Volume 52 Number 80 14 October 2016 Pages 11859–12000

ChemComm
Chemical Communications
www.rsc.org/chemcomm

ISSN 1359-7345

COMMUNICATION
P. Veeraraghavan Ramachandran et al.
Amine–boranes bearing borane-incompatible functionalities: application
to selective amine protection and surface functionalization
 ChemComm
View Article Online
COMMUNICATION View Journal | View Issue

Amine–boranes bearing borane-incompatible

functionalities: application to selective amine
Cite this: Chem. Commun., 2016,
protection and surface functionalization†
Published on 23 August 2016. Downloaded by Tufts University on 30/09/2016 15:26:50.

52, 11885

Received 21st July 2016,

Accepted 23rd August 2016 P. Veeraraghavan Ramachandran,* Ameya S. Kulkarni, Yan Zhao and Jianguo Mei

DOI: 10.1039/c6cc06031e

www.rsc.org/chemcomm

The first general open-flask synthesis of amine–boranes with

inexpensive and readily available reagents, such as sodium boro-
hydride, 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.

Lewis base complexes of borane have unlocked the potential

of reactive and pyrophoric gaseous diborane.1 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
via ligand-exchange with borane-Lewis base complexes.3 This
involves either the use of (i) pyrophoric reagents such as
borane-tetrahydrofuran (BTHF) or borane-dimethyl sulfide
(BMS) under anhydrous conditions3a or (ii) stable ammonia
borane (AB) under harsh conditions.3b Moreover, amine–
boranes bearing borane-reactive functionalities such as hydro-
xyl or thiol are not directly accessible using either route. An
approach to them will not only expand the scope of borane as
an amine-protecting group,4 but also potentially provide func-
tional materials with unique applications. Presented herein
is a novel, convenient, functionality-tolerant synthesis of
known as well as hitherto inaccessible amine–boranes utilizing
inexpensive and widely available reagents. Their utility as novel
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
images, OFET fabrication and characteristics, 11B, 1H and 13C NMR. See DOI:
10.1039/c6cc06031e
Scheme 1 Approaches to amine–boranes.
organic ligands for surface functionalization has also been
demonstrated.
We recently realized an amine–ammonium salt equili-
bration–metathesis sequence to access amine–boranes under
open-flask conditions (Scheme 1).5 Although formation of
the alkylammonium sulfate intermediate occurred at ambient
conditions, elevated temperatures were necessary to trans-
aminate the byproduct AB formed via a competing pathway.
To avoid AB formation and improve functional group compat-
ibility, an alternative to ammonium salts was sought.
We envisaged that mild acids, such as carbonic acid,
prepared from sodium bicarbonate and water,6 in the presence
of an amine could provide alkylammonium bicarbonate in situ
(Scheme 2). This would then undergo metathesis with NaBH4 at
room temperature to provide the corresponding amine–borane.
Key to the success of our plan would be the capture of carbonic
acid by amine prior to its ready decomposition and the stability
of NaBH4 under mildly acidic reaction conditions.7 The increased
probability of a facile salt metathesis due to the solubilization of
NaBH4 and alkylammonium bicarbonate in wet solvent looked
promising.

This journal is © The Royal Society of Chemistry 2016 Chem. Commun., 2016, 52, 11885--11888 | 11885

Communication
Scheme 2 Proposed synthesis of amine–boranes.
Treating an equiv. each of NaBH4 and N,N,N-triethylamine
(1a) with two equiv. of NaHCO3 in 1 M THF–H2O (1 : 1 v/v) for
1 h revealed, by 11B NMR spectroscopy, complete consumption
of NaBH4 and the presence of ca. 3 : 1 mixture of N,N,N-
triethylamine–borane (Et3N–BH3, 11B: d 14 ppm, 2a) and two
Published on 23 August 2016. Downloaded by Tufts University on 30/09/2016 15:26:50.
impurities, probably hydrolysis byproducts (d 8 and d 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 NaHCO3 led to longer
reaction times and lower yields. The order of addition was
critical. Adding amine to a mixture of NaBH4, NaHCO3, and
water in THF resulted in the borohydride hydrolysis products.
Na2CO3 was found ineffective for this transformation.
Efforts to improve the yield of 2a by screening several mono-
and dibasic sodium and potassium salts of mineral acids proved
futile.8 Replacing NaBH4 with KBH4 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 appreci-
able alteration. Finally, a reaction with 2 equiv. of NaHCO3 in
2 M THF was chosen for further improvement.
On the basis of our envisioned pathway (Scheme 2), water
should play a critical role in promoting the reaction. Indeed, a
reaction without water, even after 2 d, yielded only traces of 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
was detrimental to the yield.8
Less than quantitative yields of 2a remained a concern. To
investigate the same, the filter cake was dissolved in water and
analyzed by 11B NMR spectroscopy, which revealed the presence
of a borate salt (d 8 ppm). This was attributed to the hydrolysis
of a portion of NaBH4 under the mildly acidic conditions.7
To ensure complete conversion to amine–borane, the effect of
excess NaBH4 was studied.8 4-(Dimethylamino)pyridine (DMAP,
1b), a high-boiling amine, was chosen to prevent loss of
residual amine during workup. At least 1.5 equiv. of NaBH4
was necessary for quantitative conversion to DMAP–borane
complex (2b). Significantly, even with excess NaBH4, no borane
complexation was observed at the less nucleophilic nitrogen
in DMAP.
Under the standardized protocol (Table 1), a variety of
pri-, sec-, and tert- aliphatic and alicyclic amines (1a, 1c–1l) were
converted to the corresponding borane complexes (2a, 2c–2l)
within 4–8 h in 92–99% yields. An azacyclic diamine,
N,N 0 -dimethylpiperazine (1m), yielded the corresponding
bisborane 2m in 98% yield as a single diastereomer. Hetero-
arylamine–boranes, such as pyridine–borane (2n) and 2-picoline-
borane (2o) were prepared in near quantitative yields. Similar to
1b, 1-methylimidazole (1p) underwent facile borane complexation
11886 | Chem. Commun., 2016, 52, 11885--11888
View Article Online
ChemComm
Table 1 Scope of unfunctionalized aminesa
a
Yields of isolated products. b 2 equiv. NaBH4, 4 equiv. NaHCO3, and
4 equiv. water were used for 1 equiv. of amine for complete conversion.
c
Single diastereomer obtained.
selectively at the more nucleophilic N3 position providing 2p in
99% yield within 8 h.
The putative lack of formation of free borane persuaded us
to subject amines containing borane-susceptible function-
alities to the new synthesis, after a minor re-optimization of
the reagent equivalencies (Table 2). Alkenyl and alkynyl amines,
with an exposed hydroboration site, were examined first.9
Gratifyingly, allylamine (1q), 1,2,3,6-tetrahydropyridine (1r),
and propargylamine (1s) yielded the corresponding amine–
boranes 2q, 2r, and 2s in 96%, 73%, and 87%, respectively,
within 4 h.10 Delightfully, even amines containing the protic
hydroxyl moiety, such as, 2-(hydroxymethyl)pyridine (1t),
3-aminopropan-1-ol (1u), and (S)-(+)-2-(hydroxymethyl)pyrroli-
dine (1v), underwent borane protection yielding 2t, 2u, and 2v,
respectively, in good yields after chromatographic purification.11
This represents the first general route to hydroxyl-containing
amine–boranes from the corresponding amino alcohols.12
Extending the protocol to the more acidic thiol moiety in
2-diethylaminoethanethiol (1w) 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 amino alcohols. Dimethylaminoacetaldehyde
acetal (1x), a protected aldehyde, when subjected to the reaction
conditions, yielded 93% of the corresponding amine–borane 2x.
Pleasantly, the carbonyl moiety in the ester and amide functionalities
This journal is © The Royal Society of Chemistry 2016
 View Article Online

ChemComm Communication

Table 2 Scope of functionalized aminesa

Scheme 3 Direct approach to intermediate 4.

would deliver tailored materials possessing several unique

Published on 23 August 2016. Downloaded by Tufts University on 30/09/2016 15:26:50.

properties. They (i) will be responsive towards an acid, (ii) can

be patterned15 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 (Scheme 4).16
A 30 nm gold film thermally evaporated on a SiO2/Si
substrate was immersed into a solution of 2w in ethanol
(10 mmol L1) for 3 h, followed by sonication and drying under
nitrogen.17 Topographic images of the amine–borane-treated
gold film revealed a surface with root mean square roughness
(Rq) of B0.78 nm, compared to a different topography for bare
gold film with Rq B0.67 nm. (Fig. S1a and b in the ESI†). The
a
Yields of isolated product. b 1.5 equiv. NaBH4, 3 equiv. NaHCO3, and surface potential mapping displayed a uniform surface
3 equiv. water were used for 1 equiv. of amine. c Diastereomeric ratio = potential (Fig. S1c and d in the ESI†). The calculated work
92 : 8 (by 11B NMR spectroscopy). d 20% disulfide containing amine–
borane was formed, which could be readily separated by column chroma-
function for amine–borane functionalized gold films and bare
tography. e The monohydrolyzed silanol by-product was formed, which gold were 4.73 eV and 5.02 eV, respectively, indicating a
could be separated by column chromatography. successful surface modification. The relatively high work func-
tion of gold and the associated energy level mismatch prevents
its use for n-type organic semiconducting materials.16 The
in methyl 6-aminohexanoate (1y) and N-(3-aminopropyl)benzamide
lowering of gold work function with amine–borane treatment
(1z) was well-tolerated, furnishing 2y and 2z in 84% and 86%
provides an opportunity to overcome the above limitation.
yields, respectively.11 The nitrile group in 3-(dimethylamino)-
Success with gold functionalization prompted the function-
propanenitrile (1aa) also remained unaltered under the reac-
alization of silica, one of the most popular dielectric materials.18
tion conditions providing the corresponding amine–borane 2aa
Silica surfaces tethered with (3-aminopropyl)triethoxysilane
in 86% yield.11 Neither the nitrile-borane nor nitrile reduction
(APTES) have been previously reported,19 with applications ranging
products were observed. Finally, we subjected 2-(4-nitrophenyl)-
from drug delivery to biomolecular lab-on-a-chip.20 Accordingly, a
ethylamine (1ab), an amine containing a nitro group, to our
novel amine–borane-modified silica surface was prepared by treat-
protocol, which underwent facile borane protection to yield 2ab
ment with APTES–borane complex (APTES–BH3, 2ac, Scheme 5),17
in 86% yield.11 Notably, the amine–boranes synthesized above
which was readily accessed from APTES using our protocol in 78%
represent stable molecules containing potentially incompatible
yield. Atomic force microscopy measurements showed smooth
electrophilic and nucleophilic centers in proximity.
topography for the amine–borane-functionalized silica surface
The uniqueness of our robust and mild protocol was
with Rq B0.140 nm, similar to the bare silica surface (Rq B0.122 nm,
demonstrated by the facile synthesis of the vitronectin inhibitor
Fig. S3 in ESI†). Since the hydroxyl groups on bare silica surface
synthon 4 (Scheme 3). The presence of the protic hydroxyl
function as electronic traps for transport of charge carriers in
group was an impediment to its ready synthesis earlier.13 Our
NaHCO3/water-mediated protocol described herein provides a
direct route to 4 in 80% yield from pyridinylamino alcohol 3 via
the selective protection of the heteroaryl pyridine ring in the
presence of the less nucleophilic arylamine and the borane-
reactive hydroxyl group.
The ready access to functionalized amine–boranes offered a
new class of unexplored, reactive reagents for surface function- Scheme 4 Formation of self-assembled thiol-bearing amine–borane
alization.14 Novel amine–borane-functionalized surfaces, in turn, layer on gold surface.

This journal is © The Royal Society of Chemistry 2016 Chem. Commun., 2016, 52, 11885--11888 | 11887

Communication
Scheme 5 Formation of self-assembled APTES–BH3 layer on silica
surface.
organic field-effect transistors (OFETs),21 functionalization of
silica surface with APTES–borane layer should principally reduce
Published on 23 August 2016. Downloaded by Tufts University on 30/09/2016 15:26:50.
the traps, thereby improving the mobility of charge carriers. We
fabricated such OFETs with the APTES-borane functionalized
SiO2/Si as the dielectric layer,17 providing charge carrier mobility
10 that of devices with bare silica, as well as an improved
current on/off ratio (Fig. S4 in ESI†).
In conclusion, a general, convenient, inexpensive, and 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 environ-
mentally benign, mild reaction conditions, several functional
groups susceptible to BTHF or BMS, such as 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.
We believe that this synthetic protocol will aid in the design
and development of novel amine–boranes for various applica-
tions in organic, inorganic, and materials chemistry. In addi-
tion, 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.
11888 | Chem. Commun., 2016, 52, 11885--11888
View Article Online
ChemComm
Financial support from the Herbert C. Brown Center for
Borane Research is gratefully acknowledged.
Notes and references
1 A. Pelter, K. Smith and H. C. Brown, Borane Reagents, Academic
Press, San Diego, CA, 1988.
2 Selected reviews on amine–boranes: (a) A. Staubitz, A. P. M.
Robertson, M. E. Sloan and I. Manners, Chem. Rev., 2010, 110, 4023;
(b) B. Carboni and L. Monnier, Tetrahedron, 1999, 55, 1197; (c) R. O.
Hutchins, K. Learn, B. Nazer, D. Pytlewski and A. Pelter, Org. Prep. Proced.
Int., 1984, 16, 335; (d) C. F. Lane, Aldrichimica 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 For amine protecting groups, see: P. G. M. Wuts and T. W. Greene,
Greene’s Protective Groups in Organic Chemistry, John Wiley & Sons,
New York, 4th edn, 2007, ch. 7.
5 P. V. Ramachandran and A. S. Kulkarni, Inorg. Chem., 2015, 54, 5618.
For other approaches to amine–boranes see ref. 2 and 3.
6 K. Adamczyk, M. Premont-Schwarz, D. Pines, E. Pines and
E. T. J. Nibbering, Science, 2009, 326, 1690.
7 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.
8 See ESI† for detailed optimization studies.
9 J.-L. M. Abboud, B. Nemeth, J.-C. Guillemin, P. Burk, A. Adamson
and E. R. Nerut, Chem. – Eur. J., 2012, 18, 3981.
10 Traces of the mono-hydroborated impurity were separated by column
chromatography.
11 Despite the use of excess NaBH4 and longer reaction times, the
reactions did not proceed to completion. The unreacted amine
could be readily recovered via column chromatography.
12 b-Aminoalcohol-N-boranes have been synthesized in 42–67% yields by
reduction of a-amino acids. A. Pinaka, G. C. Vougioukalakis,
D. Dimotikali, V. Psyharis and K. Papadopoulos, Synthesis, 2012, 1057.
13 M. A. Zajac, J. Org. Chem., 2008, 73, 6899.
14 F. Tao and S. Bernasek, Functionalization of Semiconductor Surfaces,
Wiley-VCH, Hoboken, NJ, 2012.
15 P. S. Cremer, J. Am. Chem. Soc., 2011, 133, 167.
16 J. Zaumseil and H. Sirringhaus, Chem. Rev., 2007, 107, 1296.
17 See ESI† for further details.
18 W. Volksen, R. D. Miller and G. Dubois, Chem. Rev., 2010, 110, 56.
19 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.
20 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.
21 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.
This journal is © The Royal Society of Chemistry 2016