is more reactive than primary organolithium reagents.
• If tert-butyllithium (36) is mixed with iodoethane, a rapid reaction takes place to
produce ethyllithium (37) and tert-butyl iodide (2-iodo-2-methylpropane).
• The primary organolithium reagent (37) is more stable than the tertiary
organolithium reagent (36), and the reaction shown favors formation of 37.
• Because of this difference in reactivity and stability, when a tertiary organolithium
reagent such as tert-butyllithium (36) reacts with a primary alkyl halide, a new
organolithium reagent is formed if the product is more stable.
• The reaction of 36 with a primary alkyl halide (mostly the iodide) is a very
common method of producing organolithium reagents that are not
• This metal-halogen exchange reaction works best when the tertiary organolithium
reagents reacts with a primary iodide (bromides and chlorides are less reactive), but
the exchange reaction with secondary halides is much slower and often gives poor
t-BuLi , pentane-ether 39 38
t-BuLi , pentane-ether Li I
40 41 8 Oganolithium Reagents are BASES • Organolithium reagents behave as carbanions, and they are very powerful
• If methyllithium (33) reacts with water, the conjugate base is LiOH (lithium
hydroxide) and the conjugate acid is methane, which is very weak acid
• The !– carbon of a C–Li bond is more basic than the !– carbon of a C–Mg
• Organolithium reagents are stronger bases than Grignard reagents.
• Organolithium reagents are such strong bases that they react with the
protons of very weak acids, some with pKa of >30. Li !+ Li
28 H O H H CH2C3H7 + O H 9 Oganolithium Reagents are BASES • Organolithium reagents are such strong bases that they react with the
protons of very weak acids, some with pKa of >30.
BuLi , ether
Me C C H Me 42 + usually drawn as BuLi , ether
N C C: Li
43 N: Li H 44 N + H-Bu Li 45 Li H Li 36 + 39 H-Bu H Organocuprates 10 • It is possible to generate a different organometallic
reagent from an initially formed organometallic reagent, and
the new reagent may react directly with an alkyl halide.
• When copper is added to an organolithium reagent, the
coupling reaction is more facile that the similar reaction with
• This is the reaction of an organolithium reagent with the copper
CuBr or CuI. Both are cuprous salts, or Cu(I).
• When an organolithium reagent (RLi) reacts with cuprous
iiodide (CuI) in ether at –10°C, a reaction takes place to generate
what is called an organocuprate, R2CuLi (46).
organocuprate 2 RLi + CuI ether , -10°C R2CuLi
46 11 Organocuprates • The reaction of alkyl halides and organocuprates is the
preferred method for coupling an alkyl halide to an
organometallic compound. Ph2CuLi Br Ph ether
P h 49 P h 50 + C6H13CH2I
28 47 Cu Li
2 –78°C ! 0°C C6H13
48 53% 12 25: Disconnections And
• Synthesis means choosing a molecule of fewer carbons as a
starting material and building the molecule of interest by making
the necessary carbon-carbon bonds, and incorporating the
• This chapter will focus on rudimentary techniques for
assembling molecules and provide methodology to analyze a
molecule and determine what smaller molecule(s) must be used
for its synthesis. To begin, you should know: 13 • The concept of bond polarization. (chapter 3, section 3.7, chapter 5, section 5.4)
• The concept of strong and weak covalent bonds. (chapter 7, section 7,2, 7.5)
• The fundamental structure and nomenclature all functional groups in this book.
(focus on chapters 4, 5, 14, 15, 20)
• All of the functional group transformations presented in this book. (focus on
chapters 10, 11, 12, 16, 17, 18, 19, 20, 21, 23)
• All of the carbon-carbon bond forming reactions presented in this book. (focus
on chapters 11, 14, 17, 19, 20, 21, and 23)
• Mechanisms. (chapter 7, section 7.8 and chapters 10, 11, 12, 16, 17, 18, 19, 20, 21,
• All of the reagents used in this book. (chapters 10, 11, 12, 15, 17, 18, 19, 20, 21,
• The structure and bonding of organic molecules. (focus on chapters 3, 5)
• The concept of isomers. (chapter 4, section 4.5, chapter 5)
• The concept of stereoisomers, including regioisomers, enantiomers, and
diastereomers. (chapter 9, section 9.1, 9.3, 9.4, 9.5, 9.6) When completed, you should know: 14 • The target is the molecule to be synthesized. The starting material is the molecule used
to begin the synthesis. Disconnection is the process of mentally breaking bonds in a target
to generate simpler fragments as new targets to be used in the synthesis. The
disconnection approach to synthesis is sometimes called retrosynthetic analysis.
• If a starting material is designated, try to identify the carbon atoms of the starting
material in the target. The disconnections will occur at bonds connecting that fragment to
the rest of the molecule.
• Assume that ionic reactions are used, and convert each disconnect fragment into a donor
(nucleophilic) or acceptor (electrophilic) site, if possible based on the natural bond
polarity of any heteroatoms that are present. A synthetic equivalent is the molecular
fragment that correlates with the disconnect fragment in terms of the desired reactivity.
• In most retrosynthetic analyses, the bond #- to the functional group and that $- to the
functional group are the most important for disconnection.
• If no starting material is designated, use retrosynthetic analysis to ﬁnd a commercially
available or readily prepared starting material.
• Identify the relationship of functional groups and manipulate the functional group as
required to complete the synthesis.
• The most efﬁcient synthesis is usually a convergent strategy rather than a consecutive
• Disconnection of multi-functional targets requires a complete understanding of all
reactions related to those functional groups.
• When one group interferes with another, it may be protected. 15 Disconnection
• If 1 is a target that must be prepared, several questions should be asked.
• What is the starting material? What is the ﬁrst chemical step? What reagents
are used? How many chemical steps are required?
• The target will be examined and then simpliﬁed it by a series of mental bondbreaking steps called disconnections.
• The term disconnection implies a thought experiment that breaks a bond within a
molecule to generate simpler fragments.
• • If a bond is disconnected, a chemical process must be available to make that
• In other words, choosing a speciﬁc a disconnection points towards a bond that
must be made by a known chemical reaction.
bond "d" i
j b h a Ph g f Ph e
b d 1 a
c OH f g 2 e c 3 OH 16 Disconnection • Disconnection of bond d generates two smaller fragments 2 and 3
("smaller" is deﬁned as having fewer carbon atoms).
• The disconnection has simpliﬁed the target.
• Disconnection of bond d should point to a chemical reaction by
which 1 may be prepared from simpler fragments.
• This is the fundamental principle behind the disconnection process.
• Note that the reverse arrow symbol (%) is used with the
bond "d" i
j b h a Ph g f Ph e
b d 1 a
c OH f g 2 e c 3 OH 17 Disconnection • Fragments 2 and 3 are not real because each carbon (marked in red)
has only three bonds.
• There must be a protocol that converts these fragments into real
• Disconnection of the indicated bond in 4 can be correlated with two
real molecules, 5 and 6.
bond "d" i
j b h a Ph g f Ph e
b d a 1 c f g c 2 OH R2 OH 3 O
R3 e 4 R2 R1 H
6 R3 5 18 Specific Starting Material
• A synthetic problem requires that starting material 8 be converted to target 9.
• The ﬁrst step is to identify those carbons in structure 8 that are part of the structure
of target 9. Close inspection shows that the carbon atoms highlighted in red and the
OH unit in 9 correspond exactly to the carbon atoms and OH of 8.
• The bonds connected to the highlighted carbons (the green bond and the blue bond)
in 9 are disconnected because those bonds must be formed in the synthesis
• This restriction leads speciﬁcally to bonds a and b. In other words, the
retrosynthesis of 9 must be biased towards the designated starting material, 8. bb OH OH a 9 8 19 Specific Starting Material • These fragments are pieces of a molecule (call them disconnect
products; sometimes they are called retrons).
• In order to determine the reaction required for the synthesis,
convert the disconnect fragments into real molecules.
• Focus on translating the fragments into real molecules. This process
will allow an evaluation of both chemical reaction, in the context of
this speciﬁc synthesis.
• This translation of disconnect fragments to real molecules involves
the use of a synthetic equivalent. OH disconnect
9 10 OH 11 disconnect
12 13 ...
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This note was uploaded on 02/25/2012 for the course CHEM 244 taught by Professor Jardin,j during the Fall '08 term at UConn.
- Fall '08