Amine-boranes bearing borane-incompatible functionalities: Application to selective amine protection and surface functionalization

Article abstract of DOI:10.1039/c6cc06031e

The first general open-flask synthesis of amine-boranes with inexpensive and readily available reagents, such as sodium borohydride, sodium bicarbonate, water, and the desired amines is described. Even amines bearing borane-reactive functionalities, such as alkene, alkyne, hydroxyl, thiol, ester, amide, nitrile, and nitro are well tolerated. Some of these novel amine-boranes represent stable molecules containing potentially incompatible electrophilic and nucleophilic centers in proximity. This convenient scalable synthesis provides a novel class of organic ligands for surface functionalization, as demonstrated by the formation of self-assembled layers of thiol- and alkoxysilane-bearing amine-boranes on gold and silica surfaces, respectively.

Full text of DOI:10.1039/c6cc06031e

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DOI: 10.1039/C6CC06031E
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COMMUNICATION
Amine-Boranes Bearing Borane-Incompatible Functionalities:
Application to Selective Amine Protection and Surface
Functionalization
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
P. Veeraraghavan Ramachandran,* Ameya S. Kulkarni, Yan Zhao and Jianguo Mei
www.rsc.org/
The first general open-flask synthesis of amine-boranes with equilibration-metathesis sequence to access amine-boranes
5
inexpensive and readily available sodium borohydride, sodium under open-flask conditions (Scheme 1). Although formation
bicarbonate, water, and the desired amines is described. Even of the alkylammonium sulfate intermediate occurred at
amines bearing borane-reactive functionalities, such as alkene, ambient conditions, elevated temperatures were necessary to
alkyne, hydroxyl, thiol, ester, amide, nitrile, and nitro are well trans-aminate the byproduct AB formed via a competing
tolerated. Some of these novel amine-boranes represent stable pathway. To avoid AB formation and improve functional group
molecules containing potentially incompatible electrophilic and compatibility, an alternative to ammonium salts was sought.
nucleophilic centers in proximity. This convenient scalable
synthesis provides a novel class of organic ligands for surface
functionalization, as demonstrated by the formation of self-
assembled layers of thiol- and alkoxysilane-bearing amine-
boranes on gold and silica surfaces, respectively.
Lewis base complexes of borane have unlocked the potential
1
of reactive and pyrophoric gaseous diborane. Among these,
air- and moisture-stable amine-boranes have been evaluated
for several applications in organic and materials chemistry.2
Yet, amine-boranes bearing functional groups are rare. The
most common approach to unfunctionalized amine-boranes is
3
via exchange with borane-Lewis base complexes. This involves
either the use of (i) pyrophoric reagents such as borane-
tetrahydrofuran (BTHF) or borane-dimethyl sulfide (BMS)
3a
under anhydrous conditions or (ii) stable ammonia borane
AB) under harsh conditions.3b Moreover, amine-boranes
(
Scheme 1. Approaches to Amine-Boranes.
bearing borane-reactive functionalities such as hydroxyl or
thiol are not directly accessible using either route. An
We envisaged that mild acids, such as carbonic acid,
approach to them will not only expand the scope of borane as prepared from sodium bicarbonate and water,6 in the
4
an amine-protecting group, but also potentially provide presence of an amine could provide alkylammonium
functional materials with unique applications. Presented bicarbonate in situ. This would then undergo metathesis with
herein is a novel, convenient, functionality-tolerant synthesis NaBH at room temperature to provide the corresponding
4
of known as well as hitherto inaccessible amine-boranes amine-borane (Scheme 2). Key to the success of our plan
utilizing inexpensive and widely available reagents. Their utility would be the capture of carbonic acid by amine prior to its
as novel organic ligands for surface functionalization has also ready decomposition and the stability of NaBH under mildly
4
7
been demonstrated.
acidic reaction conditions. The increased probability of a facile
We recently realized an amine-ammonium salt salt metathesis due to the solubilization of NaBH4 and
alkylammonium bicarbonate in wet solvent looked promising.
Department of Chemistry, Purdue University, 560 Oval Drive, West Lafayette,
Indiana 47907, USA. E-mail: chandran@purdue.edu
Electronic Supplementary Information (ESI) available: Detailed optimization
studies, representative procedures, characterization data, SKPM images, AFM
11
1
13
images, OFET fabrication and characteristics,
B,
H
and
C NMR. See
DOI: 10.1039/x0xx00000x
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methylimidazole (1p) underwent facile borane complexation
View Article Online
DOI: 10.1039/C6CC06031E
selectively at the more nucleophilic N3 position providing 2p in
9
9% yield within 8 h.
Table 1.
Scope of unfunctionalized aminesa
Scheme 2. Proposed Synthesis of Amine-Boranes.
Treating an equiv. each of NaBH
4
and N,N,N-triethylamine
O (1:1 v/v) for 1
h revealed, by B NMR spectroscopy, complete consumption
of NaBH and the presence of ca. 3:1 mixture of N,N,N-
triethylamine-borane (Et B: δ -14 ppm, 2a) and two
(
3 2
1a) with two equiv. of NaHCO in 1 M THF-H
1
1
4
1
1
3 3
N-BH ,
impurities, probably hydrolysis byproducts (δ 8 and δ 18 ppm).
When the quantity of water was limited to one equiv., the
impurities were completely suppressed and pure 2a was
isolated in 77% yield. Lowering the equiv. of NaHCO
longer reaction times and lower yields. The order of addition
was critical. Adding amine to a mixture of NaBH , NaHCO , and
water in THF resulted in the borohydride hydrolysis products.
Na CO was found ineffective for this transformation.
3
led to
4
3
2
3
Efforts to improve the yield of 2a by screening several mono-
and dibasic sodium and potassium salts of mineral acids
8
proved futile. Replacing NaBH
4
with KBH
4
also led to slow
reactions and poor yields. Increasing the reaction
concentration to 2 or 4 M or using diethyl ether as the solvent
did not afford appreciable alteration. Finally, a reaction with 2
equiv. of NaHCO
improvement.
3
in 2 M THF was chosen for further
On the basis of our envisioned pathway (Scheme 2), water
should play a critical role in promoting the reaction. Indeed, a
aYields of isolated products. b2 equiv. NaBH
4
, 4 equiv. NaHCO
3
, and 4 equiv.
c
reaction without water, even after 2 d, yielded only traces of water were used for 1 equiv. of amine for complete conversion. Single
diastereomer obtained.
2a. Introducing 0.5 equiv. water completed the reaction, albeit
slowly, within 24 h. Conversely, increasing the water content
to 2 equiv. accelerated the reaction dramatically, complete
within 1 h, to yield 82% 2a. Further increase in water content
The putative lack of formation of free borane persuaded us
subject amines containing borane-susceptible
functionalities to the new synthesis, after a minor re-
optimization of the reagent equivalencies (Table 2). Alkenyl
to
8
was detrimental to the yield.
Less than quantitative yields of 2a remained a concern. To
and alkynyl amines, with an exposed hydroboration site, were
investigate the same, the filter cake was dissolved in water and
9
11
examined first. Gratifyingly, allylamine
(
1q),
1,2,3,6-
analyzed by B NMR spectroscopy, which revealed the
tetrahydropyridine (1r), and propargylamine (1s) yielded the
corresponding amine-boranes 2q 2r, and 2s in 96%, 73%, and
presence of a borate salt (δ 8 ppm). This was attributed to the
,
hydrolysis of a portion of NaBH
conditions. To ensure complete conversion to amine-borane,
the effect of excess NaBH
4
under the mildly acidic
1
0
7
87%, respectively, within 4 h. Delightfully, even amines
containing the protic hydroxyl moiety, such as, 2-
8
4
was studied.
4-
(
(
hydroxymethyl)pyridine (1t), 3-aminopropan-1-ol (1u), and
S)-(+)-2-(hydroxymethyl)pyrrolidine (1v), underwent borane
(
Dimethylamino)pyridine (DMAP, 1b), a high-boiling amine,
was chosen to prevent loss of residual amine during workup.
At least 1.5 equiv. of NaBH was necessary for quantitative
conversion to DMAP-borane complex (2b). Significantly, even
with excess NaBH , no borane complexation was observed at
protection yielding 2t, 2u, and 2v, respectively, in good yields
4
11
after chromatographic purification. This represents the first
general route to hydroxyl-containing amine-boranes from the
4
12
corresponding amino alcohols. Extending the protocol to the
more acidic thiol moiety in 2-diethylaminoethanethiol (1w
the less nucleophilic nitrogen in DMAP.
)
Under the standardized protocol (Table 1), a variety of pri-,
provided the borane adduct 2w in high yields with a minor
amount of the disulfide linked amine-borane, which could be
readily separated by column chromatography.
Amines containing the aldehyde and ketone functionalities
were, unfortunately, not compatible and provided the reduced
borane protected aminoalcohols. Dimethylaminoacetaldehyde
acetal (1x), a protected aldehyde, when subjected to the
reaction conditions, yielded 96% of 2x. Pleasantly, the carbonyl
sec-, and tert- aliphatic and alicyclic amines (1a
converted to the corresponding borane complexes (2a
,
1c
-
1l) were
2c-2l)
,
within 4-8 h in 92-99% yields. An azacyclic diamine, N,N’-
dimethylpiperazine (1m), yielded the corresponding bisborane
2
m
in 98% yield as a single diastereomer. Heteroarylamine-
boranes, such as pyridine-borane (2n) and 2-picoline-borane
2o) were prepared in near quantitative yields. Similar to 1b, 1-
(
2
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moiety in the ester and amide functionalities in methyl 6-
aminohexanoate (1y) and N-(3-aminopropyl)benzamide (1z
was well-tolerated, furnishing 2y and 2z in 84% and 86% yields,
View Article Online
DOI: 10.1039/C6CC06031E
)
11
respectively.
dimethylamino)propanenitrile (1aa) also remained unaltered
under the reaction conditions providing the corresponding
The
nitrile
group
in
3-
(
1
1
amine-borane 2aa in 86% yield. Neither the nitrile-borane
nor nitrile reduction products were observed. Finally, we
subjected 2-(4-nitrophenyl)ethylamine
containing a nitro group, to our protocol, which underwent
facile borane protection to yield 2ab in 86% yield. Notably,
the amine-boranes synthesized above represent stable
molecules containing potentially incompatible electrophilic
and nucleophilic centers in proximity.
(1ab), an amine
Scheme 3. Direct approach to intermediate 4.
11
The ready access to functionalized amine-boranes offered
a new class of unexplored, reactive reagents for surface
14
functionalization.
Novel
amine-borane-functionalized
surfaces, in turn, would deliver tailored materials possessing
several unique properties. They (i) will be responsive towards
Table 2. Scope of functionalized aminesa
15
an acid, (ii) can be patterned through selective removal of
borane, and (iii) provide a reducing surface, potentially useful
for protective coatings. To demonstrate that amine-boranes
can be viable ligands for surface functionalization, the thiol
bearing amine-borane 2w was chosen to functionalize gold,
which is widely used as an electrode in organic electronics
16
(Scheme 4).
Scheme 4. Formation of self-assembled thiol-bearing amine-borane layer on gold
surface.
2
A 30 nm gold film thermally evaporated on a SiO /Si
substrate was immersed into a solution of 2w in ethanol (10
mmol/L) for 3 h, followed by sonication and drying under
17
nitrogen. Topographic images of the amine-borane-treated
gold film revealed a surface with root mean square roughness
(Rq) of ~0.78 nm, compared to a different topography for bare
gold film with Rq ~0.67 nm. (Fig. S1a and S1b in the SI). The
surface potential mapping displayed a uniform surface
potential (Fig. S1c and S1d in the SI). The calculated work
function for amine-borane functionalized gold films and bare
gold were 4.73 eV and 5.02 eV, respectively, indicating a
successful surface modification. The relatively high work
aYields of isolated product. b1.5 equiv. NaBH
4
, 3 equiv. NaHCO
3
, and 3 equiv.
c
11
water were used for 1 equiv. of amine. Diastereomeric ratio = 92:8 (by B NMR function of gold and the associated energy level mismatch
d
spectroscopy). 20% disulfide containing amine-borane was formed, which could
16
prevents its use for n-type organic semiconducting materials.
e
be readily separated by column chromatography. The monohydrolyzed by-
product was formed, which could be separated by column chromatography.
The lowering of gold work function with amine-borane
treatment provides an opportunity to overcome the above
limitation.
The uniqueness of our robust and mild protocol was
demonstrated by the facile synthesis of the vitronectin
Success with gold functionalization prompted the
functionalization of silica, one of the most popular dielectric
inhibitor synthon
4 (Scheme 3). The presence of the protic
18
materials.
Silica
surfaces
tethered
with
(3-
hydroxyl group was an impediment to its ready synthesis
13
aminopropyl)triethoxysilane (APTES) have been previously
earlier. Our NaHCO
herein provides a direct route to
pyridinylamino alcohol via the selective protection of the
3
/water-mediated protocol described
19
reported, with applications ranging from drug delivery to
4
in 80% yield from
20
biomolecular lab-on-a-chip. Accordingly, a novel amine-
borane-modified silica surface was prepared by treatment with
APTES-borane complex (APTES-BH3, 2ac, Scheme 5),17 which
was readily accessed from APTES using our protocol in 78%
3
heteroaryl pyridine ring in the presence of the less nucleophilic
arylamine and the borane-reactive hydroxyl group.
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4
5
For amine protecting groups, see: P. G. M. Wuts and T. W.
yield. Atomic force microscopy measurements showed smooth
topography for the amine-borane-functionalized silica surface
with Rq ~0.140 nm, similar to the bare silica surface (Rq ~0.122
nm, Fig. S3 in SI). Since the hydroxyl groups on bare silica
surface function as electronic traps for transport of charge
carriers in organic field-effect transistors (OFETs),21
View Article Online
Greene, Greene’s Protective Groups in Organic Chemistry,
DOI: 10.1039/C6CC06031E
John Wiley & Sons, New York, 4th edn, 2007; ch. 7.
P. V. Ramachandran and A. S. Kulkarni, Inorg. Chem.,
2
015, 54, 5618. For other approaches to amine-boranes see
Ref. 2.
6
7
K. Adamczyk, M. Premont-Schwarz, D. Pines, E. Pines and E.
T. J. Nibbering, Science, 2009, 326, 1690.
Borohydrides are known to hydrolyze in aqueous solutions of
sodium bicarbonate. K. A. Grice, M. C. Groenenboom, J. D. A.
Manuel, M. A. Sovereign and J. A. Keith, Fuel, 2015, 150, 139.
See ESI for detailed optimization studies.
functionalization of silica surface with APTES-borane layer
should principally reduce the traps, thereby improving the
mobility of charge carriers. We fabricated such OFETs with the
17
2
APTES-borane functionalized SiO /Si as the dielectric layer,
8
9
J-L. M. Abboud, B. Nemeth, J-C. Guillemin, P. Burk, A.
Adamson and E. R. Nerut, Chem. Eur. J., 2012, 18, 3981.
0 Traces of the mono-hydroborated impurity were separated
by column chromatography.
providing charge carrier mobility 10x that of devices with bare
silica, as well as an improved current on/off ratio (Fig. S4 in SI).
1
1
4
1 Despite the use of excess NaBH and longer reaction times,
the reaction did not proceed to complete conversions. The
unreacted starting material could be readily recovered via
column chromatography.
1
2 -Aminoalcohol-N-boranes have been synthesized in 42-67%
yields by reduction of -amino acids. A. Pinaka, G. C.
3
Scheme 5. Formation of self-assembled APTES-BH layer on silica surface.
Vougioukalakis, D. Dimotikali, V. Psyharis and K.
Papadopoulos, Synthesis, 2012, 44, 1057.
In conclusion, a general, convenient, inexpensive, and 13 M. A. Zajac, J. Org. Chem., 2008, 73, 6899.
1
4 F. Tao and S. Bernasek, Functionalization of Semiconductor
Surfaces, Wiley-VCH, Hoboken, NJ, 2012.
5 P. S. Cremer, J. Am. Chem. Soc., 2011, 133, 167.
6 J. Zaumseil and H. Sirringhaus, Chem. Rev., 2007, 107, 1296.
7 See ESI for further details.
scalable protocol for the synthesis of a variety of amine-
boranes in excellent yields from sodium borohydride, sodium
bicarbonate, and amines in wet THF has been developed.
Under these environmentally benign, mild reaction conditions,
1
1
1
several functional groups susceptible to BTHF or BMS, such as 18 W. Volksen, R. D. Miller and G. Dubois, Chem. Rev., 2010,
1
10, 56.
alkene, alkyne, hydroxyl, thiol, ester, amide, nitrile, and nitro
are well tolerated. Some of these functionalized amine-
boranes represent stable molecules bearing potentially
incompatible electrophilic and nucleophilic groups in
proximity. This water-promoted synthesis has allowed access
to a novel class of amine-borane based organic ligands with
unique properties for surface functionalization, as
demonstrated by the formation of self-assembled layers of
thiol- and alkoxysilane-bearing amine-boranes on gold and
silica surfaces, respectively.
1
2
2
9 R. G. Acres, A. V. Ellis, J. Alvino, C. E. Lenahan, D. A.
Khodakov, G. F. Metha and G. G. Andersson, J. Phys. Chem.
C, 2012, 116, 6289.
0 For applications of APTES modified silica, see: (a) S. K.
Natarajan and S. Selvaraj, RSC Adv., 2014, 4, 14328. (b) J. A.
Howarter and J. P. Youngblood, Langmuir, 2006, 22, 11142.
1 L. L. Chua, J. Zaumseil, J. F. Chang, E. C. W. Ou, P. K. H. Ho, H.
Sirringhaus and R. H. Friend, Nature, 2005, 434, 194.
We believe that this synthetic protocol will aid in the
design and development of novel amine-boranes for various
applications in organic, inorganic, and materials chemistry. In
addition, the remarkable functional group tolerance should
enhance the utility of boranes as amine protecting groups.
Further studies on the amine-borane functionalized surfaces
are in progress.
Financial support from the Herbert C. Brown Center for
Borane Research is gratefully acknowledged.
Notes and references
1
Α. Pelter, K. Smith and H. C. Brown, Borane Reagents,
Academic Press, San Diego, CA, 1988.
Selected reviews on amine-boranes: (a) A. Staubitz, A. P. M.
Robertson, M. E. Sloan and I. Manners, Chem. Rev., 2010,
2
1
10, 4023. (b) B. Carboni and L. Monnier, Tetrahedron,
999, 55, 1197. (c) R. O. Hutchins, K. Learn, B. Nazer, D.
1
Pytlewski and A. Pelter, Org. Prep. Proced. Int., 1984, 16
3
,
35. (d) C. F. Lane, Aldrichim. Acta, 1973, 6, 51.
3
(a) H. C. Brown, Organic Synthesis via Boranes, Wiley, New
York, 1975. (b) P. V. Ramachandran and A. S. Kulkarni, RSC
Adv., 2014, 4, 26207.
4
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