Wesleyan University
The Honors College
An Investigation of
Selective Ternary Thiol-Michael Reactions
by
Raghavendra R. Murthy
Class of 2016
A thesis submitted to the
faculty of Wesleyan University
in partial fulfillment of the requirements for the
Degree of Bachelor of Arts
with Departmental Honors in Chemistry
Middletown, Connecticut
April, 2016
Acknowledgements
First and foremost, I want to thank Professor Northrop for accepting me into
his group. Working in your lab has been a privilege and learning from you is always a
pleasure. Your willingness to listen and give advice, no matter when I stuck my head in
the door with a question, has aided me throughout my time at Wesleyan. Thank you to
Professors Westmoreland and Fry for agreeing to read this work. The three of you have
taught me so much and inspired me to pursue a future in chemistry and teaching.
I also want to thank my current labmates: to Rod: for putting up with me when I
was just starting out, to Steve: for your guidance and aid on this project, to Vasili: for
your support and words of wisdom, to Claire: for your encouragement, and to Jiyoon,
Robie, and Jeanette, I wish you all the best. Thank you to my past labmates–Umesh,
Charlie, Alex, Dara, Merry, and Stuart. You have all made Northrop lab an incredible
environment for both learning and friendship with your intelligence and good humor.
To the Chemistry majors, graduate students, professors, and staff I have known,
both past and present, you have made Wesleyan, in particular Hall-Atwater, a home
these past few years. To Will: These last two years have been quite the adventure, thank
you for being an amazing friend and working together on everything from Inorganic to
Integrated. To Yael: Thank you for your friendship and knowledge over the past three
years. To Eric: You are a great scientist, thanks for being an even better friend. To
Keonmin and Ben: Thank you for being great friends this year.
Lastly, I cannot be thankful enough to my parents and grandparents for your
encouragement and being incredible role models. I would not have been able to do any
of this without your support.
i
Table of Contents
Chapters
Pages
Acknowledgements.........................................................................................................................i
Table of Contents...........................................................................................................................ii
Abstract............................................................................................................................................v
1.0 Introduction..............................................................................................................................1
1.1 Background.....................................................................................................................1
1.2 Click Chemistry..............................................................................................................1
1.3 Thiol-ene Reactions.........................................................................................................3
1.4 Michael Addiction Reactions...........................................................................................4
1.5 Thiol-Michael Reactions..................................................................................................4
1.6 Ternary and Quaternary Thiol-Michael Reactions...........................................................7
1.7 Applications of Ternary and Quaternary Reactions in Synthesis....................................11
2.0.0 Experimental.......................................................................................................................13
2.1.0 General Procedure for Thiol-Michael Adduct Standards in Chloroform......................13
2.1.1 1H NMR Data for N-methyl maleimide Thioether Michael Adducts...........14
2.1.2 1H NMR Data Ethyl Vinyl Sulfone Thioether Michael Adducts...............14
2.1.3 1H NMR Data Butyl Isocyanate Thioether Michael Adducts......................15
2.1.4 1H NMR Data Methyl Acrylate Thioether Michael Adducts......................15
2.1.5 1H NMR Data Methyl Methacrylate Thioether Michael Adducts...............16
2.1.6 1H NMR Data Ethyl Crotonate Thioether Michael Adducts......................17
2.2.0 General Procedure for Ternary Thiol-Michael Reactions in Chloroform.......................17
2.3.0 General Procedure for Ternary Thiol-Michael Reactions in Tetrahydrofuran...............18
ii
2.4.0 General Procedure for Quaternary Thiol-Michael Reactions........................................18
3.0.0 Results and Discussion......................................................................................................19
3.1.0 Methodology of Determining Selectivities.....................................................................19
3.2.0 Selectivity Data for Chloroform..................................................................................24
3.3.0 Analysis of Chloroform Results..................................................................................29
3.3.1 Initiator Influence.........................................................................................29
3.3.2 Michael Acceptor Influence...........................................................................31
3.3.3 Thiol Influence.............................................................................................31
3.4.0 Switching to Tetrahydrofuran.....................................................................................32
3.5.0 Selectivity Data for Tetrahydrofuran...........................................................................33
3.6.0 Analysis of Tetrahydrofuran Results..........................................................................37
3.6.1 Initiator Influence.........................................................................................38
3.6.2 Michael Acceptor Influence...........................................................................38
3.6.3 Thiol Influence.............................................................................................39
3.7.0 Methodology of the Development of Quaternary Reactions...........................................39
3.8.0 Quaternary Results in Chloroform..............................................................................40
3.8.1 Initial Challenges.........................................................................................40
3.8.2 Steps Toward a Solution..............................................................................42
3.8.3 A Compilation of Results.............................................................................45
4.0 Conclusions and Future Work.............................................................................................51
5.0.0 Spectroscopic Data.............................................................................................................52
5.1.0 Thiol-Michael Adduct Standards...............................................................................52
5.1.1 Standard 1H NMR Spectra of N-methyl Maleimide Adducts......................52
iii
5.1.2 Standard 1H NMR Spectra of Ethyl Vinyl Sulfone Adducts......................54
5.1.3 Standard 1H NMR Spectra of Butyl Isocyanate Adducts.............................57
5.1.4 Standard 1H NMR Spectra of Methyl Acrylate Adducts.............................59
5.1.5 Standard 1H NMR Spectra of Methyl Methacrylate Adducts......................62
5.1.6 Standard 1H NMR Spectra of Ethyl Crotonate Adducts.............................64
5.2.0 1H NMR Spectra of Ternary Reactions Run in Chloroform with Greater than 95%
Selectivity.............................................................................................................................67
5.3.0 1H NMR Spectra of Ternary Reactions Run in Tetrahydrofuran with Greater than
95% Selectivity....................................................................................................................76
References......................................................................................................................................86
iv
Abstract
Thiol-Michael reactions have become the subject of increased interest due to
their “click” nature, meaning they are broadly applicable, rapid, tolerant of many
different reaction conditions, and high yielding. These reactions have proven to be useful
in organic materials synthesis. To gain more knowledge of specific thiol-Michael
reactions which yield highly selective products in a short amount of time, an
investigation of ternary reactions between a single Michael acceptor and two thiols was
conducted. All possible ternary combinations of six Michael acceptors and five thiols
were attempted using three initiators in two solvents. The relative ratios of each product
were compared using 1H NMR spectroscopy. Results indicated a similar number of
highly selective ternary combinations in both solvents. Analysis of the results of these
combinations resulted in the development and optimization of quaternary reactions,
involving two thiols and two Michael-acceptors, to yield only two selective products. A
combination of these ternary and quaternary results might allow for the creation of large
multi-functionalized pendant polymers, dendrimers, and other macromolecules with
fewer intermediate steps and minimal purification.
v
1.0 Introduction
1.1 Background
As research in chemistry moves into new frontiers, new highly efficient reactions
are being sought for simplifying and streamlining syntheses. Such reactions are of
particular interest to chemists constructing multi-functionalized macromolecules, such as
polymers and dendrimers. A typical synthesis consists of several steps, with varying
yields, and often requires extensive purification via column chromatography or
recrystallization in between those major steps. Identifying reactions that have the ability
to overcome the hurdles of laborious purification and low selectivity, while ensuring they
are still applicable to increasingly more complex systems, is a major goal for synthetic
chemists today. Examples of such reactions that have garnered much interest, and
increased in use in, recent years are “click” reactions.
1.2 Click Chemistry
The term “click chemistry” originated from the work of K. Barry Sharpless et. al.
in 2001 to describe a novel set of reactions. The particular set of conditions a reaction
must meet before being labeled as “click” are as follows: the reaction must be modular,
wide in scope, give very high yields, generate only inoffensive byproducts that can be
removed by nonchromatographic methods, and be stereospecific. However, it is
important to note that stereospecificity in the products need not necessitate
enantioselectivity. These standards are met due to the reactions having both low kinetic
barriers and a thermodynamic driving force of often greater than 20 kcal mol-1. 1
The goal of click chemistry is to develop new compounds by attaching small
1
components together, rapidly and efficiently, using heteroatoms as linkages between
carbons (C-X-C). The quintessential click reaction is the copper catalyzed azide alkyne
Huisgen cycloaddition (CuAAC), depicted in Scheme 1. Certain Diels-Alder
cycloadditions, such as those between anthracene and maleimide derivatives, can also be
deemed as “click.”1
Scheme 1: The Copper Catalyzed Azide Alkyne Huisgen Cycloaddition
Cu(I) catalyst
O
+
O
N N
N
N N N
Even though the CuAAC2 reaction is the most widely used click reaction in
organic synthesis, several other click reactions have be applied with great success. The
mild conditions needed for click reactions allows for the possibility of running the
reactions in vivo.3 One particular click reaction that has proven to be invaluable in organic
materials synthesis is the thiol-ene reaction.4
There are several challenges in polymer and macromolecular synthesis that click
reactions are beneficial in solving.5 Polymers often have multiple functional groups, a
distribution of molecular weights, reduced reactivity of chain ends, and are extremely
difficulty to purify. Identifying and using reactions which are highly efficient, like thiolene reactions6, helps chemists bypass these roadblocks by allowing them to selectively
react certain functional groups on the polymer, while leaving others untouched. Using
click reactions can reduce the number of purification steps significantly.7
2
1.3 Thiol-ene Reactions
The thiol-ene reaction, sometimes referred to as an alkene hydrothiolation,
occurs between a thiol, an organosulfur compound with a sulfhydryl bond, and an
alkene, which results in the production an alkyl sulfide. Thiols are sometimes referred to
as mercaptans and are known for their distinctive foul odor. As shown in Scheme 2, the
thiol-ene reaction results in an anti-Markovnikov addition of the thiol to the alkene.8
Thiol-ene reactions can be carried out with radical initiators.9 They could also
follow a base- or nucleophile-initiated pathway.10,11 The radical pathway is applicable to a
wider variety of alkenes, while the base and nucleophile-catalyzed pathways primarily
work with electron poor alkenes, such as Michael acceptors. Certain types of alkenes and
thiols are more suited to certain pathways. Therefore, certain catalysts will be more
efficient than others when used with the same combination of thiol and alkene. The
prior conclusion allows for the notion that selective thiol-ene reactions can be
performed.
Scheme 2: The General Thiol-ene Click Reaction
R SH
+
R'
initiator:
light, base, or
nucleophile
R
S
R'
Although interest in this class of reactions has been sparked relatively recently
due to the advent of click chemistry, one of the first thiol-ene reactions can be traced
back to the 19th century when Charles Goodyear is attributed to have vulcanised natural
rubber (polycis-isopropene) using sulfur.12 Thiol-ene reactions fall under the umbrella of
click reactions due to their high efficiency and orthogonality to other chemistries.13
3
1.4 Michael Addition Reactions
The Michael addition occurs between Michael donor and acceptor species.
Michael donors act as nucleophiles in the Michael reaction. Michael acceptors are
generally alkenes with an electron withdrawing substituent, and quite typically are α,βunsaturated carbonyl compounds. The Michael adduct is a (1,4) conjugate addition
product that results from the nucleophilic attack of the Michael donor on the β-carbon,
the creation of an enolate intermediate, which in turn deprotonates the catalyst to yield
the product.14 The general mechanism of a Michael reaction is presented in Scheme 3.
Scheme 3: General Michael Addition Mechanism
Nu
Nu
O
R
R
O
Nu
R'
R'
H A
R
O
R'
H
1.5 Thiol-Michael Reactions
Out of the variety of Michael additions, one of the most efficient is the reaction
between thiols and maleimides, which are classified as Michael acceptors.15 Other
Michael acceptors of note include sulfones, isocyanates, acrylates, and crotonates. As a
subset of thiol-ene reaction, the thiol-Michael reaction has been found to be extremely
useful in organic materials synthesis. The mechanisms of thiol-Michael reactions that are
base- and nucleophile-initiated are presented below in Scheme 4. The nucleophileinitiated version does have the drawback of producing a nucleophilic addition byproduct,
which necessitates a lesser amount of those particular catalysts, in order to avoid the
formation of too much unwanted byproduct.15
4
Scheme 4: Thiol-Michael Reaction and Mechanisms
(b) Base-Initiated (e.g. TEA, DBU)
(a) Michael Addition Mechanism
EWG
S
R
Propagation
H
+
BH
B
Nu
Nu
R
S
R
S
(c) Nucleophile-Initiated (e.g. DBU, DMPP)
kP
Thiolate R S
+
EWG
+
EWG
EWG
Intermediate
k CT
R
S
EWG
Chain
Transfer
Nu
R
S
H
EWG
+
R
S
R
S
H
Nucleophile Addition
Byproduct
Thiol-maleimide reactions have been used to create rotaxanes in the Northrop
group,16 and other thiol-Michael reactions have been used by others to synthesize
biodegradable polymers17 and a class of macromolecules termed dendrimers.17,18
Dendrimers are nano-sized repeatedly branched, tree-like, homogeneous globular
structures.19 The synthesis of a dendrimer typically follows a pattern of: growth, followed
by an activation step, in which the external functional groups are deprotected before the
dendrimers can continue growth.
Using selective thiol-Michael chemistry, the deprotection step can be
circumvented entirely, allowing the dendrimer to grow in a continuous yet controlled
way, without the need for intermediate steps. Scheme 5 demonstrates an example the use
of selective thiol-Michael reactions for continuous growth in dendrimer synthesis by the
Bowman group.
5
Scheme 5: Dendrimer Synthesis via Thiol-Michael Chemistry17
Previous experimental and computational results from the Northrop group have
tested thiol-maleimide ternary reactions using N-methyl maleimide, two thiols, as well as
different initiators and solvents in order to find general trends in selectivity.20 Thiolmaleimide chemistry has been used over the last few decades in bioconjugate chemistry
due to its speed and selectivity.21,22
In Figure 1, a ternary thiol-Michael reaction between equimolar amounts of Nmethyl maleimide, 1-hexanethiol and thiophenol is shown to form two products, A and
B. A is the adduct formed from the reaction between N-methyl maleimide and
thiophenol, and B is the adduct formed from the reaction between N-methyl maleimide
and 1-hexanethiol. Altering only the solvent and initiator conditions leads to changes in
the percentage of each product that is generated.
In general, the reaction generally favors product A over B. As the basicity of the
initiator increases the selectivity appears to decrease. Using a more polar solvent than
deuterated chloroform (CDCl3) like dimethylformamide (DMF) decreases the selectivity
6
for the reaction using the same initiator conditions. A selectivity flip occurs with the
combination of polar solvent (DMF) and a strong base (0.1 M DBU).20 This leads to the
conclusion that altering these conditions for different combinations of a Michael
acceptor
and
two
O
thiols
would
yield
SH
Entry
Solvent
A
1
CDCl3
2
of
selectivities.
O
O
S
N
B
O
O
Product A
Product B
A/B
0.1 Et 3N
94
6
16
CDCl3
0.1 DBU
77
23
3
3
CDCl3
0.01 DBU
83
17
5
4
CDCl3
0.01 DMPP
96
4
24
5
DMF
none
97
3
32
6
DMF
0.1 Et 3N
85
15
6
7
Initiator
variety
N
SH
O
wide
S
Conditions
N
a
DMF
0.1 DBU
36
64
Figure 1: Experimental Results on Thiol-Michael Selectivity20
0.6
1.6 Ternary and Quaternary Thiol-Michael Reactions
One-pot ternary reactions occur between three compounds, all mixed together in
the same reaction vessel. From the prior experimental and computational results in the
Northrop lab, it was expected that carrying out a thorough and systematic study of the
possible combinations of potentially useful Michael acceptors and thiols would result in
the observation of several highly selective reactions.20 The focus of this thesis is an
investigation into the selective nature of ternary thiol-Michael reactions. The primary
goal is to find combinations which yield highly selective addition of one thiol to a given
7
Michael acceptor while in the presence of another thiol, that is 95% or greater favoring
one thiol over the other. For example, the reaction in Figure 1 using CDCl3 and 0.01
DMPP would be the only one of the reactions in the table to be considered highly
selective. An ideal ternary reaction, in which only one thiol reacts in its entirety with the
Michael acceptor, leaving the other thiol untouched, is shown in Scheme 6. In order to
further examine this class of reactions, several combinations of one-pot ternary reactions
involving one Michael acceptor and two thiols were performed.
Scheme 6: Ideal Ternary Thiol-Michael Reaction
R SH
R'
SH
R
initiator
S
no
R''
R'
R''
R'
S
R"
SH
one pot
Six Michael acceptors, five thiols, three initiators, and two solvents were used in
the study, leading to the screening of 360 different ternary combinations. The Michael
acceptors used were: N-methyl maleimide (1), ethyl vinyl sulfone (2), butyl isocyanate
(3), methyl acrylate (4), methyl methacrylate (5), and ethyl crotonate (6). The thiols used
were: methyl thioglycolate (8), methyl-3-mercaptoproprionate (9), thiophenol (10), 2mercaptoethanol (11), and 1-hexanethiol (12). The initiators used were: triethylamine
(Et3N), 1,8-diazobicyclo[5.4.0]undec-7-ene (DBU), and dimethylphenylphosphine
(DMPP). The chemical structures of the aforementioned materials are given in Figure 2.
The solvents were: chloroform (CHCl3) and tetrahydrofuran (THF). Please note that
the number (7) was initially given to methyl propriolate, but experiments involving that
8
Michael acceptor were discontinued.
Michael Acceptors:
O
O
N
O
S
C
N
O
O
N-methyl maleimide
(1)
Ethyl vinyl sulfone
(2)
O
O
n-Butyl isocyanate
(3)
O
O
O
O
Ethyl crotonate
(6)
Methyl methacrylate
(5)
Methyl acrylate
(4)
Thiols:
O
O
O
SH
O
Methyl thioglycolate
(8)
SH
SH
Methyl-3-mercaptoproprionate
(9)
HO
SH
Thiophenol
(10)
SH
2-mercaptoethanol
(11)
Hexanethiol
(12)
Initiators:
N
Triethylamine
(Et 3N)
P
N
N
1,8-Diazabicyclo[5.4.0]undec-7-ene
(DBU)
Dimethylphenylphosphine
(DMPP)
Figure 2: The Michael acceptors, thiols, and initiators used in this investigation
It is hypothesized that there will be several reactions with a greater than 95%
selectivity for one thiol-Michael adduct over the other. Selectivities for the same set of
thiols and Michael acceptor may also change when the type of initiator or solvent is
9
changed. After a thorough analysis of the 1H NMR spectra obtained after each ternary
reaction, the information gained from these selectivities can be used in the development
of quaternary reactions.
Scheme 7: Ideal Quaternary Thiol-Michael Reaction
R SH
R'
SH
initiator(s)
R''
R
R'''
R'
S
S
R''
R'''
one pot
A general quaternary reaction is shown in Scheme 7. These reactions involve two
Michael acceptors and two thiols, and ideally yield only two pure products. Identifying
several combinations of one-pot and sequential quaternary reactions would be very
helpful for syntheses of complex macromolecules. One-pot quaternary reactions would
require a single initiator to yield the two adducts, while a sequential quaternary reaction
would have two initiators: one initiator which forms the first product, and after an
allotted period of time a second initiator would be added to yield the second product. A
second version of sequential quaternary reactions would involve an initial ternary
reaction, which could involve two Michael acceptors or thiols, followed by the addition
of either a Michael acceptor or thiol and initiator to complete the quaternary set and
yield two pure products. However, this version would not be classified as a one-pot
synthesis.
10
1.7 Applications of Ternary and Quaternary Reactions in Synthesis
It may be possible to synthesize pendant polymers by adding several thiols to a
reaction flask that contains a polymer functionalized with several different Michael
acceptor groups and adding initiators that lead to selective additions of desired thiols to
particular Michael acceptor groups. Currently, the synthesis of such multifunctional
pendant polymers requires multiple steps, often several protection and deprotection
reactions, and laborious purification. Selective thiol-Michael reactions would eliminate
the need for extensive purification and save several synthetic steps.23 A potential
synthesis is shown below in Scheme 8.
Scheme 8: Selective Pendant Polymer Functionalization
O
O
N
H
O
O
O
O
O
N
H
R
n
N
H
O
O
O
O
O
O
N
H
R
m
N
H
O
O
O
O
O
O
N
H
R
N
H o
1) HS
R1
N
O
O
O
O
O
Et 3N
2) HS
O
O
O
N
H
O
O
N
H
R
n
N
H
O
O
O
O
3) HS
m
N
H
O
O
O
N
H
R
N
H o
O
O
O
R2
DMPP
O
R
O
O
O
O
N
H
N
O
R3
O
O
DBN
S
R2
O
O
O
S
R1
S
R3
Selective thiol-Michael reactions could also be used to synthesize Janus
dendrimers using a dithiol core molecule and adding two Michael acceptors which
selectively add to only one of the thiol groups. This could eventually result in “twofaced” dendrimers that have particular properties on both halves that allow them to
perform vital functions. For example, an amphiphilic Janus dendrimer could mimic
biologic membranes or serve as vessels for drug delivery.24
11
Figure 3: Schematic Example of a Janus Dendrimer25
Gaining a deeper understanding of the selectivities of ternary thiol-Michael click
reactions is expected to aid the Northrop group, and others, in synthesizing multifunctionalized polymers and dendrimers without the need for extensive purification
techniques and result in the elimination of intermediate steps. 26,27
12
2.0 Experimental
2.1.0 General Procedure for Thiol-Michael Adduct Standards in Chloroform
Analytical standards of thiol-Michael adducts were prepared for 1H NMR
analysis so that their spectra could be used to determine the relative quantities of
different adducts within complex ternary or quaternary mixtures. In each case, 1
equivalent of a given Michael acceptor (1–6) and a given thiol (8–12) were added to a vial
containing CHCl3. The reactions were initiated with a drop of Et3N, DBU or DMPP and
allowed to stir overnight at ambient temperature, after which the solvent was evaporated
and the resulting oils were placed under vacuum for one minute and analyzed via 1H
NMR.
9
8
O
O
1
O
S
O
O
O
S
O
H
N
S
O
O
O
S
O
S
HO
S
N
H
O
O
S
O
S
HO
N
H
S
O
S
O
S
O
O
O
N
O
O
S
O
S
N
N
O
S
O
S
O
O
O
3
O
12
O
S
HO
O
O
S
O
S
O
O
S
N
N
O
2
11
10
O
N
H
S
N
H
O
O
4
O
S
O
O
O
S
HO
O
S
O
O
O
O
S
O
O
S
O
O
O
O
5
S
O
O
O
S
S
O
O
O
O
O
HO
S
O
O
S
O
O
O
6
O
O
S
O
O
O
S
O
HO
S
O
O
O
O
O
S
O
S
O
Figure 4: Structures of the investigated thiol-Michael products. The adducts result from
Michael reactions occurring between the numbered thiol and Michael acceptor structures
structures shown in Figure 2
13
2.1.1 1H NMR Data for N-methyl Maleimide Thioether Michael Adducts
(1)+(8)+(DBU): 1H NMR data (CDCl3, 300MHz): δ 2.52 (dd, 1H, J=4.2, 4.2 Hz), 3.01 (s,
3H), 3.15 (dd, 1H, J=9.3, 9.6 Hz), 3.38 (d, 1H, J=15.9 Hz), 3.76 (s, 3H), 3.92 (d, 1H,
J=15.9 Hz) 4.03 (dd, 1H, J=4.2, 3.9 Hz)
(1)+(9)+(DMPP): 1H NMR data (CDCl3, 300MHz): δ 2.50 (dd, 1H, J=3.6, 3.6 Hz), 2.67–
2.80 (m, 3H), 3.01 (s, 3H), 3.04–3.27 (m, 3H) 3.71(s, 3H) 3.79 (dd, 1H, J=2.7, 3.6 Hz)
(1)+(10)+(Et3N): 1H NMR data (CDCl3, 300MHz): δ 2.68 (dd, 1H, J=3.6, 3.6 Hz), 2.873
(s, 3H), 3.12 (dd, 1H, J=8.7, 8.7 Hz), 4.02 (dd, 1H, J=4.2, 3.6 Hz), 7.29–7.34(m, 3H),
7.47–7.50 (m, 2H)
(1)+(11)+(Et3N): 1H NMR data (CDCl3, 300MHz): δ 2.56 (dd, 1H, J=4.2, 4.2 Hz), 2.91
(m, 1H), 3.02 (s, 3H), 3.17 (m, 2H), 3.89 (m, 3H)
(1)+(12)+(DBU): 1H NMR data (CDCl3, 300MHz): δ 0.883 (t, 3H, J=7.2 Hz), 1.26 – 1.42
(m, 6H), 1.56 – 1.66 (m, 2H), 2.52 (d, 1H, J=3.3, 3.6 Hz), 2.70 – 2.92 (m, 2H), 3.01 (s,
3H), 3.13 (dd, 1H, J=9.6, 8.7 Hz), 3.174 (dd, 1H, J=3.9, 3.6 Hz)
2.1.2 1H NMR Data for Ethyl Vinyl Sulfone Thioether Michael Adducts
(2)+(8)+(DBU): 1H NMR data (CDCl3, 300MHz): δ 1.42 (t, 3H, J=7.5 Hz), 3.07 (m, 4H),
3.28 (m, 4H), 3.75 (s, 3H)
(2)+(9)+(DMPP): 1H NMR data (CDCl3, 300MHz): δ 1.42 (t, 3H, J=7.5 Hz), 2.64 (t, 2H,
J=7.2 Hz), 2.84 (t, 2H, J=7.2 Hz), 2.96 (t, 2H, J=6.6 Hz), 3.05 (q, 2H, J=7.5 Hz), 3.21 (t,
2H, J= 8.4 Hz), 3.71 (s, 3H)
(2)+(10)+(DBU): 1H NMR data (CDCl3, 300MHz): δ 1.36 (t, 3H), 3.01 (q, 2H, J=7.5
Hz), 3.14–3.20 (m, 2H), 3.28–3.36 (m, 2H), 7.28–7.51 (m, 5H)
14
(2)+(11)+(DBU): 1H NMR data (CDCl3, 300MHz): δ 1.41 (t, 3H, J=7.5 Hz), 2.77 (t, 2H,
J=5.7 Hz), 2.96–3.09 (m, 4H), 3.21–3.27 (m, 2H), 3.79 (t, 2H, J=6 Hz)
(2)+(12)+(DMPP): 1H NMR data (CDCl3, 300MHz): δ 0.89 (t, 2H, J=7.2 Hz), 1.26 – 1.4
(m, 9H), 1.54 – 1.64 (m, 2H), 2.56 (t, 2H, J=5.1 Hz), 2.90 – 2.96 (m, 2H), 3.05 (q, 2H,
J=7.5 Hz), 3.16–3.22 (m, 2H)
2.1.3 1H NMR Data for Butyl Isocyanate Thioether Michael Adducts
(3)+(8)+(DMPP): 1H NMR data (CDCl3, 300MHz): δ 0.91 (t, 3H, J=7.2 Hz), 1.27 – 1.41
(m, 2H), 1.45 – 1.57 (m, 2H), 3.21–3.35 (m, 2H), 3.73 (d, 5H, J=4.8 Hz) 5.48 (s, 1H)
(3)+(9)+(Et3N): 1H NMR data (CDCl3, 300MHz): δ 0.92 (t, J=7.5 Hz), 1.27–1.40 (m,
2H) 1.43–1.55 (m, 2H), 2.71 (t, 2H, J=6 Hz), 3.14 (t, 2H, J=6.9 Hz), 3.16–3.33 (m, 2H),
3.70 (s, 3H), 5.288 (s, 1H)
(3)+(10)+(Et3N): 1H NMR data (CDCl3, 300MHz): δ 0.89 (t, 3H, J=6.9 Hz), 1.25–1.58
(m, 4H), 3.26 (q,2H,J=6.9 Hz), 5.27 (s, 1H), 7.27–7.58 (m, 5H)
(3)+(11)+(Et3N): 1H NMR data (CDCl3, 300MHz): δ 0.93 (t, 3H, 7.2 Hz), 1.25 – 1.39 (m,
2H), 1.40 – 1.58 (m, 2H), 3.11 (t, 2H, J= 5.7 Hz), 3.22 – 3.33 (m, 2H), 3.82 (t, J=5.7 Hz)
(3)+(12)+(DMPP): 1H NMR data (CDCl3, 300MHz): δ 0..85–0.95 (m, 6H), 1.22–1.58 (m,
10H), 2.90 (t, 2H, J=7.5 Hz), 3.25–3.30 (m, 2H), 5.25 (s, 1H)
2.1.4 1H NMR Data for Methyl Acrylate Thioether Michael Adducts
(4)+(8)+(DBU): 1H NMR data (CDCl3, 300MHz): δ 2.65 (t, 2H, J=7.5 Hz), 2.91 (t, 2H,
J=6.9 Hz) 3.25 (s, 2H), 3.70 (s, 3H), 3.74 (s, 3H)
(4)+(9)+(DBU): 1H NMR data (CDCl3, 300MHz): δ 2.61 (m, 4H, J=6.9 Hz), 2.80 (t, 4H,
J=6.6 Hz), 3.70 (s, 6H)
15
(4)+(10)+(DBU): 1H NMR data (CDCl3, 300MHz): δ 2.63 (t, 2H, J=7.8 Hz), 3.17 (t, 2H,
J=7.5 Hz), 3.68 (s, 3H) 7.20 – 7.51 (m, 5H)
(4)+(11)+(Et3N): 1H NMR data (CDCl3, 300MHz): δ 2.63 (t, 2H J = 7.2 Hz), 2.75 (t, 2H,
J=6 Hz), 2.82 (t, 2H, J = 9 Hz), 3.79 – 3.69 (m, 5H)
(4)+(12)+(DBU): 1H NMR data (CDCl3, 300MHz): δ 0.88 (t, 3H, J=6.6 Hz), 1.30 (m, H),
1.35 (m, 2H), 1.57 (p, 2H), 2.52 (t, 2H, J=7.5Hz), 2.61 (t, 2H, J=6.9 Hz), 2.78 (t, 2H,
J=6.9 Hz), 3.70 (s, 3H)
2.1.5 1H NMR Data for Methyl Methacrylate Thioether Michael Adducts
(5)+(8)+(Et3N): 1H NMR data (CDCl3, 300MHz): δ 1.24 (d, 3H, J = 7.2 Hz), 2.66-2.76
(m, 2H), 2.88–2.98 (m, 1H), 3.22 (s, 2H), 3.69 (s, 3H), 3.73 (s, 3H).
(5)+(9)+(DMPP): 1H NMR data (CDCl3, 300MHz): δ 1.24 (d, 3H, J=6 Hz),2.56 – 2.72
(m, 4H), 2.76 – 2.88 (m, 3H), 3.70 (s, 6H)
(5)+(10)+(Et3N): 1H NMR data (CDCl3, 300MHz): δ 1.30 (d, 3 H, J=6.3 Hz), 2.70 (m, 1
H), 2.93 (dd, 1 H, J=7.2, 7.2 Hz), 3.27 (dd, 1 H, J= 7.8, 7.2 Hz), 3.66 (s, 3 H), 7.30 (m,
4H), 7.50 (d, 1 H, J=7.2 Hz)
(5)+(11)+(Et3N): 1H NMR data (CDCl3, 300MHz): δ 1.24 (d, 3H, J=4.2 Hz), 2.56–2.74
(m, 3H), 2.80–2.88 (m, 1H), 3.69–3.76 (m, 5H)
(5)+(12)+(DBU): 1H NMR data (CDCl3, 300MHz): δ 0.88 (t, 3H, J=7.2 Hz), 1.23 – 1.39
(m, 9H), 1.51 – 1.60 (m, 2H), 2.47 – 2.59 (m, 3H), 2.63 – 2.71 (m, 1H), 2.82 (dd, 1H,
J=6.9, 6.3 Hz), 3.70 (s, 3H)
16
2.1.6 1H NMR Data for Ethyl Crotonate Thioether Michael Adducts
(6)+(8)+(DMPP): 1H NMR data (CDCl3, 300MHz): δ 1.25 (t, 3H, J=6.9 Hz), 1.33 (d,
3H, J=7.2 Hz), 2.45 (dd, 1H, J=8.1, 8.1 Hz), 2.64 (dd, 1H, J=6.6, 6 Hz), 3.29 (d, 2H,
J=2.4 Hz), 3.73 (s, 3H) 4.14 (q, 2H, J=6.9 Hz)
(6)+(9)+(DMPP): 1H NMR data (CDCl3, 300MHz): δ 1.26 (t, J=7.5 Hz), 1.33 (d, 3H,
J=6.9 Hz), 2.44 (dd, 1H, J=6.3, 8.1 Hz), 2.57–2.68 (m, 3H) 2.82 (t, 2H, J=7..2 Hz), 3.21
(q, 1H, J=6.9 Hz), 3.70 (s, 3H) 4.15 (q, 2H, J=6.9 Hz)
(6)+(10)+(Et3N): 1H NMR data (CDCl3, 300MHz): δ 1.25 (t, 3H, J = 7.2 Hz), 1.33 (d,
3H, J=7.2 Hz), 2.42 (dd, 1H, J=9, 8.1 Hz), 2.63 (dd, 1H, J=6, 6.3 Hz) 3.58-3.67 (m, 1H),
4.13 (m, 2H, J=7.8 Hz), 7.27–7.51 (m, 5H)
(6)+(11)+(DMPP): 1H NMR data (CDCl3, 300MHz): δ 1.26 (t, 3H, J=7.2 Hz), 1.33 (d,
3H, J=6.6 Hz), 2.47 (dd, 1H, 7.2, 7.5 Hz), 2.58 (dd, 1H, 7.5, 7.8 Hz), 2.75 (t, 2H, J=6Hz),
3.24 (m, 1H), 3.74 (t, 2H, J=5.7 Hz), 4.15 (q, 2H, J=5.9 Hz)
(6)+(12)+(DBU): 1H NMR data (CDCl3, 300MHz): δ 0.88 (t, 3H, J=6.3 Hz), 1.24–
1.41(m, 12H), 1.52 – 1.62 (m, 2H), 2.42 (dd, 1H, J=8.4, 8.1 Hz), 2.54 (t, 2H, J=7.5 Hz),
2.62 (dd, 1H, J=5.7, 6 Hz), 3.15–3.23 (m, 1H), 4.15 (q, 2H, J=6.9 Hz)
2.2 General Procedure for Ternary Thiol-Michael Reactions in Chloroform
Stock 0.1 M solutions of Michael acceptors (1–6) and thiols (8–12) were prepared
in CHCl3. Stock solutions of initiators (0.01 M TEA and DBU, and 0.001 M DMPP)
were also prepared in CHCl3. Ternary mixtures of two thiols and one Michael acceptor
were prepared by adding 0.2 ml of a given Michael acceptor and 0.2 ml each of two
different thiols, followed by 0.2 ml of a given initiator. All 180 ternary combinations of a
17
Michael acceptor, two thiols, and an initiator were screened in this fashion. The vials
were shaken for one hour at ambient temperature, uncapped, and the solvent allowed to
evaporate overnight. The vials were placed under vacuum for one minute each. The
resulting oils were taken up in CDCl3 for analysis via 1H NMR by dissolving the products
in 0.1 ml of CDCl3 and diluting the resulting solutions with an additional 0.4 ml of
CDCl3 in the NMR tube. Spectra of each sample were taken and relative integrations of
diagnostic peaks identified from the standard spectra were used to determine the
percentage of each product formed.
2.3 General Procedure for Ternary Thiol-Michael Reactions in Tetrahydrofuran
Stock 1.0 M solutions of Michael acceptors (1–6) and thiols (8–12) were prepared
in THF, as were stock solutions of initiators (0.01 M TEA and DBU, and 0.001 M
DMPP). Ternary reactions were carried out using the same procedure as previously
described. 1H NMR samples of the resulting mixtures were prepared and taken in CDCl3,
and were analyzed as previously described.
2.4 General Procedure for Quaternary Thiol-Michael Reactions
Equimolar amounts (0.48 mmol each) of two thiols and two Michael acceptors
were added to a vial containing 2 ml of CHCl3 or THF, followed by a catalytic amount of
initiator. The reaction mixture was then stirred for an hour. For the sequential quaternary
reactions, the second initiator or reagent was added after the allotted hour of time had
passed and he mixture was allowed to stir for an hour. The solution was then
concentrated and placed under vacuum. The resulting oils were analyzed via 1H NMR.
18
3.0 Results and Discussion
3.1.0 Methodology of Determining Ternary Selectivities
In order to determine the selectivities of the ternary reactions, analytical
standards of each thioether product were prepared and analyzed by 1H NMR. Once 1H
NMR spectra for the products were obtained, the observed peaks were integrated and
assigned. Using this information, relative integrations of peaks characteristic of the
products in 1H NMR spectra of ternary reactions were then compared in order to
determine the selectivity of each reaction.
The diagnostic peaks that were chosen in some cases were relatively
conservative. On occasion the selected peaks that could be used for comparison were
present in both the reactant and product, due to the fact that many ternary spectra had
overlapping product peaks. This means that certain selectivities might actually be higher
than reported, because the integration would account for both product and starting
material. When performed on a larger scale a silica plug or column would be able to
separate out the starting material, thereby circumventing this issue.
A few reactions did not run to completion in the allotted hour of stirring, and
some spectra had too many overlapping peaks to integrate, which in turn indicates rather
poor selectivity for one thiol over another. Spectra of highly selective ternary reactions
are typically easy to identify due to the fact they are relatively clean and strongly resemble
the standard spectra for the thiol-Michael adduct that is favored. Those reactions, as well
as those that had no reaction are indicated by an “×” in the tables summarizing the data.
Figures 5 and 6 depict the 1H NMR spectra of the starting and product mixtures,
19
respectively, of an unselective ternary reaction. Likewise, Figures 7 and 8 depict the 1H
NMR spectra of the starting and product mixtures, respectively, of a selective ternary
reaction.
Example of an unselective reaction N-methyl maleimide (1)+ Methyl thioglycolate (8)+
Thiophenol (10)+Et3N:
O
O
SH
O
N
SH
O
Figure 5: Ternary mixture of 1, 8, and 10 before addition of Et3N as an initiator
O
O
S
O
S
N
O
O
N
O
Figure 6: Product mixture following the addition of Et3N to ternary mixture of 1, 8, and
10. Spectroscopic signals corresponding to both thiol-maleimide products are observed,
indicating an unselective reaction
20
Example of a selective reaction N-methyl maleimide (1) + Methyl thioglycolate (8) + 1hexanethiol (12)+ Et3N:
O
SH
N
O
O
O
SH
Figure 7: Ternary mixture of 1, 8, and 12 before addition of Et3N as an initiator
O
O
S
O
S
N
O
O
N
O
Figure 8: Product mixture following the addition of Et3N to ternary mixture of 1, 8, and
12. The 1H NMR spectrum shows only the thiol-maleimide product of 1 and 8,
indicating an selective reaction (most residual 12 was evaporated during condensation of
the product mixture, although some remains)
21
Some spectra have several additional peaks in the baseline, which are observed
due to the presence of remaining initiator. DBU, in particular, was difficult to remove
from the samples, due to the limited scale on which the reactions were run. As these
reactions are scaled up, a work up or silica plug ought to eliminate the remaining initiator
that evaporation and vacuum did not remove. All spectra with a greater than 95%
selectivity for one thiol over another, as well as the others that are discussed in this thesis
can be found in the Sections 5.2 (chloroform) and 5.3 (tetrahydrofuran), beginning on
page 67 and 76, respectively.
The results of the ternary reactions run in chloroform were summarized in the
selectivity charts presented below, in Tables 1–6, for each combination of Michaelacceptor, two thiols, and initiator. The results for the ternary combinations performed in
tetrahydrofuran can be found in Tables 7–12. Calculated selectivities are rounded down
to two significant figures, in an attempt to account for any variation in NMR
integrations, which have an error of generally less than five percent. Repeated integration
of spectra that are composed of more than one thiol-Michael adduct have resulted in
changes of overall reaction selectivity of up to three percent.
The numbers in the headings of the columns and rows of the charts represent
the thiols: methyl thioglycolate (8), methyl-3-mercaptoproprionate (9), thiophenol (10),
2-mercaptoethanol (11), and 1-hexanethiol (12). The number within each cell of the
chart represents the percentage of product due to the formation of thioether product of
the thiol in the column associated with the cell and the selected Michael acceptor. The
percentage of product from the adduct formed between the thiol in the row and
investigated Michael acceptor can be found by subtracting the percentage in the cell
22
from 100.
In the 1H NMR spectrum taken after the reaction between N-methyl maleimide
(1), methyl thioglycolate (8), and 2-mercaptoethanol (11) with Et3N as an initiator there
is 72% of the (1+8) adduct and 28% of the (1+11) adduct. In the reaction between Nmethyl maleimide (1), methyl-3-mercaptoproprionate (9), and thiophenol (10), using
Et3N as an initiator, there is 8% of (1+9) and 92% of (1+10) observed. The second
reaction is therefore more selective than the first, even though the number in the cell for
the first reaction would be 72 and the number in the cell for the second reaction would
be 8.
The color in the cells are shades of either green, yellow, or red. Green represents
the most selective reactions and red the least. In the example of (1), (9), and (10), with
Et3N as the initiator the color in the cell would correspond to the 92% selectivity even
though the number in the cell would be 8, because the column heading is 9. Figure 9
shows that there is greater than 99% selectivity for the (1+8) product in the ternary
reaction between N-methyl maleimide (1), methyl thioglycolate (8) and 1-hexanethiol
(12). The reaction between N-methyl maleimide (1), methyl thioglycolate (8) and
thiophenol (10) indicates that the (1+10) adduct is favored with a 55% selectivity for that
product.
23
3.2.0 Selectivity Data for Chloroform
Thiol B
Et3N
8
12
11
10
9
8
>99
9
Thiol A
10
11
12
-
45
-
-
98+
80-85
95-98
70-80
90-95
60-70
85-90
50-60
Figure 9: Selectivity Chart Key, applicable to both CHCl3 and THF reactions
O
N
O
Thiol B
Thiol B
Et3N
8
9
12
11
10
9
8
>99
72
45
74
-
72
41
8
-
DBU
8
9
12
11
10
9
8
59
63
46
48
-
60
50
26
-
24
Thiol A
10
>99
79
-
Thiol A
10
×
50
-
11
12
73
-
-
11
12
76
-
-
Thiol B
DMPP
8
9
12
11
10
9
8
>99
84
46
85
-
93
22
4
-
Thiol A
10
>99
83
-
11
12
54
-
-
11
12
88
-
-
11
12
69
-
-
11
12
65
-
-
Table 1: Selectivity Charts for N-methyl Maleimide in Chloroform
O
S
O
Thiol B
Thiol B
Et3N
8
9
12
11
10
9
8
97
78
29
64
-
86
47
26
-
DBU
8
9
12
11
10
9
8
73
72
40
50
-
75
34
33
-
DMPP
8
9
Thiol A
10
97
95
-
Thiol A
10
59
66
-
Thiol A
10
12
98
90
93
11
×
51
89
Thiol B
10
35
24
9
84
8
Table 2: Selectivity Charts for Ethyl Vinyl Sulfone in Chloroform
25
O
C
N
Thiol B
Thiol B
Thiol B
Et3N
8
9
12
11
10
9
8
>99
72
×
56
-
80
34
40
-
DBU
8
9
12
11
10
9
8
74
×
26
43
-
69
55
47
-
DMPP
8
9
12
11
10
9
8
>99
85
49
61
-
×
27
8
-
Thiol A
10
>99
81
-
Thiol A
10
64
53
-
Thiol A
10
>99
72
-
11
12
86
-
-
11
12
52
-
-
11
12
84
-
-
11
12
72
-
-
Table 3: Selectivity Charts for Butyl Isocyanate in Chloroform
O
O
Thiol B
Et3N
8
9
12
11
10
9
8
96
86
31
87
-
89
44
11
26
Thiol A
10
92
92
-
Thiol B
Thiol B
DBU
8
9
12
11
10
9
8
65
89
37
82
-
50
51
35
-
DMPP
8
9
12
11
10
9
8
96
31
×
58
-
54
46
17
-
Thiol A
10
48
40
-
Thiol A
10
87
87
-
11
12
69
-
-
11
12
76
-
-
11
12
>99
-
-
11
12
62
-
-
Table 4: Selectivity Charts for Methyl Acrylate in Chloroform
O
O
Thiol B
Thiol B
Et3N
8
9
12
11
10
9
8
×
86
26
43
-
×
54
Thiol A
10
78
56
-
-
DBU
8
9
12
11
10
9
8
80
66
36
77
-
90
94
30
27
Thiol A
10
76
44
-
Thiol B
DMPP
8
9
12
11
10
9
8
×
×
×
70
-
61
×
73
-
Thiol A
10
59
43
-
11
12
x
-
-
11
12
×
-
-
11
12
Table 5: Selectivity Charts for Methyl Methacrylate in Chloroform
O
O
Thiol B
Thiol B
Et3N
8
9
12
11
10
9
8
>99
72
21
52
-
×
69
21
-
DBU
8
9
12
11
10
9
8
53
67
38
48
-
67
45
54
-
Thiol A
10
>99
90
-
Thiol A
10
50
75
-
No reactions observed with DMPP
Table 6: Selectivity Charts for Ethyl Crotonate in Chloroform
28
-
3.3.0 Analysis of Chloroform Results
There were several reactions identified as highly selective in chloroform (CHCl3).
There were 19 ternary reactions wherein addition of one thiol to a given Michael
acceptor was preferred over the other thiol by at least 95% to 5%, and 12 ternary
combinations favoring one thiol over the other by 98% to 2%. The results suggest that
N-methyl maleimide (1) and methyl thioglycolate (8) are the most selective Michael
acceptor and thiol, respectively.
3.3.1 Initiator Influence
The selectivity charts indicate that most of the highly selective ternary reactions
occur with the use of Et3N and DMPP as initiators. DBU, by contrast, showed less
selectivity as only two reactions were observed to have greater than 90% selectivity and
both occurred when methyl methacrylate (5) as the Michael acceptor that was
investigated. Methyl methacrylate (5) was initially considered to be one of the less
reactive Michael acceptors, and these results while not necessarily contradictory to the
conjecture, led to the new question of how a combination involving a less reactive
Michael acceptor and the strongest base might turn out to be selective.
The differences in selectivities between Et3N and DBU can be understood by
examining the basicity of the two initiators. Et3N is a relatively weak base, while DBU is
a rather strong base. Et3N and DBU, for the most part follow the base-catalyzed Michael
addition pathway. DBU might on occasion follow a nucleophilic pathway if the
nucleophilic pathway is competitive with the acid-base reaction between thiol and DBU.
It is possible that these conditions occur in the presence of methyl methacrylate (5) and
methyl-3-mercaptopropionate (9) when mixed with thiophenol (10) and
29
2-mercaptoethanol (11), since high selectivity is observed in those ternary combinations.
DMPP, which is believed to follow the nucleophile-initiated pathway, leads to a rise in
selectivity compared to most combinations involving DBU. Therefore, since DBU is
sometimes thought to follow a nucleophile-initiated pathway and those pathways
typically lead to higher selectivities then this might be what occurred in those two
reactions.
Due to the fact that DBU is a strong base, it is able to deprotonate more thiol
than Et3N, resulting in a greater amount of thiolate ions of both thiols present in the
ternary mixture. This will result in a greater amount of the product that is less favored
when Et3N is used as the initiator. Since DBU is a strong base, it is thermodynamically
favored to deprotonate thiols (8)–(12). This accounts for the significant drop in
selectivity, as it can be seen that there are no greater than 98% selective reactions that
occurred with DBU. DMPP follows the nucleophile-catalyzed pathway, as shown in
Scheme 4. This is illustrated by the changes in selectivity that are observed.
In some cases the selectivities are flipped after the change from Et3N to DBU,
because it is possible that more acidic thiols might be less nucleophilic, which leads to
the switch when more thiol is deprotonated by DBU. For example, using Et3N as an
initiator for a ternary reaction for methyl acrylate (4), thiophenol (10) wins out over 2mercaptoethanol (11) leading to 92% of (4+10) and 8% of (4+11), but with DBU the
selectivity switches to a surprising 40% to 60%, respectively. This means there is more of
the (4+11) adduct when using DBU as an initiator. It is possible that the corresponding
thiolate ion of 2-mercaptoethanol (11) is a stronger nucleophile than the corresponding
thiolate ion of thiophenol (10). However, (10) likely has a lower pKa than (11) because
30
the (4+10) adduct is favored when Et3N is used.
3.3.2 Michael Acceptor Influence
For reactions with greater than 95% selectivity, there were five favoring Nmethyl maleimide (1), five for butyl isocyanate (3), four for ethyl vinyl sulfone (2), two
for ethyl crotonate (6), two for methyl acrylate (4) and one for methyl methacrylate (5).
In certain ternary spectra of butyl isocyanate (3), methyl acrylate (4), and methyl
methacrylate (5), additional singlets or shoulders in the area of 3.7 ppm are observed.
These peaks are likely due to rotation about the carbon-sulfur bond. Generally, the
overall ordering of number of selective reactions per Michael acceptor fits rather closely
to the predicted Michael acceptor reactivity.
3.3.3 Thiol Influence
Amongst the thiols, the ternary reactions generally favored methyl thioglycolate
(8), followed by thiophenol (10), methyl-3-mercaptoproprionate (9), then 2mercaptoethanol (11), and hexanethiol (12) was found to be the least reactive of the lot.
For reactions with greater than 95% selectivity, there were nine favoring (8), seven for
(10), two for (9), two for (11), and none for (12). Methyl-3-mercaptoproprionate (9) is
generally thought to be more selective than 2-mercaptoethanol (11), because it has a
higher number of ternary reactions with selectivities of greater than 90%. This order fits
rather closely with the predictions, based upon calculations of the relative reactivities of
the deprotonated thiolate ions.20
31
3.4.0 Switching to Tetrahydrofuran
THF was chosen as the solvent for the second round of reactions, because of its
widespread use in polymer chemistry. Switching to a slightly more polar solvent (its
dielectric constant is 7.58 compared to 4.81 for chloroform) could also help to see what
role solvent plays in raising or lowering selectivity. Experimental results in Figure 1
which compare selectivities in a very polar solvent, dimethylformamide (DMF), to
CDCl3 showed a significant drop in selectivities in DMF when using an initiator.
Therefore, it was expected that the number of selective reactions would drop when using
THF. However, it is important to note that the dielectric constant of DMF is 36.7, which
is significantly higher than THF.
Most reactions involving methyl methacrylate (5), were not observed in THF. It
required the use of DBU as an initiator to get those reactions to proceed for the most
part. 1H NMR spectra showed that a lot of the less selective reactions involving butyl
isocyanate (3), methyl acrylate (4), methyl methacrylate (5), and ethyl crotonate (6) had
starting material leftover when carried out using THF. The reason for this is uncertain,
but a possibility is that it in THF, the acid-base reaction is generally more favorable. This
means the thiolate ion would be less nucleophilic and more stable in solution, which
would explain some of the reactions not proceeding to completion when they did in
CHCl3.
32
3.5.0 Selectivity Data for Tetrahydrofuran
O
N
O
Thiol B
Thiol B
Thiol B
Et3N
8
9
12
11
10
9
8
>99
89
37
75
-
81
79
10
-
DBU
8
9
12
11
10
9
8
×
63
49
39
-
×
46
x
-
DMPP
8
9
12
11
10
9
8
>99
85
78
83
-
>99
77
8
-
Thiol A
10
>99
91
-
Thiol A
10
×
47
-
Thiol A
10
>99
83
-
11
12
78
-
-
11
12
66
-
-
11
12
88
-
-
Table 7: Selectivity Charts for N-methyl Maleimide in Tetrahydrofuran
33
O
S
O
Thiol B
Thiol B
Thiol B
Et3N
8
9
12
11
10
9
>99
×
27
77
91
54
11
-
DBU
8
9
12
11
10
9
8
77
87
41
43
-
45
61
39
-
DMPP
8
9
12
11
10
9
8
>99
70
41
73
-
47
49
25
-
Thiol A
10
95
77
-
Thiol A
10
48
77
-
Thiol A
10
×
75
-
11
12
73
-
-
11
12
64
-
-
11
12
85
-
-
Table 8: Selectivity Charts for Ethyl Vinyl Sulfone in Tetrahydrofuran
O
C
N
Thiol B
Et3N
8
9
12
11
10
9
8
>99
87
74
21
-
91
58
15
-
34
Thiol A
10
>99
75
-
11
12
84
-
-
Thiol B
Thiol B
DBU
8
9
12
11
10
9
8
39
×
×
21
-
×
94
68
-
DMPP
8
9
12
11
10
9
8
>99
83
<1
90
-
48
51
11
-
Thiol A
10
×
×
-
Thiol A
10
>99
66
-
11
12
44
-
-
11
12
87
-
-
11
12
>99
-
-
11
12
77
-
-
Table 9: Selectivity Charts for Butyl Isocyanate in Tetrahydrofuran
O
O
Thiol B
Thiol B
Et3N
8
9
12
11
10
9
8
76
×
36
82
-
>99
×
73
-
DBU
8
9
12
11
10
9
8
51
70
23
54
-
82
64
66
-
35
Thiol A
10
>99
83
-
Thiol A
10
22
×
-
11
12
94
-
-
11
12
×
-
-
11
12
×
-
-
11
12
12
×
×
×
x
11
×
45
×
Thiol B
10
×
×
9
×
8
Table 11: Selectivity Charts for Methyl Methacrylate in Tetrahydrofuran
-
Thiol B
DMPP
8
9
12
11
10
9
8
>99
53
60
68
-
>99
42
56
-
Thiol A
10
74
×
-
Table 10: Selectivity Charts for Methyl Acrylate in Tetrahydrofuran
O
O
Thiol B
Thiol B
Et3N
8
9
12
11
10
9
8
×
×
×
×
-
×
54
×
-
DBU
8
9
12
11
10
9
8
42
57
×
47
-
>99
46
×
-
DMPP
8
9
36
Thiol A
10
×
×
-
Thiol A
10
×
81
-
Thiol A
10
O
O
Thiol B
Thiol B
Thiol B
Et3N
8
9
12
11
10
9
8
×
61
×
36
-
×
×
×
-
DBU
8
9
12
11
10
9
8
50
56
×
35
-
72
59
65
-
DMPP
8
9
12
11
10
9
8
×
×
37
×
-
×
67
×
-
Thiol A
10
×
75
-
Thiol A
10
×
71
-
Thiol A
10
×
×
-
11
12
>99
-
-
11
12
64
-
-
11
12
×
-
-
Table 12: Selectivity Charts for Ethyl Crotonate in Tetrahydrofuran
3.6.0 Analysis of Tetrahydrofuran Results
The reactions run in THF appeared to be about as selective as the ones
performed in CHCl3. Although this does not exactly fit with the prediction that
selectivities will decrease as the solvent used to run the reactions becomes more polar,
37
this result can be explained due to the fact that THF is only slightly more polar than
CHCl3. The hypothesis was made after witnessing the effects of DMF on selectivity,
which is highly polar. This prediction might serve to be more applicable to solvents such
as acetonitrile, with a dielectric constant of 37.5. This phenomenon could be helpful,
since a lot of polymer chemistry is performed in THF, which was a major reason why
the ternary reactions were tested using THF as solvent. If reactions are seen to be
selective in THF, then their potential applicability to polymer and dendrimer synthesis
increases.
In THF there were 20 reactions with greater than 95% selectivity for one thiol
over another and 19 reactions with greater than 98% selectivity. Once more, the most
selective Michael acceptor appeared to be N-methyl maleimide (1) and the most selective
thiol, methyl thioglycolate (8).
3.6.1 Initiator Influence
The initiator selectivities were generally similar to those in CHCl3 One major
difference was that there was a highly selective reaction using DBU. This occurred with
methyl methacrylate (5), methyl-3-mercaptoproprionate (9), and 1-hexanethiol (12). This
might indicate that the nucleophile-initiated mechanism occurred in those reactions.
3.6.2 Michael acceptor
The breakdown of ternary reactions that were greater than 95% selective were:
five for butyl isocyanate (3), five for N-methyl maleimide (1), five for methyl acrylate
(4), three for ethyl vinyl sulfone (2), two for ethyl crotonate (6), and one for methyl
methacrylate (5). N-methyl maleimide (1) was previously deemed the most selective
Michael acceptor, because it had the highest number of selective reactions greater than
38
85% of the three Michael acceptors that had five highly selective ternary reactions.
3.6.3 Thiol
The breakdown of ternary reactions that were greater than 95% selective were:
seven for methyl thioglycolate (8) six for thiophenol (10) four for methyl-3mercaptoproprionate (9) two for 2-mercaptoethanol (11) and none for 1-hexanethiol
(12).
3.7.0 Methodology of the Development of Quaternary Reactions
Using the information from the ternary selectivity charts for chloroform it was
possible to identify potential quaternary combinations of thiols and Michael acceptors
that had the potential to yield two pure products rather than statistical mixtures. The
three types of quaternary reactions, mentioned in Section 1.6, were all tested and have
been labeled: one-pot, initiator sequential, and reagent sequential. Potential candidates
for quaternary reactions were found using the selectivity charts by looking for thiol
pairings that had opposing selectivities in the presence of different Michael acceptors. If
the selectivities were opposing in the presence of the same initiator then they could be
considered good candidates for one-pot selective reactions.
For example, the combination of ethyl vinyl sulfone (2), methyl methacrylate (5),
methyl-3-mercaptoproprionate (9), 2-mercaptoethanol (11) and DBU was a potential
candidate. The ternary reactions, 2-9-11-DBU and 5-9-11-DBU, resulted in 34 and 94%
of the (9) adduct, respectively. Unfortunately, the quaternary combination did not result
in selective products when further investigated.
If the selectivities were opposing in the presence of different initiators then they
39
could be good candidates for sequential selective thiol-Michael reactions. Lastly, the
reagent sequential reactions could be carried out with a ternary combination that is
greater than 99% selective, followed by the addition of a second Michael acceptor and
initiator to produce the second adduct.
3.8.0 Quaternary Results in Chloroform
3.8.1 Initial Challenges
The one-pot quaternary reactions were rather difficult to optimize. There always
appeared to be at least a little percentage of an unwanted product present in the
spectrum of the quaternary product mixture. Although the one-pot reactions proved
troublesome, it was the initiator sequential reactions were the most stubborn of the three
methods. In a ternary reaction performed in chloroform, between butyl isocyanate (3),
methyl-3-mercaptoproprionate (9), and thiophenol (10) in DMPP, the (3+10) product
is preferred with a 92% selectivity. When ethyl crotonate (6), methyl-3mercaptoproprionate (9), and thiophenol (10) are mixed in chloroform in the presence
of DMPP, no reaction is observed. Therefore, a possible initiator sequential reaction
would involve mixing (3), (6), (9), and (10) in a roundbottom flask, followed by DMPP
to initiate the reaction.
From the ternary results, it was assumed that DMPP would promote the
selective formation of product (3+10), leaving ethyl crotonate (6) and methyl-3mercaptoproprionate (9) untouched. On the timescale of one hour for ternary reactions,
DMPP did not react quickly enough for the ethyl crotonate (6) reactions to result in the
formation of products. However, 1H NMR revealed that in the quaternary reaction a
40
mixture crotonate product was observed as shown in Figure 10 below.
Figure 10: Product mixture following the sequential addition of DMPP and DBU to 3,
6, 9, and 10 in chloroform resulting in a mixture of products. Upon examination of
what ought to be a quartet at ~4.15 ppm, it is evident there is a mixture of products
In the presence of a second Michael acceptor, the change can be explained due
to the nucleophilic initiation pathway taken by DMPP. The DMPP likely added to the
butyl isocyanate present in solution and started deprotonating the thiols in the mixture.
In essence, the presence of the butyl isocyanate served as a catalyst to accelerate the ethyl
crotonate reaction. The thiolate ions would then not be discriminatory between the
isocyanate and the crotonate. This is what leads to the formation of multiple products.
In order to test this theory, 1 equivalent each of ethyl crotonate (6) and methyl
thioglycolate (8) and 0.1 equivalents of butyl isocyanate (3) were reacted using DMPP as
an initiator. The 1H NMR spectrum of the product mixture suggests that the explanation
is likely correct, are shown in Figure 11 below. After failure to find a suitable initiator
sequential reaction, a second form of sequential reaction was developed.
41
Figure 11: Product mixture following the addition of DMPP to 1 equivalent respectively
of 6 and 8, and 0.1 equivalent of 3. The reaction between 6 and 8 is observed in the
presence of 3 and DMPP, but not with only DMPP
Quaternary spectra were characterized via 1H NMR spectroscopy, as in Figure
10. However, with products such as the ones dealt with in this investigation there are
several peaks which overlap, throwing off integrations. This most certainly introduces
some amount of error into the determination of whether a quaternary reaction is
successful. Ideally, a quaternary reaction would be characterized via HPLC to separate
and identify each component of the reaction mixture in a more definitive manner.
3.8.2 Steps Towards a Solution
The one-pot quaternary reactions on the whole worked better than the initiator
sequential reactions. N-methyl maleimide (1), methyl acrylate (4), methyl-3mercaptoproprionate (9), 1-hexanethiol (12), DMPP was fairly selective for the
formation of (1+9) and (4+12). The selectivities for (1)-(9)-(12)-DMPP and
42
(4)-(9)-(12)-DMPP are 93% to 7% and 54% to 46% respectively. The reason this
reaction worked was likely due to the fact that (4) was only slightly selective for (9),
while (1) was entirely selective towards (9). It is possible that between (9), (1), and (4)
with DMPP that (9) is more selective for (1), which would have helped this process.
Figure 12: Product mixture following the addition of DMPP to 1, 9, and 12 in
chloroform resulting in a mixture of products 1+9 (93%) and 1+12 (7%)
43
Figure 13: Product mixture following the addition of DMPP to 4, 9, and 12 in
chloroform resulting in a mixture of products 4+9 (54%) and 4+12 (46%)
Figure 14: Product mixture following the addition of DMPP to 1, 4, 9, and 12 in
chloroform resulting in a mixture of products
44
3.8.3 A Compilation of Results
After a great amount of trial and error using the results from the one Michael
acceptor, two thiol set of ternary reactions, which resulted in several failed quaternary
reactions it was evident that more information was needed. Using ternary results for a
single thiol and two Michael acceptors which were collected by another member of the
Northrop group, Stephen Frayne, it was possible to design more effective quaternary
reactions. The reaction between methyl acrylate (4), ethyl crotonate (6), methyl
thioglycolate (8), 1-hexanethiol (12), DBU is selective to yield (4+8) and (6+12) as
depicted in Scheme 9. This result is surprising, since (4) and (6) are traditionally thought
of as less reactive Michael acceptors and the use of DBU as an initiator typically results
in the lowest selectivities out of all the initiators. The way the reaction was designed was
that 4-8-12-DBU is 66% selective for (4+8) and for 6-8-12-DBU is 53% selective for
(6+8). However, the combination of 8-4-6-DBU is greater than 99% in favor of the
(4+8) adduct. This suggests that combining the four together could yield two distinct
products of (4+8) and (6+12).
Scheme 9: One-pot quaternary reaction involving 4, 6, 8, and 12, using DBU to initiate
O
O
SH
O
O
DBU
O
O
S
O
O
O
O
SH
O
S
one-pot
45
O
Figure 15: Product mixture following the addition of DBU to 4, 8, and 12 in chloroform
resulting in a mixture of products 4+8 (66%) and 4+12 (34%)
Figure 16: Product mixture following the addition of DBU to 6, 8, and 12 in chloroform
resulting in a mixture of products 6+8 (53%) and 6+12 (47%).
46
Figure 17: Product mixture following the addition of DBU to 8, 4, and 6 in chloroform
resulting in only product 4+8 (>99%) and with some residual 628
Figure 18: Product mixture following the addition of DBU to 4, 6, 8, and 12 in
chloroform resulting in products 4+8 and 6+12, with residual DBU present in the
spectrum. The integrations match the expected values at the shifts at which they appear
47
One possible solution to the issues posed by the initiator sequential quaternary
reaction is the reagent sequential reaction. In theory, it ought to be easier to control than
either of the other quaternary reactions. The reagent sequential reaction involves an
initial highly selective ternary reaction, ideally with selectivity of nearly 100% selectivity
for one thiol over another. The reaction would yield a single product and have a leftover
Michael acceptor or thiol. Then a complementary thiol or Michael acceptor would be
added along with a suitable initiator to yield the second thioether adduct.
For example, equimolar amounts of N-methyl maleimide (1), ethyl vinyl sulfone
(2), and 1-hexanethiol (12) were combined28, followed by a drop of Et3N, and stirred for
an hour. This was followed by the addition of 2-mercaptoethanol (11) and another drop
of Et3N. The reaction was successful in yielding the (1+12) and (2+11) adducts. This
type of quaternary reaction could be performed using only the ternary results reported in
this thesis, but demands an reaction with selectivity of nearly 100% to begin with.
Scheme 10: Reagent sequential quaternary reaction involving 1, 2, 11, and 12, using
Et3N as an initiator for both steps of the reaction
O
N
O
S
Et 3N
S
O
O
SH
HO
S
Et 3N
O
N
N
O
O
SH
O
O
S
O
HO
S
O
S
48
O
Figure 19: Product mixture following the addition of TEA to 1, 11, and 12 in
chloroform, followed by the addition of 11, resulting in a mixture of products 1+11
(73%) and 1+12 (27%)
Figure 20: Product mixture following the addition of TEA to 2, 11, and 12 in
chloroform, followed by the addition of 11, resulting in a mixture of products 2+11
(88%) and 2+12 (12%)
49
Figure 21: Final product mixture following the addition of TEA to 1, 2, and 12 in
chloroform, followed by the addition of 11, resulting in a mixture of products 1+12 and
2+11
Although the concept of one-pot quaternary reactions is captivating, the reagent
sequential quaternary reaction might be more useful in synthesis. The reagent sequential
method could allow for the isolation of specific desirable intermediates, in order to
better quantify yields and control selectivity.
50
4.0.0 Conclusions and Future Work
In accordance with predictions, several highly selective ternary reactions were
observed in both CHCl3 and THF, using Et3N and DMPP. DBU generally yielded less
selective ternary reactions due its stronger basicity, but was able to yield a selective
quaternary reaction. In the future, changing solvents for the previously tested thiolMichael ternary combinations again could provide interesting results. One possibility
could be DMF, which was shown to catalyze some thiol-Michael reactions without an
initiator.20 Perhaps trying to run the reactions that use DBU as an initiator, but with 0.01
M DBU, rather than 0.1 M, even in CHCl3 or THF, might result in higher selectivities, as
seen in Figure 1. Completing ternary results for the entirety of the one thiol, two Michael
acceptor combinations would allow for an easier time in designing quaternary reactions.
This would be helpful, since it was difficult to successfully design even a one pot
quaternary reaction using only ternary data from the one Michael acceptor, two thiol
version, let alone any form of sequential reaction. The results of quaternary reactions can
then be applied in macromolecular syntheses, allowing for selective addition to certain
functional groups on a polymer or dendrimer, leaving other functional groups untouched
for later reactions.
51
5.0 Spectroscopic Data
5.1.0 Thiol-Michael Adduct Standards
5.1.1 Standard 1H NMR Spectra of N-methyl Maleimide (1) Adducts
O
(g)H 3C
S
O
(f)H
H(b) O
N
H(e)
(c)H
CH 3(a)
H(d) O
Figure 22: 1-8-DBU, trace peaks are residual DBU
O
(h)H 3C
O
H(f)
C
H2
(g)
H(e)
S
N
(c)H
Figure 23: 1-9-DMPP
52
H(b)O
H(d) O
CH 3(a)
H(g)
(f)H
H(d)
(c)H
O
S
(b)H
(e)H
N
CH 3(a)
H(g) O
H(f)
Figure 24: 1-10- Et3N
(Hg) H(g)
(h)HO
S
(f)H H(e)
(c)H
H(b)O
N
CH 3(a)
H(d) O
Figure 25: 1-11- Et3N
53
(k)H 3C
C
H2
(j)
(i)
H2
C
(g)
H2
C
S
H(b)O
C
H2
(h) (f)H H(e)
(c)H
N
CH 3(a)
H(d) O
Figure 26: 1-12-DBU, trace peaks are residual DBU
5.1.2 Standard 1H NMR Spectra of Ethyl Vinyl Sulfone (2) Adducts
O
(f)H 3C
Figure 27: 2-8-DBU, trace peaks are residual DBU
54
O
C
H2
(e)
S
(c)
H2
C
O
C
S
CH 3(a)
H2
C
O
H2
(d)
(b)
(g)H 3C
(f)
H2
C
O
O
C
H2
(e)
S
(c)
H2
C
S
(c)
H2
C
O
C
S
CH 3(a)
H2
C
H2
(d) O
(b)
Figure 28: 2-9-DMPP
H(e)
(f)H
O
C
S
CH 3(a)
H2
C
O
H
(d)
2
H(e)
(b)
(g)H
H(f)
Figure 29: 2-10-DBU, trace peaks are residual DBU
55
(g)HO
Figure 30: 2-11-DBU, trace peaks are residual DBU
(j)H 3C
C
H2
(i)
(h)
H2
C
C
H2
(g)
(f)
H2
C
C
H2
(e)
S
(c)
H2
C
O
C
S
CH 3(a)
H2
C
O
H
(d)
2
(b)
Figure 31: 2-12-DMPP
56
(f)
H2
C
C
H2
(e)
S
(c)
H2
C
O
C
S
CH 3(a)
H2
C
H2
(d) O
(b)
5.1.3 Standard 1H NMR Spectra of Butyl Isocyanate (3) Adducts
(e)
H
N
O
(g)H 3C
O
C
H2
(f)
S
O
C
H2
(d)
(c)
H2
C
C
H2
(b)
CH 3(a)
Figure 32: 3-8-DMPP
O
(h)H 3C
O
Figure 33: 3-9-Et3N, residual Et3N present
57
C
H2
(g)
(f)
H2
C
O
S
N
H
(e)
(d)
H2
C
C
H2
(c)
(b)
H2
C
CH 3(a)
H(g)
(h)H
H(f)
O
(g)H
S
H(f)
N
H
(e)
(d)
H2
C
C
H2
(c)
(b)
H2
C
CH 3(a)
Figure 34: 3-10-Et3N
(h)HO
C
H2
(g)
(f)
H2
C
O
S
N
H
(e)
(d)
H2
C
C
H2
(c)
(b)
H2
C
CH 3(a)
Figure 35: 3-11- Et3N, residual Et3N still present, some residual 11 present
58
(k)H 3C
(j)
H2
C
C
H2
(i)
(h)
H2
C
C
H2
(g)
(f)
H2
C
O
S
N
H
(e)
(d)
H2
C
C
H2
(c)
(b)
H2
C
CH 3(a)
Figure 36: 3-12-DMPP
5.1.4 Standard 1H NMR Spectra of Methyl Acrylate (4) Adducts
(e)H 3C
(d)
H2
C
O
O
Figure 37: 4-8-DBU, trace peaks are residual DBU
59
S
(c)
H2
C
O
C
H2
(b)
O
CH 3(a)
O
(f)H 3C
O
C
H2
(e)
(d)
H2
C
S
(c)
H2
C
O
C
H2
(b)
O
Figure 38: 4-9-DBU, trace peaks are residual DBU
H(e)
(f)H
(e)H
H(d)
H(d)
(c)
O
H2
CH 3(a)
C
S
C
O
H2
(b)
Figure 39: 4-10-DBU, trace peaks are residual DBU
60
CH 3(a)
HO
C
H2
(e)
Figure 40: 4-11- Et3N
(i)H 3C
(h)
H2
C
C
H2
(g)
(f)
H2
C
C
H2
(e)
(d)
H2
C
S
(c)
H2
C
O
C
H2
(b)
Figure 41: 4-12-DBU, trace peaks are residual DBU
61
O
CH 3(a)
(d)
H2
C
S
(c)
H2
C
O
C
H2
(b)
O
CH 3(a)
5.1.5 Standard 1H NMR Spectra of Methyl Methacrylate (5) Adducts
(g)H 3C
O
O
(f) (e)H
H(d) O
H2
CH 3(a)
C
S
O
H(b)
(c)H C
3
Figure 42: 5-8- Et3N
O
(h)H 3C
Figure 43: 5-9-DMPP
62
O
(f) (e)H
H(d) O
H2
CH 3(a)
C
C
S
O
H2
H(b)
(c)H 3C
(g)
H(g)
H(f)
(e)H H(d) O
(h)H
(g)H
S
H(f)
(c)H 3C
O
H(b)
CH 3(a)
Figure 44: 5-10-Et3N
(f) (e)H
H(d) O
H2
(h)HO
CH 3(a)
C
C
S
O
H2
H(b)
(c)H 3C
(g)
Figure 45: 5-11- Et3N
63
(k)H 3C
(j)
H2
C
C
H2
(i)
(h)
H2
C
(f) (e)H
H(d) O
H2
CH 3(a)
C
C
S
O
H2
H(b)
(c)H 3C
(g)
Figure 46: 5-12-DBU, trace peaks are residual DBU
5.1.6 Standard 1H NMR Spectra of Ethyl Crotonate Adducts
(b)
(g)
CH 3(f)O
H2
H 2(e)H
O
C
C
(h)H 3C
S
O
CH 3(a)
(d)H H(c)
O
Figure 47: 6-8-DMPP
64
O
(i)H 3C
O
(b)
(g)
CH 3(f)O
H2
H 2(e)H
C
C S
O
C
CH 3(a)
H2
(d)H H(c)
(h)
Figure 48: 6-9-DMPP
(e)H
(g)H
CH 3(f)O
S
O
(d)H
(h)H
(b)
H2
C
H(c)
H(g)
(i)H
H(h)
Figure 49: 6-10- Et3N, trace peaks are residual DBU
65
CH 3(a)
(i)HO
(b)
(g)
CH 3(f)O
H2
H 2 (e)H
C
C
S
O
CH 3(a)
C
(d)H H(c)
H2
(h)
Figure 50: 6-11-DMPP
(e)H
(l)H 3C
CH 3(f)O
(h)
(j)
H2
S
H2
C C
(d)H
C C
H2
C
H2
(g)
H2
(i)
(k)
O
(b)
H2
C
CH 3(a)
H(c)
Figure 51: 6-12-DBU
66
5.2 Greater than 95% Selective Ternary Spectra Chloroform
For the 1H NMR spectrum of see 1-8-12-Et3N, please see Figure 8.
1+8 (>99%) and 1+12 (<1%)
Figure 52: 1-10-12- Et3N, 1+10 (>99%) and 1+12 (<1%)
Figure 53: 1-8-12-DMPP, 1+8 (>99%) and 1+12 (<1%)
67
Figure 54: 1-9-10-DMPP, 1+9 (4%) and 1+10 (96%)
Figure 56: 1-10-12-DMPP, 1+10 (>99%) and 1+12 (<1%)
68
Figure 57: 2-8-12- Et3N, 2+8 (97%) and 2+12 (3%)
Figure 58: 2-10-11- Et3N, 2+10 (95%) and 2+11 (5%)
69
Figure 59: 2-10-12- Et3N, 2+10 (97%) and 2+12 (3%)
Figure 60: 2-8-12- DMPP, 2+8 (98%) and 2+12 (2%)
70
Figure 61: 3-8-12- Et3N, 3+8 (>99%) and 3+12 (<1%)
Figure 62: 3-10-12- Et3N, 3+10 (>99%) and 3+12 (<1%)
71
Figure 63: 3-8-12-DMPP, 3+8 (>99%) and 3+12 (<1%)
Figure 64: 3-10-12-DMPP, 3+10 (>99%) and 3+12 (<1%)
72
Figure 65: 4-8-12- Et3N, 4+8 (96%) and 4+12 (4%)
Figure 66: 4-8-12-DMPP, 4+8 (96%) and 4+12 (4%)
73
Figure 67: 5-11-12- Et3N, 5+11 (>99%) and 5+12 (<1%)
Figure 68: 6-8-12-Et3N, 6+8 (>99%) and 6+12 (<1%)
74
Figure 69: 6-10-12- Et3N, 6+10 (>99%) and 6+12 (<1%)
75
5.3 Greater than 95% Selective Ternary Spectra Tetrahydrofuran
Figure 70: 1-8-12- Et3N, 1+8 (>99%) and 1+12 (<1%)
Figure 71: 1-10-12- Et3N, 1+10 (>99%) and 1+12 (<1%)
76
Figure 72: 1-8-12-DMPP, 1+8 (>99%) and 1+12 (<1%)
Figure 73: 1-9-12-DMPP, 1+9 (>99%) and 1+12 (<1%)
77
Figure 74: 1-10-12-DMPP, 1+10 (>99%) and 1+12 (<1%)
Figure 75: 2-8-12- Et3N, 2+8 (>99%) and 2+12 (<1%)
78
Figure 76: 2-10-12- Et3N, 2+10 (95%) and 2+12 (5%)
Figure 77: 2-8-12-DMPP, 2+8 (>99%) and 2+12 (<1%)
79
Figure 78: 3-8-12- Et3N, 3+8 (>99%) and 3+12 (<1%)
Figure 79: 3-10-12- Et3N, 3+10 (>99%) and 3+12 (<1%)
80
Figure 80: 3-8-10-DMPP, 3+8 (<1%) and 3+10 (>99%)
Figure 81: 3-8-12-DMPP, 3+8 (>99%) and 3+12 (<1%)
81
Figure 82: 3-10-12-DMPP, 3+10 (>99%) and 3+12 (<1%)
Figure 83: 4-9-12- Et3N, 4+9 (>99%) and 4+12 (<1%)
82
Figure 84: 4-10-12- Et3N, 4+10 (>99%) and 4+12 (<1%)
Figure 85: 4-11-12- Et3N, 4+11 (>99%) and 4+12 (<1%)
83
Figure 86: 4-8-12-DMPP, residual hexanethiol, 4+8 (>99%) and 4+12 (<1%)
Figure 87: 4-9-12-DMPP, 4+9 (>99%) and 4+12 (<1%)
84
Figure 88: 5-9-12- DBU, 5+9 (>99%) and 5+12 (<1%)
Figure 89: 6-11-12- Et3N, 6+11 (>99%) and 6+12 (<1%)
85
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